Reimbursement Review

Antihemophilic Factor VIII (Recombinant, B-Domain Deleted), Fc-VWF-XTEN Fusion Protein (Altuviiio)

Sponsor: Sanofi-Aventis Canada Inc.

Therapeutic area: Congenital factor VIII deficiency

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

FVIII = factor VIII; NOC = Notice of Compliance.

Introduction

Hemophilia is a bleeding disorder caused by deficiencies in coagulation factor VIII (FVIII) or factor IX.^1-3 Hemophilia A is the most common form.⁴ It is a rare, congenital bleeding disorder caused by mutations in the gene that produces FVIII, a glycoprotein critical for hemostasis, which leads to excessive bleeding due to the inability to form blood clots.^2,3,5 It predominantly affects male patients, although females who are heterozygous carriers can have factor levels in the hemophilia range.⁴ According to a 2023 Canadian Bleeding Disorders Registry report, there were 3,510 people in Canada living with hemophilia A, of whom 1,158 had severe disease.⁶ Disease severity is categorized as mild, moderate, or severe and is based on factor levels.⁷ For reference, normal FVIII activity is considered to be 40% or higher. Mild hemophilia A is defined by factor levels 5% to 40% of typical FVIII activity levels in the blood, moderate is defined by levels of 1% to 5%, and severe defined by levels less than 1% of typical FVIII activity levels.⁸ Patients with hemophilia A experience symptoms such as bleeding into joints, soft tissues and muscles, the mouth, and urine, as well as surface bleeding and easy bruising.⁹ Bleeding associated with hemophilia A can result in complications such as joint damage from repetitive bleeding, deep internal bleeding, and neurologic problems or death associated with bleeding in the brain.⁷ The challenges experienced by patients with hemophilia A can substantially impact patient quality of life (QoL) and physical, mental, social, and educational well-being.^4,10 Hemophilia A is diagnosed based on a combination of clinical evaluation, family history, and laboratory tests (factor assay obtained through blood tests, such as the 1-stage clotting assay and chromogenic assay, which measure FVIII activity levels to demonstrate factor deficiency and FVIII genetic testing).¹¹ Patients with a family history of hemophilia A are typically diagnosed at birth, while those without a family history are typically diagnosed after bleeding is observed, often during the first year of life for those with severe hemophilia.¹²

The International World Federation of Hemophilia (WFH) guidelines recommend primary prophylaxis as the standard of care for all patients with severe hemophilia A.⁸ Primary prophylaxis is defined as regular infusion of missing FVIII or administration of a factor mimetic to increase factor activity. The key for primary prophylaxis is to start a patient on treatment before a bleeding event. The goal of prophylactic therapy is to maintain factor levels greater than 3% to 5% (3 IU/dL to 5 IU/dL) to reduce the risk of spontaneous bleeding and for better preservation of joint function.¹³ Three options for primary prophylactic treatment exist in the current Canadian landscape: regular IV infusion of standard half-life (SHL) FVIII concentrate (Kovaltry, Xyntha, Zonovate), regular IV infusion of extended half-life (EHL) FVIII concentrate (Adynovate, Jivi, Eloctate, Esperoct), or regular subcutaneous injection of emicizumab. Apart from emicizumab, which provides a FVIII activity equivalence level of 10% to 15%, the trough levels of SHL and EHL FVIII concentrates are between 3% to 5% immediately before the next infusion. Based on the typical frequency of administration for currently available SHL and EHL products (2 to 3 times per week), the trough levels are often inadequate to provide bleeding protection. Patients with hemophilia A who participate in regular physical activities may time their prophylactic infusion to align with their physical activities or require additional doses on top of their prophylaxis just before certain physical activities to mitigate the risk of provoked bleeding.

Altuviiio is a recombinant FVIII analogue fusion protein that temporarily replaces the missing coagulation factor (FVIII) required for effective hemostasis. It is a new class of FVIII replacement therapy that functions independently of endogenous von Willebrand factor (VWF) to overcome the half-life limit imposed by FVIII–VWF interactions. FVIII half-life is significantly influenced by VWF plasma levels while circulating together as a noncovalent complex. Under typical physiological circumstances, the half-life of free FVIII is substantially reduced (approximately 2 hours) compared to that of VWF-bound FVIII (approximately 12 hours). By circulating independently of endogenous VWF, Altuviiio has demonstrated a 3-fold to 4-fold prolonged half-life compared to other SHL and EHL FVIII molecules. Altuviiio is approved by Health Canada for the treatment of hemophilia A (congenital FVIII deficiency) in adults and children for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding. The sponsor’s reimbursement request aligns with the Health Canada indication. The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of Altuviiio (lyophilized powder for IV infusion; 250 IU, 500 IU, 1,000 IU, 2,000 IU, 3,000 IU, and 4,000 IU per vial) for the treatment of adults, adolescents, and children with hemophilia A (congenital FVIII deficiency) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, treatment and control of bleeding episodes, or perioperative management of bleeding (surgical prophylaxis).

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical expert(s) consulted by for the purpose of this review.

Patient Input

One patient group submission from the Canadian Hemophilia Society (CHS) was received for this review. The CHS is a national voluntary health charity that advocates for improvements in health and QoL for patients living with inherited bleeding disorders in Canada. Information provided for this submission was gathered through a national online survey distributed both in English and French between April 1, 2024, to June 1, 2024. A total of 104 responses were received. This included 57 patients with severe hemophilia A, 33 with mild hemophilia A, and 14 with moderate hemophilia A. Of these patients, 33 reported a history of FVIII inhibitors.

The patients highlighted joint pain and loss of function, pain from bleeding episodes, invasive medical procedures, surgical complications, restrictions on sport participation, difficulty performing everyday tasks, and long recovery times from bleeding episodes as significant symptoms and challenges associated with hemophilia A disease. Respondents also noted the detrimental effects of hemophilia A on their social and psychological well-being.

Overall, 11 patients were receiving FVIII prophylaxis; 6 were on FVIII on-demand therapy while most patients were receiving emicizumab for prophylaxis. Notably, 1 patient had undergone gene therapy. Overall, most respondents considered their current treatment regimen as “very effective” or “quite effective” in stopping or preventing bleeding. Although most respondents indicated that hemophilia A treatment has become simpler and less burdensome with emicizumab, the pain associated with the injection is a challenge and breakthrough bleeding still occurs. Patients reported that new therapies that can improve hemophilia A disease outcomes such as higher bleed protection, less pain management, reduced frequency (fewer doses with longer half-life) of treatment are needed to improve disease outcomes.

One patient with severe hemophilia A who had received Altuviiio through a special access program reported that since initiating treatment, this patient reported experiencing a sustained high FVIII level, with a factor trough of approximately 15%, which has reduced their risk of major and subclinical bleeding. Similar effects were reported by other patients, which appear to be maintained even if the injection is up to 2 days late. According to the patient, this has helped reduce the risk of bleeding, and travel has become easier with Altuviiio, due to the more flexible storage requirements compared to previous treatments. The patient reported no disadvantages or side effects of Altuviiio.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts consulted for this review indicated that the most important treatment goals for patients with hemophilia A are to prevent bleeding, including spontaneous and traumatic bleeding events, reduce joint pain, improve health-related QoL (HRQoL), and achieve an unrestricted lifestyle comparable to the general population. The clinical experts noted that the current standard of care for patients with severe hemophilia A in Canada is primary prophylactic therapy. The goal of prophylactic treatment is to prevent bleeding, and as newer treatments are available, the overall goal is for patients to attain higher factor levels or near-normal factor levels. According to the clinical experts consulted for this review, there is no current therapy that can modify the underlying disease mechanism of hemophilia A outside of gene therapy which is currently unavailable in Canada. In addition, apart from emicizumab, which provides bleeding protection roughly equivalent to a steady-state trough FVIII level of 10% to 15%, the trough levels of available SHL and EHL FVIII concentrates are between 3% to 5% before the next infusion, with subsequent clearance dependent on the product half-life (but generally 14 to 18 hours) resulting in less bleed protection. Patients who participate in regular physical activities are at risk of bleeding with current prophylactic regimens when their FVIII levels are suboptimal. As a result, these patients need additional doses of factor concentrates on top of their regular prophylaxis just before certain physical activities to mitigate the risk of provoked bleeding.

According to the clinical experts, Altuviiio will change the treatment landscape for acute bleed and perioperative management, but they do not envision Altuviiio altering the underlying disease process of congenital hemophilia A. Both clinical experts indicated that Altuviiio will be the first agent in which a period of “normal hemostasis” (FVIII activity > 40% for the first 4 days of treatment) can be achieved without a trade-off in burden of treatment. Compared to available treatment options, the clinical experts suggested that Altuviiio would likely be used as a first-line therapy for patients who desire to use FVIII replacement rather than FVIII mimetic therapy or as an alternative or complementary therapy to emicizumab. The clinical experts noted that with the availability of Altuviiio, there would be no need for SHL FVIII products as the same FVIII levels could be achieved with fewer doses of Altuviiio.

The clinical experts noted that patients on emicizumab who have experienced a suboptimal response due to breakthrough bleeding events or adverse events (AEs) like injection pain, or more rarely, neutralizing antibodies to emicizumab, and those on SHL or EHL FVIII prophylaxis who still struggle with the frequent dosing interval would be best suited for Altuviiio. In addition, patients participating in high-level physical activities may benefit from the sustained high FVIII activity level with improved bleed protection as would patients requiring surgery regardless of their current FVIII treatment. Conversely, both experts indicated that Altuviiio will not be suitable for patients who have developed inhibitors to FVIII.

The clinical experts noted that outcomes used in clinical practice are largely aligned with those used in the pivotal trials, particularly regarding annualized bleeding rate (ABR), which is a common trial end point. Other clinical trial outcomes including joint health, QoL (Haemophilia Quality of Life questionnaire for adults [Haem-A-QoL]), and FVIII activity levels, are also closely monitored in clinical practice. Both clinical experts indicated that treatment with Altuviiio will be discontinued if there is evidence of the development of FVIII inhibitors, no evidence of improvement in bleeding episodes, occurrence of AEs with treatment administration (allergy or anaphylaxis), or loss of IV access.

According to the clinical experts, treatment with Altuviiio should be primarily managed within a hemophilia treatment centre, where specialized hematologists and multidisciplinary teams can monitor treatment including pharmacokinetics (PK) testing, manage complications, and provide perioperative or periprocedural guidance.

Clinician Group Input

Three clinician groups, the Association of Hemophilia Clinic Directors of Canada (AHCDC; 5 clinicians contributed to the input), Canadian Association of Nurses in Hemophilia Care (CANHC; 6 clinicians contributed), and Canadian Physiotherapists in Hemophilia Care (CPHC; 5 clinicians contributed), provided input for this review. AHCDC gathered input through national advisory boards, expert opinions, and clinical trial experience with Altuviiio. Information from CANHC was provided by members who responded to the call for input while the submission from CPHC was gathered via information from clinician experience, conferences attended, and in-services.

Clinician groups noted that the ultimate treatment goal for patients with hemophilia A is to minimize the number of bleeds while slowing hemophilic arthropathy progression. With currently available treatments, achieving this goal requires frequent administration of high treatment doses to overcome short treatment half-lives. This treatment burden is particularly notable in patients who require elevated trough levels due to recent surgical procedures, compromised joint health, or high physical activity levels, according to clinician group input. Consistent with expert input, the clinician groups agreed that current therapies demonstrate variable efficacy.

Aligning with expert input, clinician groups noted that Altuviiio could be used as first-line therapy for patients aged 2 years or older with hemophilia A or offered as an alternative treatment to those receiving other therapies. Patients best suited for treatment with Altuviiio, as identified by clinician groups, were consistent with that of the clinical expert input. Additional patient populations who clinicians noted may benefit from Altuviiio treatment included patients with hemophilic arthropathy or poor venous access. In addition, clinician groups noted that patients with mild hemophilia A receiving on-demand or episodic therapy and those undergoing surgery or procedures may benefit from Altuviiio. The clinician groups indicated that patients least likely to benefit from Altuviiio are those who are averse to IV infusions, have developed FVIII inhibitors, or have achieved 0 bleeds on prophylaxis and who feel that switching therapies would have a minimal positive impact on QoL.

The clinician groups agreed with the consulted experts that the outcomes used in the trials to assess response are realistic for clinical practice, adding that patients should be assessed every 6 months to 2 years, depending on disease severity. CANHC noted that a clinically meaningful response to Altuviiio treatment would involve favourable PK profile (half-life improved to near-normal levels), an absence of FVIII inhibitors, absence of bleeding events, improved stable joint health, improved QoL, and infrequent hospitalizations. The clinician groups’ suggested criteria for discontinuation aligned with expert input. AHCDC and CANHC also suggested discontinuation if the patient switches to a nonfactor replacement therapy, other experimental therapies, or if the treatment centre is unable to perform the required clotting assay. The input received from the clinician group regarding Altuviiio prescribing considerations, including the follow-up of patients by a hemophilia clinic director, was consistent with the clinical expert inputs received for this review.

Drug Program Input

Input was obtained from the drug programs that participate in our reimbursement review process. Please refer to Table 5 for further information. The following were identified as key factors that could potentially impact the implementation of Altuviiio:

• considerations for initiation of therapy

• considerations for continuation or renewal of therapy

• considerations for prescribing of therapy

• generalizability.

Clinical Evidence

Systematic Review

Description of Studies

Two pivotal, phase III, open-label, nonrandomized, multicentre studies (XTEND-1 and XTEND-Kids) were included in the systematic literature review (SLR) conducted by the sponsor.

A total of 159 patients who were at least 12 years of age with severe hemophilia A without inhibitors were enrolled in the XTEND-1 trial (including 8 patients living in Canada from 2 study sites) and divided into 2 treatment groups: arm A (n = 133) and arm B (n = 26). Patients on a current FVIII prophylactic treatment regimen and who participated in an observational prestudy (242HA201/OBS16221) for at least 6 months before baseline of the XTEND-1 trial were assigned to arm A. Those on an on-demand treatment regimen for hemophilia A were assigned to arm B. Patients in arm A received a dose of 50 IU/kg once-weekly Altuviiio as prophylactic treatment for 52 weeks and those in arm B received Altuviiio 50 IU/kg as on-demand treatment of bleeding episodes for the first 26 weeks and then switched to the 50 IU/kg weekly prophylactic treatment regimen with Altuviiio for another 26 weeks. The primary objective of the XTEND-1 trial was to evaluate the efficacy of Altuviiio as a prophylactic treatment based on the ABR in arm A (described in the following). The key secondary end point was to evaluate the efficacy of Altuviiio as a prophylactic treatment based on the intrapatient comparison of ABR during the trial compared to the historical prophylaxis ABR in the 78 patients in arm A who participated in the observation study.

The XTEND-Kids trial included a total of 74 previously treated patients with severe hemophilia A who were aged younger than 12 years old and comprised 2 age cohorts: children aged less than 6 years (n = 38) and children aged between 6 years to 12 years (n = 36) (including 9 patients living in Canada from 4 study sites). All 74 patients received once-weekly IV doses of 50 IU/kg Altuviiio prophylactic treatment for 52 weeks. The primary objective of the XTEND-Kids trial was to evaluate the safety of Altuviiio in previously treated pediatric patients with severe hemophilia A based on occurrence of inhibitors. The key secondary end point was to evaluate the efficacy of Altuviiio as prophylactic treatment based on ABR, annualized joint bleeding rate (AjBR), joint health, and QoL outcomes.

In both trials, patients with a history of a positive inhibitor test result at screening (defined as ≥ 0.6 Bethesda units [BU]/mL at screening), those with serious active bacterial or viral infection within 30 days of screening, history of hypersensitivity or anaphylaxis associated with any FVIII product, or who had received emicizumab within the 20 weeks before screening were excluded. Both trials evaluated the safety, efficacy, and PK of Altuviiio administered IV once weekly as prophylactic or on-demand treatment in previously treated patients with severe hemophilia A without inhibitors.

The objective of both trials was to assess the safety and efficacy of Altuviiio to maintain hemostasis in the following settings: routine prophylaxis, control and prevention of bleeding, and perioperative management, as measured by ABR and AjBR; intrapatient comparison of ABR (only XTEND-1; participants served as their own controls); and development of FVIII inhibitors (only XTEND-Kids) at week 52 following Altuviiio infusion. Other efficacy and safety end points in both trials included joint health (Hemophilia Joint Health Score [HJHS]); Haem-A-QoL and Haemophilia Quality of Life questionnaire for children (Haemo-QoL); withdrawal due to AEs (WDAEs); treatment-emergent AEs (TEAEs); treatment-emergent serious AEs (TESAEs); deaths; and notable harms. In the XTEND-1 trial, efficacy end points were tested hierarchically to maintain the overall type I error rate of 0.05 or less. All analyses in the XTEND-Kids trial were descriptive in nature and adjustments for multiplicity were not applied.

In the XTEND-1 trial, the mean age of patients at baseline was 35.4 years (standard deviation [SD] = 15.1 years), ranging from 12 years to 72 years, and most patients (78.6%) had no family history of FVIII inhibitors. In the 12 months before the study, the mean number of bleeding episodes reported was 3.2 (SD = 5.4) in arm A patients who all previously received a different prophylaxis regimen and 35.7 (SD = 22.2) in arm B patients who previously received on-demand treatment. In the XTEND-Kids trial, the mean age at baseline was 5.99 years (SD = 2.91 years; ages ranged from 1.4 to 11.0 years), the majority (77%) had no family history of FVIII inhibitor, and the mean bleeding episodes in patients on a prophylactic regimen before the study was 2.1 (SD = 4.2). The XTEND-1 study was completed on February 3, 2022, and the XTEND-Kids trial was completed on January 18, 2023. There were no reported important protocol deviations that could potentially influence the efficacy results in either the XTEND-1 or XTEND-Kids studies.

Efficacy Results

XTEND-1 Trial

Bleeding Outcomes

Annualized bleeding rate: The primary efficacy end point in the XTEND-1 trial was ABR in arm A (prophylaxis arm) assessed following 52 weeks of Altuviiio for prophylactic use. In the full analysis set (FAS), a total of 86 bleeding episodes were treated with Altuviiio in 133 patients in arm A during the efficacy period. The median ABR at week 52 was 0.00 (interquartile range [IQR], 0.00 to 1.04) and the mean ABR was 0.71 (95% confidence interval [CI], 0.52 to 0.97). In arm A, 131 (98.5%) patients had 5 or fewer bleeding episodes per year and 86 (64.7%) patients had no bleeding episodes during the study (Table 15). Sensitivity analyses were consistent with those of the primary analysis.

Annualized joint bleeding rate: Results for AjBR were consistent with the results for ABR. In arm A, 37 patients in the FAS had a total of 61 treated joint bleeds. The estimated mean AjBR at week 52 was 0.51 (95% CI, 0.36 to 0.72). Of the 133 patients in arm A, 131 (98.5%) patients had an AjBR of 5 or fewer episodes per year with 96 (72.2%) patients with no joint bleeds during the study.

In arm B, estimated mean AjBR at week 52 was 17.48 (95% CI, 14.88 to 20.54). The mean AjBR in arm B was similar to arm A after patients had switched to prophylactic treatment: mean exposure days were 0.62 (95% CI, 0.25 to 1.52). In an intrapatient comparison of AjBR in arm B, the joint bleeding rate ratio for prophylaxis versus on-demand treatment was 0.04 (95% CI, 0.01 to 0.08).

Intrapatient comparison of ABR between Altuviiio prophylaxis versus historical prophylaxis: Overall, the number of patients with ABR of 0 who had historical prophylaxis or received Altuviiio was 42.3% and 64.1%, respectively. In the FAS (N = 78), intrapatient comparison in arm A showed a mean ABR reduction of 77% (ABR ratio = 0.23; 95% CI, 0.13 to 0.42; P < 0.0001) in the efanesoctocog prophylaxis group compared to historical prophylaxis.

For the 26 patients in arm B, the bleeding rate ratio for prophylaxis versus on-demand treatment was 0.03 (95% CI, 0.02 to 0.07). With on-demand treatment, most patients (96.2%) had an ABR greater than 10, whereas most patients (76.9%) had no bleeds after switching to prophylactic treatment.

Physical Functioning and Pain (QoL)

Haem-A-QoL Physical Health score and Haemo-QoL score: In the XTEND-1 study, QoL data were collected in adult patients aged 17 years or older via the Haem-A-QoL Physical Health score and in adolescent patients aged 12 years to 16 years via the Haemo-QoL. In arm A, for patients aged 17 years or older (n = 98), the estimated mean change from baseline to week 52 in Haem-A-QoL Physical Health score was –6.74 (95% CI, −10.13 to –3.36; P = 0.0001). The Haemo-QoL results in the study’s adolescent population (all in arm A) mirrored those of the group aged 17 years or older, with improvements in Haemo-QoL Physical Health score (mean change from baseline to week 52 of −2.18 [SD = 22.05]) and total score (−3.45 [SD = 8.83]), in the group aged 13 years to 16 years (n = 18). In arm B, a mean change in Haem-A-QoL Physical Health score of –25.91 (SD = 22.29) by week 52 was reported. A sensitivity analysis performed for patients aged 17 years or older in arm A who had rolled over from the OBS16221 study (n = 66) also showed an improvement in Haem-A-QoL Physical Health score (least squares [LS] mean change from baseline to week 52 = −4.04; 95% CI, −8.06 to −0.03).

Patient-Reported Outcomes Measurement Information System (PROMIS) pain intensity and physical function: Item 3a of the PROMIS instrument assessed a patient’s worst pain in the last 7 days. This item was used to assess pain intensity in the XTEND trials. In arm A, in participants aged 12 years or older, the estimated mean change from baseline to week 52 in pain intensity was a difference in score of −0.21 (95% CI, −0.41 to −0.02; P = 0.0276). In arm B, the mean change from baseline to week 52 pain intensity was a difference in score of −0.77 (SD = 0.81).

The PROMIS instrument was also used to assess physical function in adult patients only (aged ≥ 18 years). In arm A, of 108 patients, 103 completed the PROMIS Short Form Physical Function questionnaire at baseline and 102 at week 52. The mean change in Physical Health score was 46.80 (SD = 8.82) at baseline to 47.35 (SD = 9.28) with a mean change from baseline to week 52 of 0.62 (SD = 4.77).

Joint Health

Hemophilia Joint Health Score: In arm A, the mean HJHS total score at baseline was 18.1 (SD = 18.4). The estimated mean change in the HJHS total score from baseline to week 52 was −1.54 (95% CI, −2.70 to −0.37; P = 0.0101). In arm B, the mean change from baseline to week 52 in HJHS total score was −4.1 (SD = 8.7). A sensitivity analysis performed using the data of patients in arm A who rolled over from the prospective observational OBS16221 study also showed an improvement in HJHS total score. The LS mean change from baseline to week 52 was −0.86 (95% CI, −2.38 to 0.66).

Perioperative Management Outcomes

Number of injections and dose to maintain hemostasis during major surgery: In the XTEND-1 study, 11 out of 12 major surgeries that occurred during the treatment regimen required a single injection of Altuviiio (i.e., the preoperative loading dose) to maintain hemostasis. The mean dose per injection was 41.65 IU/kg (SD = 15.21 IU/kg). For 1 surgery, conducted during routine prophylaxis, no preoperative loading dose was reported on the day before or the day of the surgery.

XTEND-Kids Trial

Inhibitor Development to FVIII

The primary end point of the XTEND-Kids study was the occurrence of inhibitor development against FVIII based on all patients who had reached at least 50 exposure days. Overall, 65 patients who had reached at least 50 exposure days were analyzed for inhibitors. The incidences of inhibitor development to FVIII were 0.0% (95% CI, 0.0 to 5.5) in patients with 50 exposure days or more to Altuviiio and 0.0% (95% CI, 0.0 to 4.9) in all treated patients.

Bleeding Outcomes

Annualized bleeding rate: The overall mean ABR at week 52 was 0.89 (95% CI, 0.56 to 1.42) and a median ABR was 0 (IQR, 0 to 1.02). Of the 74 patients, 47 (63.5%) had an ABR of 0, and 25 (33.8%) had an ABR of greater than 0 to 5 at 52 weeks. A total of 64 bleeding episodes were treated with Altuviiio in 27 of the 74 patients. Results of sensitivity analyses based on mean ABR at 52 weeks on the per-protocol set (PPS) or mean ABR on FAS including patients with data at week 26 were consistent with the primary analysis.

Annualized joint bleeding rate: The overall estimated mean AjBR was 0.59 (95% CI, 0.27 to 1.28), with 0.19 (95% CI, 0.06 to 0.62) in the cohort aged younger than 6 years, and 0.99 (95% CI, 0.38 to 2.60) in the cohort aged 6 years to younger than 12 years. Of the 74 patients who were included in the analysis, 61 (82.4%) patients reported no joint bleeds, while 12 (16.2%) patients reported 1 to 5 joint bleeds. One (1.4%) patient had 21 joint bleeds as per analysis, 18 of which were not confirmed by the investigator nor reported by the patient. A sensitivity analysis excluding the participant who did not receive the weekly prophylactic treatment for an extended period of time showed that the estimated mean AjBR in the cohort aged 6 years to younger than 12 years decreased to 0.41 (95% CI, 0.19 to 0.89) and the overall estimated mean AjBR to 0.30 (95% CI, 0.16 to 0.57).

Physical Functioning and Pain (QoL)

Haemo-QoLPhysical Health score and Haem-A-QoL score: For patients aged 4 years to 7 years, 8 years to younger than 12 years, and their respective caregivers, data were collected using 4 separated Haemo-QoL. For patients between the age of 4 years and 7 years, the mean change from baseline to week 52 was –5.31 (SD = 10.83) in the cohort aged younger than 6 years and 4.69 (SD = 5.41) in the cohort aged 6 years to younger than 12 years. In patients aged 4 years to 7 years, overall, the mean change from baseline to week 52 was −2.46 (SD = 10.49). Parents of children between the age of 4 years and 7 years were also asked to complete the Haemo-QoL for a parent-proxy assessment of this outcome. For the overall group, the mean change from baseline based on the parent proxy was –2.85 (SD = 11.82), which is aligned with the patient-reported results. For patients aged 8 years and older, the mean change from baseline to week 52 was –9.79 (SD = 12.18).

PROMIS Pain Intensity and Physical Function: Similar to the XTEND-1 trial, pain intensity was assessed in the XTEND-Kids study using item “a” of the PROMIS pediatric instrument as a change from baseline to week 52. For patients between the age of 5 years and 12 years, a parent or caregiver response was used as a proxy for the child. In the cohort of patients aged less than 6 years, the mean change from baseline was –0.44 (SD = 2.65) and for patients between the age of 6 years and 12 years, the mean change from baseline was −0.75 (SD = 2.53). Overall, the mean change in scores form baseline was –0.62 (SD = 2.52). Patients between the age of 8 years and 12 years responded to this outcome independently. For patients aged 8 years or older in the cohort aged 6 years to 12 years, the mean change from baseline was 0.00 (SD = 2.98).

In the cohort aged younger than 6 years, 8 parents of participants 5 years of age or older completed the PROMIS Short Form Physical Function questionnaire at baseline, and 8 parents at week 52. The mean change from baseline to week 52 in the cohort aged younger than 6 years was 3.96 (SD = 6.73; n = 7). In the cohort aged 6 years to younger than 12 years, 14 participants aged 8 years or older completed the PROMIS Short Form Physical Function questionnaire at baseline, and 16 participants at week 52. The mean change from baseline to week 52 was 0.78 (SD = 10.48; n = 10). In the cohort aged 6 years to younger than 12 years, 16 parents of participants aged younger than 12 years completed the questionnaire at baseline, and 16 parents at week 52. The mean change from baseline to week 52 was −1.36 (SD = 12.15; n = 10).

Joint Health

Hemophilia Joint Health Score: In the cohort aged younger than 6 years, 20 patients were aged 4 years or older and the mean change in HJHS total score from baseline to week 52 was 0.2 (SD = 8.3). In the cohort aged 6 years to younger than 12 years, the mean change in HJHS total score from baseline to week 52 was −1.1 (SD = 4.3) in 33 patients.

Perioperative Management Outcomes

Number of injections and dose to maintain hemostasis during major surgery: In the XTEND-Kids study, both major surgeries required a single injection of Altuviiio to maintain hemostasis. The mean dose per injection was 61.13 IU/kg (SD = 1.06 IU/kg).

Harms Results: AEs

XTEND-1: Of the 159 patients in the safety analysis set, 123 (77.4%) patients experienced at least 1 TEAE, resulting in a total of 394 TEAEs in the study. The most frequently reported TEAEs in more than 3% of patients were headache (20.1%); arthralgia (16.4%); fall (6.3%); back pain (5.7%); COVID-19 and fatigue (4.4% each); contusion, hemophilic arthropathy, and nasopharyngitis (3.8% each); and joint injury, pain in extremity, and toothache (3.1% each). Of the 159 patients, 77 (48.4%) patients had no TEAEs classified as moderate or severe but at least 1 TEAE that was classified as mild. In addition, 39 (24.5%) patients had no TEAEs classified as severe but at least 1 TEAE was classified as moderate, and 7 (4.4%) patients had at least 1 TEAE classified as severe.

XTEND-Kids: Of the 74 patients in the safety analysis set, 62 (83.8%) experienced at least 1 TEAE, resulting in a total of 255 TEAEs. The most frequently reported TEAEs (> 5% of patients overall) were SARS-CoV-2 test positive and upper respiratory tract infection (14.9% each); pyrexia (12.2%); asymptomatic COVID-19 (9.5%); gastroenteritis viral, head injury, and nasopharyngitis (8.1% each); arthralgia, pain in extremity, and vomiting (6.8% each); and contusion, diarrhea, viral infection, and viral upper respiratory tract infection (5.4% each). The majority of TEAEs were assessed by the investigator as mild in severity. Of the 74 patients, 43 (58.1%) had at least 1 TEAE of mild intensity and 13 (17.6%) patients had at least 1 TEAE of moderate intensity.

Harms Results: Serious AEs

XTEND-1: A total of 18 TESAEs were experienced in 15 (9.4%) patients, of which 16 TESAEs were reported in 13 patients in arm A and 2 TESAEs in 2 patients in arm B. Hemophilic arthropathy was the most commonly reported serious adverse event (SAE), which was reported in 2 (1.3%) patients in arm A. All other TESAEs were reported in 1 (0.6%) patient each. The majority of TESAEs were assessed by the investigator as mild to moderate in severity.

XTEND-Kids: A total of 10 TESAEs were experienced in 9 (12.2%) patients. The majority of TESAEs were assessed by the investigator as mild to moderate in severity. The 5 TESAEs assessed by the investigator as severe were TESAEs of circumcision and bacteremia, each in 1 patient aged less than 6 years and TESAEs of vascular device occlusion, head injury, and eosinophilic esophagitis, each in 1 patient aged 6 to less than 12 years.

Withdrawals Due to AEs

XTEND-1: Two TEAEs in 2 (1.3%) patients resulted in permanent treatment discontinuation. The reason for WDAE was due to a decrease in CD4 lymphocytes in 1 patient with a history of HIV infection (reported as a TESAE), and due to a combined tibia–fibula fracture in the other patient who withdrew due to an AE.

XTEND-Kids: No patients discontinued Altuviiio treatment due to a TEAE during the study.

Mortality

XTEND-1: Death was reported in 1 patient overall who was in arm B. The patient had a medical history of hepatitis C and died of metastatic pancreatic carcinoma, which was reported as a TESAE. The TESAE was assessed by the investigator as not related to Altuviiio treatment.

XTEND-Kids: There were no deaths reported during the study.

AEs of Special Interest

XTEND-1: There were no reports of inhibitor development to FVIII nor thromboembolic events during the study.

XTEND-Kids: An event of “hives around eyes, mouth, face, and chest” was reported in a 2-year-old patient after “eating chocolate.” This patient had no history of allergies at baseline. The event occurred approximately 3 months after the first dose of Altuviiio (weekly prophylaxis) and 3 days after the last injection. There were no reports of thromboembolic events during the study.

Critical Appraisal

The 2 pivotal trials (XTEND-1 and XTEND-Kids) included in the sponsor’s SLR were phase III, single-arm, open-label clinical trials. Although nonrandomized, open-label, single-arm design limits the interpretation of the efficacy results for both pivotal trials, the clinical experts consulted by Canada’s Drug Agency (CDA-AMC) for this review indicated that while traditional randomized controlled trials (RCTs) remain the gold standard for many conditions, these are not feasible in hemophilia A due to ethical constraints, challenges in patient recruitment, and the availability of effective treatments. According to the clinical experts, alternative designs like intrapatient comparisons and historical controls provide practical evaluation of new therapies such as Altuviiio. It was noted that participants in both trials were previously treated patients with severe hemophilia A without inhibitors and in particular, 92 patients (n = 82 in arm A and n = 10 in arm B) in the XTEND-1 trial were previously enrolled in an observational prestudy (242HA201/OBS16221). This was determined by CDA-AMC to be a potential selection bias. Additionally, although the sponsor provided data on the baseline characteristics of all participants in the prestudy observational study, the baseline clinical characteristics specific to the patients who continued into the XTEND-1 study from the observational study were not provided. CDA-AMC notes that this limits the ability to identify preexisting differences, potentially introducing bias and confounding, although the clinical experts indicated that the rolled over patients and those in the XTEND-1 study were likely similar and were not systematically different based on the baseline characteristics for the overall group.

In both trials, bleeding outcomes were measured using ABR and AjBR, both of which are widely accepted end points in hemophilia research that provides an objective assessment of bleeding outcomes. Joint health was measured using HJHS, which is a validated outcome measure but is subject to potential bias particularly due inter-rater variability. Additionally, although the study design was deemed appropriate for data collection across varied populations, the lack of blinding introduces potential bias, as knowledge of treatment assignment may influence reporting on subjective or patient-reported outcomes such as, HRQoL, physical function, and pain outcomes (outcomes related to the Haem-A-QoL and PROMIS instruments). As such, reliable assessments of these outcomes could not be made and there is potential for risk of bias that could lead to the overestimation of the treatment effect of Altuviiio.

Both trials appear to be adequately powered for assessing ABR and joint health outcomes; however, smaller subgroup analyses, such as surgery, perioperative management, or specific age groups, may not be fully powered to detect AEs or efficacy. Both trials included follow-up safety assessments for a few weeks after the last dose, but the duration of the XTEND-1 and XTEND-Kids trials was considered too short to sufficiently evaluate delayed adverse effects and assess the long-term safety of Altuviiio.

While the XTEND-1 study included a historical control through intrapatient comparison with patients’ prior prophylactic regimens in a previous study, this approach lacks randomization, is affected by temporal trend, and is prone to measurement bias, making causal inferences less robust compared to a concurrent randomized control group. Additionally, CDA-AMC notes that the reliance on historical data may introduce variability due to changes in patients' current conditions or other external factors unrelated to treatment efficacy such as carryover effects, making causal inferences less robust. Specifically, the XTEND-1 trial was conducted during the COVID-19 pandemic while the observational prestudy was conducted a few years before the pandemic (patients in these studies were enrolled between 2009 to 2017) (Table 23). Therefore, impact from possible change in physical activities related to social distancing which was required on many occasions during the pandemic (e.g., intensity, types of physical activities) on the risk of bleeding in patients with hemophilia is uncertain. In both trials, perioperative management outcomes were assessed descriptively based on the rating of hemostatic response on a 4-point ordinal scale performed 24 hours after the surgery by the surgeon or study investigator, as well as the number of injections and mean dose needed to maintain hemostasis per major surgery. CDA-AMC notes that while this subjective assessment is aligned with how this outcome would be assessed in clinical practice, it is likely subject to bias, especially given that the assessments were performed by those involved in the study.

CDA-AMC identified several considerations related to the generalizability of the XTEND trials in evaluating the efficacy and safety of Altuviiio. The trials enrolled patients from 6 study sites in Canada and included both adults and children with severe hemophilia A, which enhances the generalizability of the findings. In contrast, the results from the 2 trials may have limited generalizability as the study population was restricted to patients (without inhibitors) with severe hemophilia A. The clinical experts consulted for this review indicated that there is a subset of patients with mild or moderate hemophilia who may require prophylaxis. The design of the XTEND-1 and XTEND-Kids studies did not include these patients and therefore, the magnitude of the treatment effect in patients with mild and moderate hemophilia A is unclear. According to the clinical experts, the once-weekly dosing of 50 IU/kg used in the trials reflects what is expected in clinical practice. However, specific subgroups, such as patients with obesity or those participating in higher-risk physical activity may require adjusted dosing, which was not explored in the trials, and this limits the generalizability of the results to these populations. Although the clinical experts indicated the difficulty in the direct comparison of efanesoctocog with current standard of care, CDA-AMC notes that the lack of direct head-to-head comparison with the current standard of care, such EHL FVIII products or nonfactor therapies like emicizumab, limits external validity regarding the effectiveness and safety of Altuviiio compared to currently available therapies.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^14,15

Although GRADE guidance is not available for noncomparative studies, the CDA-AMC review team assessed the 2 single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 2 and Table 3 present the GRADE summary of findings for Altuviiio from the XTEND-1 and XTEND-Kids trials for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding in adults and children with hemophilia A. The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• ABR

• AjBR

• intrapatient comparison of ABR

• FVIII inhibitor formation

• HJHS

• physical functioning and pain outcome (Haem-A-QoL, Haemo-QoL)

• perioperative management outcome (mean number of injections to maintain hemostasis during major surgery)

• harms (TESAEs, TEAEs, mortality)

Long-Term Extension Studies

Description of Studies

One long-term extension (LTE) study was submitted for review, XTEND-ed (NCT04644575).¹⁸ The XTEND-ed LTE study is an ongoing phase III, open-label, multicentre study to assess long-term safety and efficacy of Altuviiio in previously treated patients with severe hemophilia A. The study began in February 2021 and is estimated for completion in 2027.¹⁸ At the time of this submission, the available evidence was limited to interim analyses based on conference presentations.^19,20 The submitted interim analyses pertain only to patients rolled over from the XTEND-1 and XTEND-Kids studies into arm A of the XTEND-ed LTE study and reports on efficacy and safety-related outcomes over 2 additional years of treatment with Altuviiio.

Table 2: Summary of Findings for the Efficacy and Safety of Altuviiio for Adults With Hemophilia A (XTEND-1 Trial)

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; CI = confidence interval; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; HJHS = Hemophilia Joint Health Score; PROMIS = Patient-Reported Outcomes Measurement Information System; QoL = quality of life; SD = standard deviation; TESAE = treatment-emergent serious adverse event.

Notes: All serious concerns with study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias are documented in the table footnotes.

^aIn absence of a comparator arm, conclusions about efficacy relative to any comparator cannot be drawn and certainty of evidence started at very low for all end points. In addition, all outcomes were rated down 1 level for indirectness due to the exclusion of patients with mild or moderate hemophilia A.

^bDespite the study limitations resulting in the certainty of evidence starting as “very low,” the CDA-AMC review team considered the strength of evidence sufficient to rate up 1 level to “low” based on the proportion of patients with an ABR of 0 (i.e., no bleeds) reported during the trial, a mean ABR < 1 that was considered as clinically meaningful by the clinical experts consulted for this review, and an intrapatient comparison suggestive of an improvement in ABR compared to prior historical prophylactic treatment.

^cRated down 1 level for serious study limitations: risk of bias due to the nonrandomized study design.

^dRated down 1 level for serious study limitations: risk of bias due to the nonrandomized, open-label study design.

^eRated down 1 level for serious study limitations due to risk bias in measurement of the outcome because of the nonrandomized, open-label study design. Rated down 1 level due to imprecision due to insufficient sample size.

^fRated down 1 level due to imprecision due to insufficient sample size.

Source: XTEND-1 Clinical Study Report.¹⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 3: Summary of Findings for the Efficacy and Safety of Altuviiio for Children With Hemophilia A (XTEND-Kids Trial)

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; BU = Bethesda unit; CI = confidence interval; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; HJHS = Hemophilia Joint Health Score; PROMIS = Patient-Reported Outcomes Measurement Information System; QoL = quality of life; SD = standard deviation; TESAE = treatment-emergent serious adverse event.

Note: All serious concerns with study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias are documented in the table footnotes.

^aIn absence of a comparator arm, conclusions about efficacy relative to any comparator cannot be drawn and certainty of evidence started at very low for all end points. In addition, all outcomes were rated down 1 level for indirectness due to the exclusion of patients with mild or moderate hemophilia A.

^bRated down 1 level for serious study limitations due to risk of bias due to missing data and nonrandomized study design. Of note, this outcome was the primary end point for XTEND-Kids and assessed as a safety end point. It was reported descriptively and not adjusted for multiple comparisons.

^cRated down 1 level for serious study limitations: risk of bias due to the nonrandomized study design.

^dRated down 1 level for serious study limitations: risk of bias due to the nonrandomized and missing data.

^eRated down 1 level for serious study limitations: risk of bias due to the nonrandomized, open-label study design.

^fRated down 1 level for serious study limitations due to risk bias in measurement of the outcome because of the nonrandomized, open-label study design. Rated down 1 level due to imprecision due to insufficient sample size.

^gRated down 1 level due to imprecision due to insufficient sample size.

Source: XTEND-Kids Clinical Study Report.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy Results

In the first 2 years of the XTEND-ed study, the mean overall ABR was 0.72 (SD = 1.26) for patients in arm A of the XTEND-1 study (prophylaxis arm), 0.42 (SD = 0.89) for patients in arm B of the XTEND-1 study (on-demand switch to prophylaxis), and 0.70 (SD = 1.27) for patients from the XTEND-Kids study. Mean ABR in the XTEND-Kids study was also comparable across age groups, between patients aged younger than 6 years (ABR = 0.63; SD = 1.18) and aged 6 years to 12 years (ABR = 0.77; SD = 1.37).

Harms Results

As of the XTEND-ed study’s interim analysis cut-off date, 74% of patients from the XTEND-1 study group had at least 1 TEAE and 12% had at least 1 serious TEAE. The most common TEAEs (in > 5% of patients) included COVID-19 (22%), arthralgia (13%), headache (9%), nasopharyngitis (8%), and influenza (6%). Two patients discontinued therapy due to TEAEs.

In the XTEND-Kids study group, 61% of patients experienced at least 1 TEAE and 3% had at least 1 serious TEAE. The most common TEAEs (in > 5% of patients) included pyrexia (9%), arthralgia (7%), cough (7%), upper respiratory tract infection (6%), viral upper respiratory tract infection (6%), and oropharyngeal pain (6%). There were no treatment discontinuations in this group due to TEAEs.

As of the XTEND-ed study’s interim analysis cut-off date, there was no development of FVIII inhibitors in either group and no deaths were reported.

Critical Appraisal

The XTEND-ed LTE study was designed as an open-label extension to assess long-term efficacy and safety of Altuviiio for the treatment of patients with hemophilia A. This open-label design could bias the magnitude of treatment effect for subjective efficacy outcomes and reporting of safety parameters due to unblinded exposure to the study medication during the treatment period. Statistical hypothesis testing was not part of the design and there was no active comparator or placebo arm. The mean treatment duration in the XTEND-Kids study group was less than half of that of the XTEND-1 study group, 36.2 weeks and 82.5 weeks, respectively. Clinical experts noted that while 36 weeks is likely sufficient to assess treatment efficacy, more time is needed to evaluate long-term safety outcomes, such as inhibitor development.

The XTEND-ed arm A study population for this interim analysis consisted of patients who took part in the XTEND-1 and XTEND-Kids studies, and therefore it is reasonable to expect that the same strengths and limitations related to generalizability apply to the LTE. Given that patients needed to complete the XTEND-1 or XTEND-Kids studies before enrolling, the LTE population is inherently enriched and introduces some selection bias for responders.

Indirect Comparisons

Description of Studies

In the absence of head-to-head evidence comparing Altuviiio to other relevant therapies used to manage hemophilia A, the sponsor submitted 1 indirect treatment comparison (ITC) report²¹ comparing relative treatment effects of Altuviiio versus relevant comparator therapies as prophylactic treatment for adult patients with severe hemophilia A. The ITC report included 2 matching-adjusted indirect comparisons (MAICs) for comparing Altuviiio with a nonfactor replacement therapy agent (emicizumab) or an SHL product (octocog alfa), and 1 analysis using a propensity score matching (PSM) method for comparing Altuviiio with an EHL agent (efmoroctocog alfa). Outcome measures assessed in this ITC included ABRs for any bleeding, spontaneous bleeding, and joint bleeding.

Efficacy Results

Compared to Emicizumab

Emicizumab once weekly was assessed in 63 patients in arm D of the HAVEN 3 trial and 119 patients in arm A of the XTEND-1 trial. The estimated effective sample size (ESS) for arm A in the XTEND-1 study was reduced from 119 patients to 76 patients following matching, which corresponded to 63.8% of the original sample.

Compared to emicizumab once weekly, treatment with Altuviiio was associated with lower rate of any bleeding (treated and untreated) (incidence rate ratio [IRR] = 0.32; 95% CI, 0.19 to 0.56), treated spontaneous bleeding (IRR = 0.62; 95% CI, 0.25 to 1.50), and treated joint bleeding (IRR = 0.48; 95% CI, 0.24 to 0.95).

Compared to Octocog Alfa

Octocog alfa was assessed on 62 patients in arms A and B of the LEOPOLD I trial and 159 patients in pooled arms A and B of the XTEND-1 trial. Baseline characteristics of the XTEND-1 study pooled arms were adequately matched to aggregated data from the LEOPOLD I study arms A and B. The estimated ESS was reduced from 128 patients to 29 patients following matching, which corresponded to 22.7% of the original sample.

Compared to octocog alfa, treatment with Altuviiio was associated with lower rate of any bleeding (mean difference [MD] = –2.97; 95% CI, –4.28 to −1.67), spontaneous bleeding (MD = –2.23; 95% CI, –3.10 to –1.35), and joint bleeding (MD = –2.67; 95% CI, –3.85 to –1.49).

Compared to Efmoroctocog Alfa

Efmoroctocog alfa was assessed on 117 patients with individualized prophylaxis data in the A-LONG trial and 159 patients in the pooled arms A and B of the XTEND-1 trial. The estimated ESS for the XTEND-1 study was reduced from 145 patients to 87 patients following matching which corresponded to 60% of the original sample, and for the A-LONG study individual patient data were reduced from 116 patients to 30 patients following matching which corresponded to 26% of the original sample.

Compared to efmoroctocog alfa, treatment with Altuviiio was associated with lower frequency of any treated bleeding (IRR = 0.29; 95% CI, 0.17 to 0.51), spontaneous bleeding (IRR = 0.21; 95% CI, 0.09 to 0.49), and joint bleeding (IRR = 0.37; 95% CI, 0.20 to 0.71).

Harms Results

Harms outcomes were not assessed in these analyses.

Critical Appraisal

In this ITC, unanchored MAIC or a PSM method was used in balancing the baseline characteristics between the included trials. In the MAICs, these potential effect modifiers or prognostic factors were adjusted for if adequate data were reported in the comparator studies: age, body weight, race, prior treatment regimen, prior frequency of bleeding, presence of targeted joints, comorbidities, and baseline patient-reported outcome values. The clinical experts consulted for this review agreed that these are relevant effect modifiers and prognostic variables and also noted that physical activity level at baseline is an important factor in result interpretation. In addition, the use of historical control for intrapatient comparison of ABR in the XTEND-1 study may introduce variability due to changes in patients’ characteristics or external factors including temporal events unrelated to treatment efficacy. For example, the XTEND-1 trial coincided with the COVID-19 pandemic, where changes in the level of physical activity before or during the COVID-19 pandemic may have affected patients’ risk of bleeding due to changes in lifestyle and behaviour related to physical activity. As such, there is potential for risk of bias in the included studies due to potential confounding by the heterogeneity in physical activity level at baseline, and the time that patients were treated and evaluated (prepandemic versus during pandemic); however, the direction of bias is unclear, and the clinical experts consulted by CDA-AMC did not expect this to significantly impact the results. Furthermore, the clinical experts consulted for this review noted that clinical practice and management of patients with hemophilia A have evolved considerably in the past 10 years. For example, there has been an increase in the use of factor prophylaxis in patients of all ages and disease severities, and factor prophylaxis dosing and frequency are tailored based on patient’s own PK profile, bleeding profile, activity levels, and potential impact of a bleeding event. Further, the risk of severe bleeding in patients with factor levels indicative of mild to moderate disease range is recognized and such patients can still benefit from prophylactic treatment (either factor or nonfactor). In addition, many clinicians in Canada have adopted the WFH clinical practice guidelines. All these changes have not been considered in the ITC analyses. Therefore, the study results may be biased.

In the MAIC and PSM analyses, the reduction in ESS after the weighting process ranged from 36% to 77% of the original sample size in the included studies. A significant reduction in sample size can contribute to imprecision and increase uncertainty of the results. A notable reduction in ESS also suggests that the study results may be heavily influenced by a subset of the sample in the trials that may not be representative of the full sample. Harms outcomes, which are important to patients and clinicians, were not assessed in the analyses, representing a gap in evidence.

In the sponsor-submitted ITC report, indirect comparisons were conducted to compare Altuviiio (XTEND-1) against emicizumab (HAVEN 3), EHL products such as efmoroctocog alfa (A-LONG), and SHL products such as octocog alfa (LEOPOLD I). The clinical experts consulted for this review agreed with the sponsor’s assumption that all currently reimbursed drugs in EHL or SHL classes are expected to demonstrate equivalent efficacy within their own classes; therefore, 1 single drug in the EHL or SHL class can represent all currently available drugs in that particular drug class.

Studies Addressing Gaps in the Evidence From the Systematic Review

No relevant studies addressing gaps in the evidence from the systematic review were submitted by the sponsor.

Conclusions

Two pivotal phase III, nonrandomized, open-label clinical trials, XTEND-1 (N = 159) and XTEND-Kids (N = 74), were included in the sponsor’s systemic review to provide evidence on the efficacy and safety of Altuviiio in adult and pediatric patients with severe hemophilia A. Based on the inputs from patients, clinicians, and clinical experts, the most important treatment goals for patients with hemophilia A are to prevent bleeding, including spontaneous and traumatic bleeding events, reduce joint pain, improve HRQoL, and achieve unrestricted lifestyle comparable to the general population. In the XTEND-1 and XTEND-Kids studies, patients who received once-weekly Altuviiio administered as weekly prophylaxis for 52 weeks experienced an annual rate of treated bleeds that was considered clinically meaningful, with a mean ABR of 0.71 (95% CI, 0.52 to 0.97) and 0.89 (95% CI, 0.56 to 1.42) in the 2 trials, respectively. Further, the proportion of patients who did not report experiencing a treated bleed was 64.7% and 63.5% in the XTEND-1 and XTEND-Kids studies, respectively. Additionally, the XTEND-1 study included an intrapatient comparison that suggests that Altuviiio may result in an improved ABR compared to the patients’ historical prophylactic therapy, although the evidence is still uncertain. Patients enrolled in the pivotal trials also experienced an annual rate of joint bleeds that was considered clinically meaningful, and although the change from baseline to week 52 in HJHS indicated an improvement in joint health, the magnitude of this effect is unclear due to the small within-group differences and the lack of validated minimal important differences (MIDs) for this outcome. In adults (XTEND-1) the change from baseline in HRQoL based on the Haem-A-QoL Physical Health score indicated an improvement in QoL; however, the change was not considered clinically meaningful based on the within-group MID identified in the literature. Results for Haem-A-QoL total score in the XTEND-Kids study suggest an improvement for children aged 8 years to 12 years, but these data are highly uncertain due to a small sample size. While the results suggest an improvement in PROMIS Pain Intensity scores at week 52 for adults in the XTEND-1 study, it is unclear whether this change corresponds to a clinically meaningful difference due to the absence of validated MIDs for this outcome. Additionally, the evidence was insufficient to support an improvement in pain intensity among pediatric patients based on the results from the XTEND-Kids study. Perioperative management of bleeds was also assessed and although the evidence is limited by a small sample size, all surgeries were reported as having a good or excellent hemostatic response to perioperative use of Altuviiio. Regarding safety, Altuviiio was well tolerated and the reported TESAEs were generally consistent with what is anticipated in an adult, adolescent, and pediatric population with severe hemophilia A. The majority of TESAEs across both pivotal studies were assessed to be mild in severity. There was no development of inhibitors to FVIII detected in either study, and there were no reports of serious allergic reactions, anaphylaxis, or embolic or thrombotic events.

It should be noted that the certainty of evidence was assessed as very low for all outcomes identified as clinically relevant for this review, with the exception of ABR in adults, which was rated to be of low certainty due to the intrapatient comparison and proportion of patients reporting no bleeds. The review team acknowledges that there are challenges associated with conducting a traditional RCT for rare diseases such as hemophilia A, and that the study design used in the XTEND trials is consistent with other trials for this condition. Nonetheless, the study design limits the interpretation of the safety and efficacy of Altuviiio, particularly as it relates to any comparator. The sponsor submitted indirect evidence to address this gap in the evidence, which suggested that prophylactic treatment with Altuviiio was associated with improved bleeding outcomes compared with the other treatments currently available in practice, such as EHL agents, SHL agents, or emicizumab. However, the magnitude of the clinical benefit of Altuviiio versus these comparator therapies is uncertain and likely overestimated by the study findings due to the limitations of the available indirect evidence, such as a sizable reduction in the ESS from the original sample size after the propensity score weighting analyses, and inadequate or lack of adjustment for potential prognostic factors, which may introduce unmeasurable confounding in the relative treatment effect estimates. Overall, Altuviiio used prophylactically resulted in clinically meaningful rates of bleeding outcomes over 52 weeks of use. Additionally, due to the prolonged half-life relative to other SHL and EHL FVIII molecules that is noted in the product monograph, the evidence suggests that Altuviiio represents an additional option that supports a patient-centred approach to the management of hemophilia A.

In the perioperative setting, hemostatic response by Altuviiio was rated as excellent by the investigators or surgeons for all major surgeries. The clinical experts consulted for this review were in agreement that alternative designs like single-arm trials and intrapatient comparison provide practical evaluation of new therapies. Further concerns with generalizability of the results included no control for multiplicity in the XTEND-Kids study, and potential biases introduced by assumptions in the statistical models used to make the comparisons. In addition, the lack of control for physical activity and the potential temporal trends due to the pandemic limit the interpretation of the efficacy outcomes.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of Altuviiio 50 IU/kg IV in the treatment of hemophilia A (congenital FVIII deficiency) in adults and children.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

Hemophilia is a bleeding disorder caused by deficiencies in coagulation FVIII and factor IX .^1-3 Hemophilia A is the most common form.⁴ It is a rare, congenital bleeding disorder caused by mutations in the gene that produces FVIII, a glycoprotein critical for hemostasis, which leads to excessive bleeding due to the inability to form blood clots.^2,3,5 FVIII circulates as a noncovalent complex with VWF to regulate platelet aggregation and clot formation.²² VWF is required for normal survival of FVIII in circulation.²²

Hemophilia A is an X-linked disorder predominantly affecting male patients, although females who are heterozygous carriers can have factor levels in the hemophilic range.⁴ Disease severity is categorized as mild, moderate, or severe, and is based on factor levels.⁷ For reference, normal FVIII activity is considered 40% or higher. Mild hemophilia A is defined by factor levels of 5% to 40% of FVIII activity levels in the blood, moderate is defined by levels of 1% to 5%, and severe is defined by levels less than 1% of normal FVIII activity levels.⁸ According to a 2023 Canadian Bleeding Disorders Registry report, there were 3,510 Canadians living with hemophilia A, of whom 1,158 had severe disease.²³

Patients with hemophilia A experience symptoms such as bleeding into joints, soft tissues and muscles, the mouth, and urine, as well as surface bleeding and easy bruising.⁹ In some cases, bleeding is due to a known cause such as an injury; alternatively, some causes of bleeding may be unknown and are referred to as a spontaneous bleed.⁷ Spontaneous bleeding events are more common in patients with severe hemophilia A compared to mild or moderate disease.^7,24 Bleeding associated with hemophilia A can result in complications such as joint damage from repetitive bleeding, deep internal bleeding, and neurologic problems or death associated with bleeding in the brain.⁷ Additionally, the challenges experienced by patients with hemophilia A can substantially impact patient QoL and physical, mental, social, and educational well-being.^4,10 In patients with moderate to severe disease, reduced mobility due to joint bleeding is associated with increased reported pain, discomfort, and mental health challenges.^1,25 In children and adolescents, restriction on certain sport-related activities to prevent trauma, frequent school absences due to repeated bleeding events, and accompanying pain associated with bleeding events, can impact physical, social, and intellectual development.²⁶ In patients with severe hemophilia, joint bleeding is the most common clinical manifestation and can progress to hemophilic arthropathy, a disabling condition characterized by joint remodelling and chronic pain, which may necessitate future joint replacement.^4,10

A definitive hemophilia A diagnosis is based on a factor assay, obtained through blood tests, such as the 1-stage clotting assay and chromogenic assay, which measure FVIII activity levels and can demonstrate factor deficiency.¹¹ Patients with a family history of hemophilia A are typically diagnosed at birth, while those without a family history are typically diagnosed after bleeding is observed, often during the first year of life for individuals with severe hemophilia.¹² In Canada, patients with hemophilia A are typically treated in a hemophilia treatment centre by a multidisciplinary care team that includes a physician with specific skills in treating bleeding disorders, a nurse, a physiotherapist, and a social worker.² In patients with comorbidities, the care team may also include an orthopedic surgeon, internal medicine specialists, and infectious disease specialists.⁸

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

The international WFH guidelines for the management of hemophilia recommend primary prophylaxis as the standard of care for all patients with hemophilia A. This standard of treatment aligns with the recently released updated clinical practice guidelines for the treatment of hemophilia A by the International Society on Thrombosis and Haemostasis (ISTH).²⁷ In patients with hemophilia A, primary prophylaxis is defined as regular infusion of missing FVIII to increase FVIII levels, or administration of a factor mimetic. The key for primary prophylaxis is to start patients on treatment before a bleeding event. According to the clinician group input and the 2 clinical experts consulted for this review, the main goal of primary prophylaxis is to prevent bleeding and enable patients with hemophilia A to live an active lifestyle and have an improved QoL, comparable to that of the general population. The goal of prophylactic therapy is to maintain factor levels greater than 3% to 5% (3 IU/dL to 5 IU/dL) to reduce the risk of spontaneous bleeding and for better preservation of joint function.⁸ Current WFH guidelines now recognize that patients remain at risk of bleeding at a trough level of 1%, and now recommend to target FVIII trough levels of 3% to 5% or higher,⁸ while higher FVIII levels around normal to near-normal levels (15% to 50%) may be needed achieve near-zero bleeds.^28-33 However, normal FVIII activity levels have not been attainable with current treatments without trade-offs with burden of treatment.

Prophylactic treatment for hemophilia A includes FVIII replacement therapy, nonfactor therapy, and gene therapy. FVIII replacement therapies used in prophylactic, on-demand, and perioperative treatment settings for hemophilia A are categorized as SHL and EHL therapies.⁸ SHL therapies include virally inactivated products made from donated plasma or recombinant products manufactured using genetically engineered cells. The WFH do not express a preference for recombinant over plasma-derived clotting factor concentrates, and clinical experts consulted by the sponsor suggest the use of plasma-derived products is nearly nonexistent in the population of people with hemophilia A living in Canada.^8,34 The half-life of SHL therapies is approximately 12 hours in adults (shorter in young children and increasing with age), requiring IV administration 3 to 4 times weekly .⁸ According to the clinical experts consulted for this review, available SHL therapies used in clinical practice in Canada are Kovaltry, Xyntha, and Zonovate. With EHL therapies (agents used in clinical practice are Adynovate, Jivi, Eloctate, and Esperoct), fusion technologies and PEGylation are used to extend product half-life by 1.4 times to 1.6 times that of SHL products, to approximately 19 hours (half-life is shorter in pediatric populations). The dosing of EHL therapies is thus reduced to twice weekly or every 3 days.⁸ If patients develop inhibitors to FVIII replacement therapy, immune tolerance induction therapy aimed at eradicating inhibitors using infusions of varying FVIII doses, or bypassing agents with mechanisms that bypass the need for FVIII replacement can be used.

Nonfactor replacement therapy provides hemostasis through a different mechanism than FVIII replacement. Currently the only available nonfactor therapy in Canada is emicizumab, a bispecific monoclonal antibody that mimics the function of missing FVIII by bridging activated factor IXa and factor X, to facilitate the coagulation cascade and achieve hemostasis. Based on the typical frequency of administration for currently available SHL and EHL products (2 to 3 times per week), the trough levels are often inadequate to provide bleed protection. Unlike SHL and EHL therapies, emicizumab is not approved for the treatment of bleeding episodes or for perioperative management.³⁵ Additionally, Alhemo (concizumab injection) is another nonfactor therapy (antitissue factor pathway inhibitor antibody) that has been approved by Health Canada for the treatment of adolescent and adult patients with hemophilia A and B who have FVIII or factor IX inhibitors;³⁶ Alhemo has not undergone review by CDA-AMC at the time of this review. Emerging adeno-associated virus gene therapy for hemophilia A offers promise of increased FVIII activity levels and protection against bleeds with a single dose and has been approved for use in Europe and in the US.^37,38 There are several limitations associated with expected use of gene therapy including high proportions of individuals who carry adeno-associated virus neutralizing antibodies,^39,40 substantial variability in factor trough levels achieved across individuals,⁴¹ and unknown long-term persistence of gene expression following gene therapy.⁴² Gene therapy for hemophilia A is not currently available in Canada.

The clinical experts consulted for this review confirmed that these approaches align with the Canadian clinical practice. According to the clinical experts, while the standard of care for severe hemophilia A is FVIII prophylaxis, some patients choose to remain on an episodic FVIII regimen.⁴³ The experts also indicated that Hemlibra (emicizumab), Eloctate (efmoroctocog alfa), Kovaltry (octocog alfa), Xyntha (antihemophilic factor [recombinant]), Zonovate (antihemophilic factor [recombinant]), Adynovate (antihemophilic factor [recombinant], PEGylated), Jivi (antihemophilic factor [recombinant], PEGylated-aucl), and Esperoct (antihemophilic factor [recombinant], Fc fusion protein) are relevant comparators for the drug under review.

Drug Under Review

Key characteristics of Altuviiio are summarized in Table 4 with other treatments available for hemophilia A (congenital FVIII deficiency).

Altuviiio is a recombinant FVIII analogue fusion protein that temporarily replaces the missing coagulation factor (FVIII) required for effective hemostasis. Altuviiio is a new class of FVIII replacement therapy that functions independently of endogenous VWF to overcome the half-life limit imposed by FVIII–VWF interactions. FVIII half-life is significantly influenced by VWF plasma levels while circulating together as a noncovalent complex. Under typical physiological circumstances, the half-life of free FVIII is substantially reduced (approximately 2 hours) compared to that of VWF-bound FVIII (approximately 12 hours). By circulating independently of endogenous VWF, Altuviiio has demonstrated 3-fold to 4-fold prolonged half-life compared to other SHL and EHL FVIII molecules.

Altuviiio is approved by Health Canada for the treatment of hemophilia A (congenital FVIII deficiency) in adults, adolescents, and children with hemophilia A (congenital FVIII deficiency) for routine prophylaxis for prevention or reduction in the frequency of bleeding episodes, treatment and control of bleeding episodes, and perioperative management of bleeding (surgical prophylaxis). Altuviiio is administered intravenously as a single dose of 50 IU/kg once weekly for routine prophylaxis.⁴⁴ The sponsor’s reimbursement request is as per the approved Health Canda indication. In the US, Altuviiio indication aligns with that of the requested Health Canada indication.⁴⁵ In the European Union, Altuviiio is indicated for the treatment and prophylaxis of bleeding in patients with hemophilia A (congenital FVIII deficiency) in all age groups.⁴⁶

Table 4: Key Characteristics of FVIII Replacements Available in Canada

FVIII = factor VIII; SC = subcutaneous.

Note: The generic name for Kovaltry is antihemophilic factor (recombinant). The generic name for Eloctate is antihemophilic factor (recombinant) B-domain deleted Fc fusion protein.

^aHealth Canada indication.

Source: Altuviiio product monograph,⁴⁴ Kovaltry product monograph,⁴⁷ Eloctate product monograph,⁴⁸ and emicizumab product monograph.⁴⁹

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

One patient group input submission from the CHS was received for this review. The CHS is a national voluntary health charity that advocates for improvements in health and QoL for patients living with inherited bleeding disorders in Canada. The CHS is a member of the Network of Rare Blood Disorder Organization which follows safety, supply, and access issues for the broader category of blood and plasma-derived medicinal products in Canada. The CHS gathered input for this submission through a national online survey distributed both in English and French between April 1, 2024, to June 1, 2024. The survey received a total of 104 responses from patients in Canada with hemophilia A. This included 57 patients with severe hemophilia A, 33 with mild hemophilia A, and 14 with moderate hemophilia A. Of these patients, 33 reported a history of FVIII inhibitors. Among the 104 patients, 59 were receiving regular prophylactic therapy, 30 were receiving on-demand treatment, and 15 were not receiving treatment for hemophilia A.

When asked about their disease experience, survey respondents highlighted the following symptoms and challenges associated with hemophilia A: joint pain and loss of function, pain from bleeding episodes, invasive medical procedures, treatment side effects, surgery complications, and sleep difficulty. Respondents further indicated that hemophilia A-related restrictions impact their day-to-day functioning through limitations on physical activity and sport participation, loss of mobility, long recovery times from bleeding episodes, and restrictions on choice of jobs. Respondents also noted the detrimental effects on their social and psychological well-being, impacts on travelling due to concern over emergency hemophilia care, financial and educational constraints due to the risks of needing to stop working or days lost from work due to hospitalization, and the logistics of needing factor products with them at all times.

Of 104 survey respondents, 41% of patients were receiving emicizumab prophylaxis, 11% were receiving FVIII prophylaxis, and 6% were receiving FVIII on-demand therapy. Notably, 1 patient had undergone gene therapy. Most respondents indicated that they were “very satisfied” (49%) or “quite satisfied” (37%) with their current treatment. Only a few patients reported that they were “not very satisfied” (11%), or “not satisfied at all” (4%) with their current treatment. While most respondents (58%) noted no challenges in administering their current treatment, some indicated that geographical challenges were barriers to accessing treatment centres for bleeding episodes. Overall, most respondents considered their current treatment regimen “very effective” (48%) or “quite effective” (20%) in stopping or preventing bleeding. Most respondents indicated that treatment has become simpler and less burdensome with emicizumab as it can be self-administered at home, but injection pain is a challenge. Some respondents (6%) reported that emicizumab is effective in preventing bleeding episodes but not stopping active bleeding. Patients reported that new therapies that can improve hemophilia A disease outcomes such as higher bleed protection, improved pain management, and reduced frequency (fewer doses with longer half-life) of treatment are needed to improve their ability to engage in everyday activities.

One patient who had received Altuviiio through a special access program provided detailed input on their experience with the therapy. This patient has severe hemophilia, with a history of significant musculoskeletal bleeding and continued ankle joint pain that persisted even after total ankle replacement. In early 2024, this patient switched from emicizumab prophylaxis for breakthrough bleeds with an EHL FVIII agent (Jivi) to Altuviiio (5,000 IU) once per week. Since initiating treatment, this patient reported experiencing a sustained high FVIII level, with a factor trough of approximately 15%, that has reduced their risk of major and subclinical bleeding. Similar effects were reported by other patients, which appear to be maintained even if the injection is up to 2 days late. The patient indicated travel has become easier with Altuviiio, due to the more flexible storage requirements compared to previous treatments. The patient reported no disadvantages or side effects of Altuviiio. The patient indicated they have become self-sufficient, infuse themselves, and no longer require a caregiver, and highlighted substantial improvements in treatment burden, stress, and QoL.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of hemophilia A.

Unmet Needs

The 2 clinical experts consulted for this review indicated that the most important treatment goals for patients with hemophilia A are to prevent bleeding, including spontaneous and traumatic bleeding events, reduce joint pain, improve HRQoL, and achieve unrestricted lifestyle comparable to the general population. The clinical experts noted that the current standard of care for patients with severe hemophilia A in Canada is primary prophylactic therapy to increase patients’ FVIII levels to normal or near normal. There are 3 options for primary prophylactic treatment in the Canadian landscape: regular IV infusion of SHL FVIII concentrate (Kovaltry, Xyntha, Zonovate), regular IV infusion of EHL FVIII concentrate (Adynovate, Jivi, Eloctate, Esperoct), or regular emicizumab subcutaneous injection. Regarding unmet needs for patients with hemophilia A, the 2 clinical experts indicated that at this time, there is no therapy that can modify the underlying disease mechanism of hemophilia A outside of gene therapy which is currently unavailable in Canada. In addition, apart from emicizumab which provides bleeding protection roughly equivalent to the steady-state trough levels of 10% to 15%, the trough level of currently available SHL and EHL FVIII concentrates are between 3% to 5% before the next infusion, with subsequent clearance dependent on the product half-life (but generally 14 to 18 hours) resulting in less bleed protection. Patients with hemophilia A who participate in regular physical activities are at risk of bleeding with the present prophylactic regimen when their FVIII levels are suboptimal. As a result, patients need additional doses on top of their prophylaxis just before certain physical activities to mitigate the risk of provoked bleeding, even with emicizumab.

Place in Therapy

Overall, the experts indicated that Altuviiio will change the treatment landscape for acute bleed and perioperative management, but do not envision Altuviiio to alter the underlying disease process of congenital hemophilia A. Both clinical experts suggested that Altuviiio will be the first agent in which a period of “normal hemostasis” (FVIII activity > 40% for the first 4 days of treatment) can be achieved without a trade-off in burden of treatment and this is clinically relevant. Compared to available treatment options, the clinical experts suggested Altuviiio would likely be used as a first-line therapy for patients who desire to use FVIII replacement rather than FVIII mimetic therapy or as an alternative or complementary therapy to emicizumab. Individuals receiving emicizumab for prophylaxis may benefit from the EHL of Altuviiio for bleeding or perioperative management in place of SHL or EHL FVIII concentrates because of reduced infusion frequency. If approved as a first-line treatment, there would be no need for SHL FVIII products as Altuviiio will provide sustained FVIII levels with fewer doses, which SHL would require a higher frequency of infusions and doses to attain.

Patient Population

The 2 clinical experts indicated that all patients with congenital hemophilia A (without inhibitors) are expected to respond to Altuviiio. According to the experts, identifying patients best suited for Altuviiio should be based on individual patient circumstances, including bleeding phenotype, activity level, PK, and current treatment responses to tailor treatment options. The clinical experts noted that patients best suited for Altuviiio include patients receiving emicizumab who have experienced a suboptimal response due to breakthrough bleeding events or AEs like injection pain or neutralizing anti-emicizumab antibodies; patients on SHL or EHL FVIII prophylaxis who still struggle with the frequent dosing interval; patients participating in high-level physical activities who may benefit from the sustained high FVIII activity level with improved bleed protection; and patients requiring surgery regardless of their current treatment. The clinical experts noted that there would be no issues with diagnosis, misdiagnosis, or underdiagnosis of hemophilia A in routine clinical practice, given the presence of positive family history in some cases, and availability of clear diagnostic criteria and genetic testing. According to the clinical experts, several factors modify FVIII PK and influence dosing regimens in patients with hemophilia A as younger patients, particularly children, have faster FVIII clearance, leading to shorter half-lives and the need for more frequent dosing compared to adults. Patients living with elevated body mass index may experience altered FVIII distribution, requiring dose adjustments to achieve target levels. Both experts indicated that like other FVIII therapies, Altuviiio is not suitable for patients with inhibitors to FVIII.

Assessing the Response Treatment

The clinical experts noted that in general, outcomes used in clinical practice are largely aligned with those used in clinical trials, particularly regarding ABR, which is a common trial end point. Other clinical trial outcomes including joint health, QoL (Haem-A-QoL), and FVIII activity levels are also closely monitored in clinical practice. Patients and patient organizations also expressed a desire to experience a “hemophilia-free mind,” which was further described as freedom from bleeding, arthropathy, pain, and treatment burden.

Discontinuing Treatment

Both clinical experts indicated that treatment with Altuviiio will be discontinued if there is evidence of the development of FVIII inhibitors, no evidence of improvement in bleeding episodes, occurrence of AEs with treatment administration (allergy/anaphylaxis), or loss of IV access.

Prescribing Considerations

According to the clinical experts, treatment with Altuviiio should be primarily managed within a hemophilia treatment centre, where specialized hematologists and multidisciplinary teams can monitor treatment including PK testing, manage complications, and provide perioperative or periprocedural guidance. Additionally, 1 clinical expert noted that Altuviiio, like other FVIII therapies, is well-suited for home therapy, as many patients can self-administer IV treatment following training by hemophilia treatment centre staff; however, regular follow-up at the hemophilia treatment centre remains crucial to monitor treatment response, while benefiting from the convenience of home administration.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Three clinician groups provided input for this review: AHCDC (5 clinicians contributed to the input), CANHC (6 clinicians contributed), and CPHC (5 clinicians contributed). AHCDC is a national, nonprofit organization of hemophilia clinic directors in Canada aiming to improve care for individuals with bleeding disorders through clinical services, research, and education. CANHC is a Canadian association of nurses who work in hemophilia treatment centres caring for individuals with bleeding disorders and offers resources for education, research, and professional development. CPHC comprises physiotherapists working in hemophilia treatment centres with experience managing hemophilia-related musculoskeletal complications and aims to assess and make recommendations around hemophilia management. AHCDC gathered input through national advisory boards, expert opinions, and clinical trial experience with Altuviiio. Information from CANHC was provided by members who responded to the call for input while the submission from CPHC was gathered via information from clinician experience, conferences attended, and in-services.

The clinician groups noted that the current standard of care for patients with hemophilia A consists of regular prophylactic replacement therapy with clotting factor concentrates or nonfactor subcutaneous therapy. Clinician groups noted that the ultimate treatment goal for patients with hemophilia A is to minimize the number of bleeds to 0 or near-zero while slowing hemophilic arthropathy progression, enabling patients to live healthier, active lives. According to clinician groups, achieving this goal currently requires frequent administration of high therapeutic doses to overcome short treatment half-lives, which may not be feasible in pediatric populations or individuals with poor venous access. This treatment burden is particularly notable in patients who require elevated trough levels due to recent surgical procedures, compromised joint health, or high physical activity levels, according to clinician group input. Consistent with expert input, the clinician groups agreed that current therapies demonstrate variable efficacy.

Aligning with expert input, clinician groups noted that Altuviiio could be used as first-line therapy for patients aged 2 years or older with hemophilia A or offered as an alternative treatment to those receiving other therapies. Patients best suited for treatment with Altuviiio, as identified by clinician groups, were consistent with that of the clinical expert input. Additional patient populations that clinician groups noted may benefit from Altuviiio treatment included patients with hemophilic arthropathy or poor venous access, patients with mild hemophilia A receiving on-demand or episodic therapy, and those undergoing surgery or procedures. The clinician groups indicated that patients least likely to benefit from Altuviiio are those who are averse to IV infusions, have developed FVIII inhibitors, or who have achieved 0 bleeds on prophylaxis and who feel that switching therapies would have a minimal positive impact on QoL.

The clinician groups agreed with consulted experts that the outcomes used in the trials to assess response are realistic for clinical practice, adding that patients should be assessed every 6 months to 2 years, depending on disease severity. CANHC noted that a clinically meaningful response to Altuviiio treatment would involve favourable PK profile (half-life improved to near-normal levels), an absence of FVIII inhibitors, absence of bleeding events, improved stable joint health, improved QoL, and infrequent hospitalizations. The clinician groups’ suggested criteria for discontinuation aligned with expert input. AHCDC and CANHC also suggested discontinuation if the patient switches to a nonfactor replacement therapy, other experimental therapies, or if the treatment centre is unable to perform the required clotting assay. The clinician group input regarding Altuviiio prescribing considerations, including the follow-up of patients receiving treatments in hemophilia treatment centres, was consistent with the expert input received for this review.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

EHL = extended half-life; FVIII = factor VIII; SHL = standard half-life.

Clinical Evidence

The objective of the CDA-AMC Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of Altuviiio (lyophilized powder for IV infusion, 250 IU, 500 IU, 1,000 IU, 2,000 IU, 3,000 IU, and 4,000 IU per vial) for the treatment of adults and children with hemophilia A for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, or perioperative management of bleeding. The focus will be placed on comparing Altuviiio to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of Altuviiio is presented in 4 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted LTE study. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following are included in this review and appraised in this document:

• two pivotal studies, the XTEND-1 study (NCT04161495) and the XTEND-Kids study (NCT04759131) identified in systematic review

• one LTE study (XTEND-ed: ongoing)

• one ITC using 3 different approaches.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

Two studies (XTEND-1, XTEND-Kids) met the inclusion criteria of the sponsor-submitted systematic review.

The XTEND-1 study (NCT04161495) was a phase III, open-label, multicentre study to determine the safety, efficacy, and PK of Altuviiio administered IV once weekly as prophylaxis or on-demand treatment in previously treated patients aged at least 12 years with severe hemophilia A without inhibitors. The study consisted of a screening period of up to 8 weeks, a washout period (≥ 96 hours if patients previously received a SHL FVIII product and ≥ 120 hours for a EHL FVIII product), and an open-label treatment period up to 52 weeks. Safety was assessed throughout the study and for 2 weeks to 3 weeks after the last study treatment dose. The XTEND-1 study was completed on February 3, 2022. A total of 159 patients were enrolled in the XTEND-1 trial (including 8 patients living in Canada from 2 study sites) and divided into 2 treatment groups.

• Arm A: Altuviiio prophylaxis (n = 133) — Patients who were on a current FVIII prophylactic treatment regimen and participated in an observational prestudy (242HA201/OBS16221) for at least 6 months before baseline of the XTEND-1 trial were assigned to arm A. This included a total of 78 patients who had at least 6 months of participation in the observational prestudy. The observational prestudy was a global, multicentre, prospective study of up to 12 months conducted in patients aged 12 years or older with severe hemophilia A who were receiving a marketed FVIII product. Patients in arm A received a once-weekly dose of 50 IU/kg Altuviiio as prophylactic treatment for 52 weeks.

• Arm B: Altuviiio on-demand treatment followed by prophylaxis (n = 26) — Participants who were receiving an on-demand treatment regimen for hemophilia A before the baseline of the XTEND-1 trial were assigned to arm B. Patients in arm B received Altuviiio 50 IU/kg as on-demand treatment of bleeding episodes for the first 26 weeks and then switched to the 50 IU/kg weekly prophylactic treatment regimen with Altuviiio for another 26 weeks.

The primary objective of the XTEND-1 study was to evaluate the efficacy of Altuviiio as a prophylactic treatment based on the ABR in arm A (described in the following). The key secondary end point was to evaluate the efficacy of Altuviiio as a prophylactic treatment based on the intrapatient comparison of ABR during the trial compared to the historical prophylaxis ABR in the 78 patients in arm A who participated in the observation study.

All patients underwent PK assessments after the initial Altuviiio dose on day 1, with a subgroup of arm A (the sequential PK subgroup) receiving more extensive PK assessments at baseline and week 26. In addition, peak and trough FVIII sampling was performed in all patients throughout the study. Patients from either arm who underwent major surgery after the first dose of the study drug were included in the surgery subgroup to assess the control and prevention of bleeding during use of Altuviiio in the surgical setting.

Figure 1: Study Design of XTEND-1

Note: “Efanesoctocog alfa” indicates Altuviiio.

^aProspective prestudy is Study 242HA201/OBS16221.

^bA total of 92 patients rolled over from the observational prestudy into the XTEND-1 study, including 82 patients into arm A and 10 into arm B.

Source: Sponsor’s clinical evidence summary.⁵¹

The XTEND-Kids study (NCT04759131) was a phase III, open-label, multicentre, nonrandomized study that evaluated the safety, efficacy, and PK of weekly Altuviiio prophylaxis in patients with previously treated severe hemophilia A who were aged younger than 12 years. The XTEND-Kids study also evaluated the efficacy of Altuviiio for treating bleeding episodes and for perioperative management. The trial comprised 2 age cohorts, children aged younger than 6 years (n = 38) and children aged 6 years to younger than 12 years (n = 36) (including 9 patients living in Canada from 4 study sites). There was a screening period up to 8 weeks and washout period of 96 hours or longer for children aged 6 years to younger than 12 years, and 72 hours or longer for patients aged younger than 6 years, followed by an open-label, 52-week treatment period. All 74 patients received once-weekly IV doses of 50 IU/kg Altuviiio for prophylactic treatment. Safety was assessed throughout the study and for 2 weeks to 3 weeks after the last Altuviiio dose. The XTEND-Kids study was completed on January 18, 2023. PK assessments were performed at baseline (day 1), and peak and trough activity levels were evaluated for all patients in the study. A total of 37 patients (19 patients aged < 6 years and 18 patients aged 6 to < 12 years) were included in the PK subgroup which had PK sampling conducted at baseline and up to 7 days (168 hours) after Altuviiio injection. Patients enrolled in the XTEND-Kids study who underwent major surgery during the study were included in a surgery subgroup.

The primary objective of the XTEND-Kids study was to evaluate the safety of Altuviiio in previously treated pediatric patients with severe hemophilia A based on occurrence of inhibitor development. The key secondary end point was to evaluate the efficacy of Altuviiio as prophylactic treatment based on ABR, AjBR, joint health, and QoL outcomes.

Characteristics of the included studies are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

ABR = annualized bleeding rate; AE = adverse event; AI = accumulation index; AjBR = annualized joint bleeding rate; ALT = alanine aminotransferase; ASA = acetylsalicylic acid; AST = aspartate aminotransferase; AUC = area under the activity-time curve; BU = Bethesda unit; CL = total clearance; CLss = total clearance at steady state; C_max = maximum FVIII activity; C_trough = trough activity; DNAUC = dose-normalized area under the activity-time curve; EHL = extended half-life; EQ-5D-5L = 5-Level EQ-5D; EQ-5D-Y = EQ-5D Youth; FVIII = factor VIII; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; Haemo-QoL = Haemophilia Quality of Life questionnaire for children; HAL = Haemophilia Activities List; HCV = hepatitis C virus; HEAD-US = Hemophilia Early Arthropathy Detection with Ultrasound; HJHS = Hemophilia Joint Health Score; IR = incremental recovery; ISTH = International Society on Thrombosis and Haemostasis; JADE = Joint Activity and Damage Exam; MRT = mean residence time; NA = not applicable; NSAID = nonsteroidal anti-inflammatory drug; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetics; PRO = patient-reported outcome; PROMIS = Patient-Reported Outcomes Measurement Information System; SAE = serious adverse event; SHL = standard half-life; t_1/2 = elimination half-life; TSQM-9 = 9-item Treatment Satisfaction Questionnaire for Medication; ULN = upper limit of normal; Vss = volume of distribution at steady state.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Populations

Inclusion and Exclusion Criteria

Both the XTEND-1 and XTEND-Kids trials included patients with severe hemophilia A (< 1% endogenous FVIII activity), who had previously received treatment with any recombinant or plasma-derived FVIII replacement product or cryoprecipitate. The XTEND-1 study evaluated Altuviiio in adult and adolescent patients aged 12 years or older, while the XTEND-Kids study included children aged at least 12 years. Patients with a history of a positive inhibitor test or a positive inhibitor result at screening (defined as ≥ 0.6 BU/mL at screening), serious active bacterial or viral infection within 30 days of screening, history of hypersensitivity or anaphylaxis associated with any FVIII product, or abnormal renal function (defined as serum creatinine > 2.0 mg/dL) at screening and who had used emicizumab within the 20 weeks before screening were excluded from both trials. A summary of the inclusion and exclusion criteria for both trials are presented in Table 5. In the XTEND-1 trial, a key exclusion criterion was the presence of concurrent clinically significant liver disease that, in the opinion of the investigator, would make the patient unsuitable for enrolment. This may include, but was not limited to cirrhosis, portal hypertension, and acute hepatitis.

Interventions

XTEND-1 Trial

In the XTEND-1 trial, patients who were currently receiving a FVIII prophylactic treatment regimen who participated in an observational prestudy (242HA201/OBS16221) for at least 6 months before baseline were assigned to arm A. Patients who were receiving an on-demand treatment regimen for hemophilia A were assigned to arm B. All patients enrolled in the XTEND-1 trial received a 50 IU/kg dose of Altuviiio delivered via a slow push IV injection of 8 minutes (± 2 minutes) with the rate of administration determined by patient’s comfort level. Patients enrolled in arm A received Altuviiio prophylaxis once every week for 52 weeks. Individuals enrolled in arm B received on-demand treatment with Altuviiio as needed during the first 26 weeks, followed by Altuviiio prophylaxis once every week for the last 26 weeks. A single dose of 50 IU/kg was recommended for treating all bleeding episodes. Additional and adjusted doses were only given after consultation with the investigator. If a bleeding episode did not improve, additional doses of 30 IU/kg or 50 IU/kg every 2 days to 3 days were considered. For minor or moderate bleeding episodes occurring within 2 days to 3 days after a recent prophylactic dose, an initial 30 IU/kg dose may also be used. A single dose of Altuviiio before surgery was used to treat bleeding during a minor surgery whereas additional doses of 30 IU/kg or 50 IU/kg every 2 days to 3 days were administered to treat bleeds during a major surgery (allowed after 6 exposure days).

In the XTEND-1 trial, the concomitant mediations most frequently used by patients were paracetamol, tozinameran, and celecoxib. The intake of FVIII products other than Altuviiio was a major deviation to the protocol leading to treatment discontinuation unless it occurred in a life-threatening emergency or because of an accidental use and the sponsor agreed to retain the participant in the study.

XTEND-Kids Trial

In the XTEND-Kids trial, all patients received Altuviiio prophylaxis at a dose of 50 IU/kg once weekly during scheduled study visits via a slow push IV injection at a rate of administration determined by the patient’s comfort level, taking into account minimum injection duration per vial as per protocol. Treatment of bleeding episodes with Altuviiio during prophylaxis and dosing during minor or major surgeries aligns with dosing in the XTEND-1 trial, as summarized previously. In the XTEND-Kids trial, the most frequently used concomitant medications (< 10% of participants) were paracetamol, tranexamic acid, sodium chloride, amoxicillin, and tozinameran (COVID-19 vaccine). Outside of a clinical trial setting, Altuviiio was available for administration in hospital or at home in both the XTEND-1 and XTEND-Kids studies. The only criteria for stopping the administration of Altuviiio was the development of inhibitors against FVIII. All participants who completed the study in both trials were invited to enrol in an ongoing open-label extension study (XTEND-ed, NCT04644575), based on eligibility criteria.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical expert(s) consulted by CDA-AMC and input from patient and clinician groups and public drug plans. Using the same considerations, the CDA-AMC review team selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; FVIII = factor VIII; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; Haemo-QoL = Haemophilia Quality of Life questionnaire for children; HJHS = Hemophilia Joint Health Score; PROMIS = Patient-Reported Outcomes Measurement Information System; QoL = quality of life; SD = standard deviation; TESAE = treatment-emergent serious adverse event.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aIdentified as important to clinician groups.

^bIdentified as important by consulting clinical experts.

^cStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

^dIdentified as important for the pharmacoeconomic analysis.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Bleeding Outcomes

Annualized Bleeding Rate

The primary efficacy end point in the XTEND-1 study was the ABR in the prophylaxis arm (arm A). The ABR for each individual patient was calculated using the following formula:

A bleeding episode was defined as an episode that starts from the first sign of bleeding and ends no more than 72 hours after the last injection to treat the bleeding episode. A bleeding episode was counted in the primary analysis if it was treated with Altuviiio. All types of bleeding episodes were included in determining the annualized number. An intrapatient comparison of ABR, based on the same definition, was also included in the studies.

Annualized Joint Bleeding Rate

AjBR was calculated using the number and location of all bleeds (spontaneous, traumatic, and type unknown) occurring in all joints during the efficacy period. In the XTEND-1 trial, an intrapatient comparison of AjBR in arm B between Altuviiio weekly prophylaxis and on-demand treatment was performed.

Development of Inhibitor Development Against FVIII

The primary end point in the XTEND-Kids study was the occurrence of inhibitor development against FVIII. This was defined as an inhibitor result of greater than 0.6 BU/mL, confirmed by a second test result from a separate sample, drawn 2 weeks to 4 weeks following the date when the original sample was drawn. Both tests were performed using the modified Nijmegen-Bethesda assay. The date of inhibitor development was the date of the sample with the first positive test result which was subsequently confirmed by the second sample. The overall incidence of positive inhibitor formation was calculated using the following formula:

Haem-A-QoL

Across the XTEND trials, QoL data were collected in patients aged 17 years or older using the Haem-A-QoL, and via the Haemophilia Quality of Life Questionnaire for Children (Haem-A-QoL Kids short version) in patients aged 4 years to 16 years. Details of these questionnaires are in Table 8. In the XTEND-Kids study, parents also completed the Haem-A-QoL parent-proxy versions of the questionnaire. Questionnaires were summarized in terms of subscale scores and a total score. Scores were transformed to produce a Transformed Scale Score ranging from 0% to 100% with higher Transformed Scale Score values representing a worse QoL. Changes in total scores of Haem-A-QoL from baseline to week 52 were analyzed as secondary end points for the XTEND-1 study (arm A) and the XTEND-Kids study, respectively.

PROMIS Instruments

PROMIS instruments were used to evaluate QoL. In arm A of the XTEND-1 study, changes in PROMIS Pain Intensity and PROMIS Short Form Physical Function (in those aged ≥ 18 years) from baseline to week 52 were secondary end points. The assessment of pain in the XTEND-1 study was based on item 3a (intensity of pain at its worst score over the past 7 days). In the XTEND-Kids study, 3 PROMIS instruments (Pediatric Pain Intensity 1a, Pediatric Short Form Pain Interference, and Pediatric Short Form Physical Function) were used in exploratory end point analyses, completed by pediatric patients aged between 6 years to 12 years; if patients were aged younger than 6 years, parents completed the questionnaire as a proxy. The Pain Intensity instrument is a 3-item scale that evaluates pain severity using a 5-point Likert scale ranging from 0 (no pain) to 5 (very severe). The first 2 items assess pain utilizing a 7-day recall period, while the last item asks patients to rate their current level of pain. This tool is available for adults aged 18 years and older. The PROMIS Pediatric Pain Intensity form includes 1 item, rating pain intensity over the past 7 days, with a numeric rating scale ranging from 0 to 10, with 0 indicating no pain and 10 indicating worse pain. For each PROMIS instrument, the total raw score was converted to a standardized t score with a mean of 50 and a SD of 10; for negatively worded concepts like pain intensity, a t score of 60 was 1 SD worse than average, whereas for positively worded concepts like physical function, a t score of 60 was 1 SD better than average.

Hemophilia Joint Health Score

HJHS is a functional measure of joint health which was used to evaluate the effect of Altuviiio prophylaxis on joint health outcomes. HJHS was assessed in the XTEND-Kids study for patients aged 4 years and older and in arm A of the XTEND-1 study. The HJHS total score was calculated based on the sum of scores from 6 evaluated joints (ankles, elbows, and knees evaluated in terms of swelling, muscle atrophy, crepitus, flexion loss, extension loss, joint pain, and strength) and gait score (based on walking and climbing stairs). Total score ranges from 0 to 124, with higher scores indicating increased disease severity.

Response to Perioperative Management

Patients who underwent major surgery during the XTEND trials were included in the surgery subgroups to assess the efficacy of Altuviiio in the control and prevention of bleeding in the perioperative setting. Response to perioperative management was assessed as investigator’s or surgeon’s assessment of the patient’s hemostatic response to treatment and the number of injections and dose needed to maintain hemostasis during major surgery. Investigator or surgeon assessment of patient’s hemostatic response to Altuviiio treatment was collected 24 hours postsurgery based on the ISTH 4-point scale. Responses were given a numeric score (excellent = 1, good = 2, fair = 3, poor or none = 4), with a lower average score indicating better patient response to surgery with Altuviiio treatment. The number of injections, mean dose per injection (IU/kg), and total dose (IU/kg) required to maintain hemostasis during surgery was summarized for all major surgeries for patients in the surgery subgroup.

Additional Outcomes

Other outcomes of interest to the CDA-AMC review team including patient response to Altuviiio treatment of bleeding episodes and total annualized consumption of Altuviiio are shown in Appendix 1 (the XTEND-1 study) and Appendix 2 (the XTEND-Kids study).

Harms

All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1. The primary focus of AE reporting was on TEAEs. An AE with incomplete or missing date or time of onset (occurrence, worsening, or becoming serious) was classified as a TEAE unless there was definitive information to determine it was a pretreatment AE.

The occurrence of embolic and thrombotic events was also described. Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging. The analysis consisted of a search of TEAE data using the embolic and thrombotic events Standardized MedDRA Query.

Table 8: Summary of Outcome Measures and Their Measurement Properties

Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; HJHS = Hemophilia Joint Health Score; MID = minimal important difference; OHS = Oxford Hip Score; PROMIS = Patient-Reported Outcomes Measurement Information System; SD = standard deviation; WFH = World Federation of Hemophilia.

Statistical Analysis

Sample Size and Power Calculation

XTEND-1 Trial

The sample size in the XTEND-1 study was based on risk of immunogenicity, the primary end point, and the key secondary end point.

• Immunogenicity: To rule out a greater than acceptable risk of immunogenicity, assuming a dropout rate of 15% with a sample size of 124 patients in the prophylaxis arm, there would be 104 evaluable patients with 50 exposure days or more. If 2 patients or less out of 104 evaluable patients develop an inhibitor, then the upper bound of an exact 95% CI would exclude 6.8%, a threshold determined at the FDA FVIII Inhibitor Workshop that was held in 2003.

• Primary end point: The primary efficacy objective of this study was to evaluate the efficacy of Altuviiio weekly prophylaxis as estimated by the mean ABR and 1-sided 97.5% CI in arm A. Based on currently marketed FVIII products, the mean ABR during clinical trials ranges from approximately 2 bleeds to 5 bleeds per year but can be as high as 6 bleeds per year.^73-76 To show adequate control of bleeding consistent with currently marketed FVIII products, and to account for this variability, a clinically meaningful treatment effect may be claimed if the upper bound of the CI of the estimated ABR is 6 or less. In a phase III study of a recombinant FVIII Fc fusion protein, the mean ABR for an individualized prophylaxis arm was 2.9 and the dispersion factor was estimated at 2.3.⁵⁴ Based on 2,000 simulations of a negative binomial regression model with mean ABR of 2.9 and dispersion factor of 2.3, a sample size of 124 patients will provide at least 90% power for the upper bound of the CI to exclude an ABR greater than 6, assuming a 15% dropout rate.

• Key secondary end point: For the key secondary efficacy end point, an intrapatient comparison of ABR during the Altuviiio weekly prophylactic treatment period versus the historical prophylaxis ABR was performed using noninferiority testing for patients in arm A. The noninferiority margin was estimated based on the known treatment effect between on-demand and prophylactic treatment. A meta-analysis of phase III registrational studies for recombinant FVIII products that include both on-demand and prophylactic treatment arms estimated an average reduction of 31 bleeds per year between on-demand and prophylactic treatment regimens. The lower bound of this treatment effect was 27 bleeds per year. Using a fixed margin approach to maintain a substantial amount (85%) of the treatment effect results in a noninferiority margin of 4. For a noninferiority test, a sample size of 63 achieves 90% power to detect noninferiority using a 1-sided paired Wilcoxon signed rank test at a 0.025 significance level when the actual mean of paired differences is 0 and the noninferiority margin is 4. Without prior knowledge of the SD of the paired differences, a conservative estimate of 10 was assumed. To account for dropout and the use of the PPS, a total of at least 75 subjects who had completed 6 or more months of participation in the observational prestudy 242HA201/OBS166221 were to be enrolled in arm A.

XTEND-Kids Trial

In the XTEND-Kids study, the primary end point was FVIII inhibitor development and key secondary end points were bleeding outcomes including ABR and AjBR. The determination of the number of patients was based on clinical rather than statistical considerations. Taking into consideration the guideline from the Committee for Medicinal Products for Human Use,⁷⁷ approximately 65 previously treated patients would need to be enrolled to obtain 50 or more patients with 50 or more exposure days at the end of the study. At least 12 patients in each age cohort needed to have completed adequate blood sample collection to assess key PK parameters.

Statistical Testing

XTEND-1 Trial

In the XTEND-1 trial, the primary end point, key secondary end point, and selected secondary end points of high clinical importance in hemophilia treatment were tested hierarchically to maintain the overall type I error rate of 0.05 or less. The end points included in the hierarchy were measured in arm A (the prophylaxis arm) in the following order.

• Primary end point: The primary efficacy end point was ABR in arm A. The primary analysis of the primary end point estimated mean ABR and 1-sided 97.5% CI using a negative binomial model for the weekly prophylaxis arm (arm A) was based on the FAS. If the upper limit of the CI is less than or equal to 6, the weekly prophylactic treatment regimen was considered to have provided adequate bleeding control. Sensitivity analyses of the primary end point were performed using the PPS, and the FAS which included participants with an efficacy period of at least 26 weeks.

• Key secondary end point: A key secondary end point was intrapatient comparison of ABR during Altuviiio weekly prophylaxis versus ABR during historical prophylaxis — noninferiority analysis. The intraparticipant comparison of ABR between Altuviiio weekly prophylaxis and historical prophylaxis was performed using a negative binomial regression model accounting for overdispersion with the dependent variable as “total bleeding episodes,” covariate as “treatment regimen,” repeated variable as “subject,” and log time as an offset variable. The mean paired difference and 95% CI were estimated using the PPS (as primary analysis) and FAS (as supportive analysis). Noninferiority was declared if the upper bound of the 1-sided 97.5% CI is less than 4. As a supportive analysis, the noninferiority analysis was also performed using the Wilcoxon signed rank test using the PPS. The null hypothesis that the median difference is 4 or more will be tested against the alternative hypothesis that the median difference is less than 4. The null hypothesis was rejected if P was less than 0.025, establishing noninferiority of Altuviiio weekly prophylactic treatment to historical prophylaxis. The 95% CI of the median of the ABR difference was calculated using Walsh averages and a Hodges-Lehmann estimate of the median difference.

• Key secondary end point: Another key secondary end point was intrapatient comparison of ABR during Altuviiio weekly prophylaxis versus ABR during historical prophylaxis — superiority analysis. If noninferiority is achieved, then superiority was evaluated sequentially using a negative binomial regression model as specified previously. The paired ABR ratio and 95% CI were estimated using the FAS. The null hypothesis that the paired ABR ratio (Altuviiio: historical prophylaxis) is 1 or more was tested against the alternative hypothesis that the ABR ratio is less than 1. Superiority was declared if the upper bound of the 1-sided 97.5% CI is less than 1. A supportive analysis will also be performed for the superiority test when noninferiority is achieved. The mean paired ABR difference and 95% CI were estimated using the same negative binomial regression model as specified previously based on the FAS. The null hypothesis that the paired ABR difference is 0 or more was tested against the alternative hypothesis that the ABR difference is less 0. Superiority was declared if the upper bound of the 1-sided 97.5% CI is less than 0.

• Selected secondary end points: These included Haem-A-QoL Physical Health domain, PROMIS Pain intensity 3a first item (i.e., PAINQU6), and HJHS total score. These outcomes were analyzed as a change from baseline to week 52. The change from baseline to week 52 was analyzed using a mixed-effects model with repeated measures (MMRM) analysis using observed data in arm A and excluding visits that are coincidental with a major surgical or rehabilitation period. The MMRM model included the baseline value of the end point as a covariate and visit as a fixed effect. The adjusted mean change in Haem-A-QoL Physical Health score from baseline to week 52, along with its 95% CI, were estimated by the MMRM model. A sensitivity analysis was performed for study participants who rolled over from the lead-in observational study using the same MMRM model.

XTEND-Kids Trial

All analyses in the XTEND-Kids trial were descriptive in nature and adjustments for multiplicity were not applied.

Sensitivity Analyses

A summary of the sensitivity analyses for select end points is provided in Table 9. Sensitivity analyses of the primary end point were performed using the PPS, and with FAS, including participants with an efficacy period of at least 26 weeks.

Subgroup Analyses

XTEND-1 Trial Primary End Point: ABR in Arm A

To assess the homogeneity of the treatment effect across various subgroups, analyses were performed on the primary end point across the following subgroups (categories with < 5 patients could be combined with other categories):

• by age (12 to 17 years, 18 to 64 years, ≥ 65 years)

• baseline bleeding phenotype (estimated bleeds in prior 12 months = 0, < 0 to 5, > 5 to 10, or > 10)

• by number of target joints (none, less than or equal to median of number present, greater than median of number present)

• by dosing and dosing interval compliance (< 80%, ≥ 80%).

The estimated mean ABR and the corresponding 95% CI were provided, using a negative binomial model for the weekly prophylaxis arm (arm A) based on the FAS for each subgroup, and using the same method as applied to the primary analysis. If the upper limit of the CI is less than or equal to 6, the weekly prophylactic treatment regimen was considered to provide adequate bleeding control.

XTEND-Kids Trial Secondary End Point: ABR

To assess the homogeneity of the treatment effect across various subgroups, analyses of the ABR were performed across the following subgroups (categories with < 5 patients could be combined with other categories):

• baseline bleeding phenotype (estimated bleeds in prior 12 months = 0, < 0 to 5, > 5 to 10, or > 10)

• by number of target joints (none, less than or equal to median of number present, greater than median of number present)

• by dosing and dosing interval compliance (< 80%, ≥ 80%).

The mean and 95% CI of ABR were estimated using a negative binomial model. The model included the number of treated bleeding episodes during the efficacy period as the response variable and the log-transformed duration of efficacy period as the offset variable to account for variable duration. Individual ABR was calculated for each participant and summarized descriptively. The summaries were presented by age cohort and overall, for the FAS.

Table 9: Statistical Analysis of Efficacy End Points

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; CI = confidence interval; FAS = full analysis set; FVIII = factor VIII; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; Haemo-QoL = Haemophilia Quality of Life questionnaire for children; HJHS = Hemophilia Joint Health Score; LOCF = last observation carried forward; MMRM = mixed-effects model of repeated measures; NA = not applicable; NR = not reported; PROMIS = Patient-Reported Outcomes Measurement Information System; SE = standard error.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Analysis Populations

Analysis populations of the XTEND-1 and XTEND-Kids trials are presented in Table 10.

Table 10: Analysis Populations of XTEND-1 and XTEND-Kids Trials

FAS = full analysis set; PK = pharmacokinetics; PKAS = pharmacokinetic analysis set; PPS = per-protocol set.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Results

Patient Disposition

Overall, 159 patients were included in the XTEND-1 trial. This consisted of 133 participants in arm A and 26 participants in the arm B. Participants in the arm B were assigned to on-demand treatment followed by prophylaxis. The XTEND-Kids trial included a total of 74 patients, with 38 aged younger than 6 years and 36 between the age of 6 years and 12 years. Screening failure rates were similar in both the XTEND-1 trial (6.5%; 11 of 170) and the XTEND-Kids trial (6.3%; 5 of 79). The proportion of patients who discontinued from the study in the XTEND-1 trial was 6.8% (9 of 133) in arm A and 3.8% (1 of 26) in arm B. In the XTEND-Kids trial, 5.3% (2 of 38) of patients who were in the cohort of patients aged younger than 6 years discontinued from study.

The reasons for discontinuation in the XTEND-1 trial were mostly withdrawn consent or prohibited concomitant medication; other reasons were cited for discontinuation in the XTEND-Kids trial. There were no reported important protocol deviations that could potentially influence the efficacy results in either the XTEND-1 or XTEND-Kids trial. The summary of patient disposition is presented in Table 11.

Table 11: Summary of Patient Disposition in XTEND-1 and XTEND-Kids Trials

FAS = full analysis set; NA = not available; PK = pharmacokinetics.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aAll patients who received at least 1 dose of study drug.

^bFAS population with at least 1 day of treatment for episodic regimen or at least 2 prophylactic injections for prophylactic regimen.

^cAll patients who received at least 1 dose of study drug.

^dA subset of FAS including patients who do not have important protocol deviations potentially impacting efficacy.

^ePatients who have completed adequate blood sample collection to assess key PK parameters, as determined by the PK scientist.

^fPatients who have evaluable PK profiles for both the baseline and repeat PK profiles, as determined by the PK scientist.

^gPatients who have undergone major surgery after the first dose of study drug.

^hPatients are without any major deviation related to COVID-19.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Baseline Characteristics

The baseline characteristics of the XTEND trials are summarized in Table 12. In the XTEND-1 study, the mean age of patients was 35.4 years (SD = 15.1 years), ranging from 12 years to 72 years; there were 25 (15.7%) adolescents patients aged 12 years to 17 years (all were in arm A), 129 (81.1%) adult patients aged 18 years to 64 years, and 5 (3.1%) patients aged greater than 65 years. One female patient was enrolled; all other patients were male. Additionally, most patients (78.6%) had no family history of FVIII inhibitors. In the 12 months before the study, the mean number of bleeding episodes reported was 3.2 (SD = 5.4) in arm A for patients who all previously received a different prophylactic regimen and 35.7 (SD = 22.2) in arm B patients who previously receiving on-demand treatment. When the analysis was restricted to a North American subset, the mean age of patients was 31.1 years (SD = 16.7 years), ranging from 12 years to 72 years. The majority of patients were male, excluding 1 female patient. Only 1 (3.9%) patient had a family history of inhibitors.

In the XTEND-Kids trial, all 74 pediatric patients were male with a mean age of 6.0 years (SD = 2.9 years); ages ranged from 1.4 years to 11.0 years. The majority (77%) had no family history of an inhibitor. In the 12 months before the study, the mean bleeding episodes in patients on a prophylactic regimen was 2.1 (SD = 4.2) in the overall study population.

Table 12: Summary of Baseline Characteristics From Studies Included in the Systematic Review

FVIII = factor VIII; SD = standard deviation; VWF = von Willebrand factor.

Notes: Percentages based on the number of patients with nonmissing data in the full analysis set.

Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aA target joint was defined as a major joint with at least 3 spontaneous bleeding episodes in a consecutive 6-month period before study entry.

^bValues for the Hemophilia Joint Health Score range from 0 to 124, with higher scores indicating worse joint health.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

The mean bleeding episodes and bleeding into joint in the past 12 months were both higher in the XTEND-1 trial compared to the XTEND-Kids trial. The baseline characteristics outlined in Table 12 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

Exposure to Study Treatments

All 159 patients included in the XTEND-1 study received at least 1 dose of Altuviiio. A total of 152 (95.6%) patients were treated for at least 39 weeks and 98 (61.6%) patients for at least 52 weeks. The overall mean duration of Altuviiio dosing (calculated from the date and time of the first Altuviiio dose to the end date and time of the last treatment regimen in the study) was 49.64 weeks (SD = 8.34), 49.76 (SD = 8.74) in arm A and 26.13 (SD = 1.21) in arm B with on-demand treatment, and 22.89 (SD = 6.00) in arm B with prophylactic treatment. Of the 159 patients who received at least 1 dose of Altuviiio, 115 (72.3%) had 50 or more exposure days. The mean total number of exposure days was 48.4 (SD = 10.5) in the overall population, 50.9 (SD = 9.1) in arm A, 11.9 (SD = 4.3) in arm B with on-demand treatment, and 23.8 (SD = 6.1) in arm B with prophylactic treatment. The mean total numbers of injections per patient were similar to the respective mean number of exposure days in each arm.

In the XTEND-Kids trial, all the 74 pediatric patients received at least 1 dose of Altuviiio, 66 (89.2%) achieved 50 or more exposure days, with 31 (81.6%) patients in the cohort aged younger than 6 years and 35 (97.2%) patients in the cohort aged 6 years to younger than 12 years. There were 73 (98.6%) patients treated for at least 39 weeks and 56 (75.7%) patients treated for at least 52 weeks. The overall mean duration of Altuviiio dosing was 51.08 weeks (SD = 6.15 weeks), 49.80 weeks (SD = 8.40 weeks) in the cohort aged younger than 6 years and 52.43 weeks (SD = 0.85 weeks) in the cohort aged 6 years to younger than 12 years. The total number of exposure days was 52.5 (SD = 7.2) in the overall population, 51.2 (SD = 8.6) in the cohort aged younger than 6 years and 53.9 (SD = 4.9) in the cohort aged 6 years to younger than 12 years; the mean total number of injections per patient were similar to the respective mean number of exposure days in each age cohort.

Table 13: Summary of Patient Exposure From Studies Included in the Systematic Review

ED = exposure day; SD = standard deviation.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aAn ED is a 24-hour period in which ≥ 1 Altuviiio injections are given. All injections over the study course are counted. For the XTEND-1 trial, the count from the overall column is the summation of EDs from arm A and arm B overall (i.e., the total EDs are based on the final treatment regimen that patients arrive at; thus, the overall count might not be equal to the summation of the count from the columns of treatment arm and regimen).

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Concomitant Medications

Table 14 summarizes the concomitant medication used in the XTEND-1 trial. Most of the patients in the XTEND-1 trial (n = 147; 92.5%) received at least 1 concomitant medication during the study. The most frequently used concomitant medication was paracetamol in 65 (40.9%) patients, tozinameran in 57 (35.8%) patients, and celecoxib in 25 (15.7%) patients. Medication for hemophilia-related pain was taken by 115 (72.3%) patients. In total, 4 patients in arm A took a prohibited concomitant medication (FVIII products other than Altuviiio in 3 patients and Aspirin in 1 patient) that was reported as a major deviation to the protocol. This use of FVIII products other than Altuviiio was prohibited and led to permanent study treatment discontinuation unless it occurred in a life-threatening emergency or as a result of an accidental use.

In the XTEND-Kids trial, the use of concomitant medications or procedures were reported by 59 (79.7%) and 9 (12.2%) patients, respectively, in the safety analysis set. The most frequently used concomitant medications (in > 10% of patients) were paracetamol in 42 (56.8%) patients, tranexamic acid in 13 (17.6%) patients, sodium chloride in 9 (12.2%) patients, amoxicillin in 9 (12.2%) patients, and tozinameran in 8 (10.8%) patients. Medication for hemophilia-related pain was taken by 6 (8.1%) patients within 14 days before study visits.

Efficacy

XTEND-1 Trial

A summary of key efficacy outcomes in the XTEND-1 trial are presented in Table 15.

Bleeding Outcomes

Annualized bleeding rate: The primary efficacy end point in the XTEND-1 trial was ABR in arm A (prophylaxis arm) assessed at week 52. In the FAS, a total of 86 bleeding episodes were treated with Altuviiio in 133 patients in arm A during the efficacy period. The median ABR at week 52 was 0.00 (IQR, 0.00 to 1.04) and the mean ABR was 0.71 (95% CI, 0.52 to 0.97). In arm A, 131 (98.5%) patients had 5 or fewer bleeding episodes per year and 86 (64.7%) patients had no bleeding episodes during the study (Table 15). Two sensitivity analyses of the mean ABR at 52 weeks were performed and both results were consistent with those of the primary analysis.

Table 14: Concomitant Medication (≥ 10% of Patients in Either Treatment Arm) in XTEND-1 and XTEND-Kids Trials — Safety Analysis Set

^aMedications are coded using the World Health Organization Drug Dictionary.

Source: XTEND-1 Clinical Study Report⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Annualized joint bleeding rate: Results for AjBR were consistent with the results for ABR. In arm A, 37 patients in the FAS had a total of 61 treated joint bleeds. The estimated mean AjBR at week 52 was 0.51 (95% CI, 0.36 to 0.72). Of the 133 patients in arm A, 131 (98.5%) patients had an AjBR of 5 or fewer episodes per year with 96 (72.2%) patients having no joint bleeds during the study.

In arm B, the estimated mean AjBR at week 52 was 17.48 (95% CI, 14.88 to 20.54). The mean AjBR in arm B was similar to arm A after patients had switched to prophylactic treatment (mean = 0.62; 95% CI, 0.25 to 1.52). In an intrapatient comparison of AjBR in arm B, the joint bleeding rate ratio for prophylaxis versus on-demand treatment was 0.04 (95% CI, 0.01 to 0.08). Nine patients (34.6%) had an AjBR of more than 20 with on-demand treatment while no patients had an AjBR greater than 5 with prophylactic treatment.

Intrapatient Comparison of ABR

Intrapatient comparison of ABR between Altuviiio prophylaxis versus historical prophylaxis: Overall, the number of patients with an ABR of 0 who had historical prophylaxis or Altuviiio was 42.3% and 64.1%, respectively. In the FAS (n = 78), the intrapatient comparison in arm A reported a mean ABR reduction of 77% (ABR ratio = 0.23; 95% CI, 0.13 to 0.42; P < 0.0001) in the efanesoctocog prophylaxis group compared to historical prophylaxis. The assessment for noninferiority based on the PPS met the prespecified criteria. In the PPS (n = 77), intrapatient comparison between Altuviiio prophylaxis and historical prophylaxis led to a MD of −2.30 (95% CI, −3.49 to −1.11).

Intrapatient comparison of ABR between prophylaxis and on-demand use of Altuviiio: For the 26 patients in arm B, the efficacy of weekly prophylaxis in terms of ABR was compared to on-demand treatment with Altuviiio, as a secondary end point. The bleeding rate ratio for prophylaxis versus on-demand treatment was 0.03 (95% CI, 0.02 to 0.07). With on-demand treatment, most patients (96.2%) had an ABR of more than 10; whereas, after switching to prophylactic treatment, most patients (76.9%) had no bleeds.

Physical Functioning and Pain (QoL)

Haem-A-QoL Physical Health score and Haem-A-QoL score: In the XTEND-1 study, QoL data were collected in adult patients aged 17 years or older via the Haem-A-QoL Physical Health score and in adolescent patients aged 12 years to 16 years via the Haem-A-QoL. In arm A, for patients aged 17 years or older (n = 98), the estimated mean change from baseline to week 52 in Haem-A-QoL Physical Health score was –6.74 (95% CI, –10.13 to –3.36; P = 0.0001). The Haem-A-QoL results in the study’s adolescent population (all in arm A) mirrored those of the group aged 17 years or older, with improvements in Haem-A-QoL Physical Health score (mean change from baseline to week 52 = –2.18 [SD = 22.05]) and total score (mean change from baseline to week 52 = –3.45 [SD = 8.83]) in the group aged 13 years to 16 years (n = 18). In arm B, a mean change in Haem-A-QoL Physical Health score of –25.91 (SD = 22.29) by week 52 was reported. A sensitivity analysis performed for patients aged 17 years or older in arm A who had rolled over from the OBS16221 study (n = 66) also showed an improvement in Haem-A-QoL Physical Health score (LS mean change from baseline to week 52 = –4.04; 95% CI, –8.06 to –0.03).

PROMIS Pain Intensity and Physical Function: Item 3a of the PROMIS instrument assessed a patient’s worst pain in the last 7 days. This item was used to assess pain intensity in the XTEND trials. In arm A, in participants aged 12 years or older, the estimated mean change from baseline to week 52 in pain intensity was a difference in score of –0.21 (95% CI, –0.41 to –0.02). In arm B, the mean change from baseline to week 52 pain intensity was a difference in score of –0.77 (SD = 0.81).

The PROMIS instrument was also used to assess physical function in adult patients only (aged at least 18 years). In arm A, of 108 patients, 103 completed the PROMIS Short Form Physical Function questionnaire at baseline and 102 at week 52. The mean Physical Health score at baseline was 46.80 (SD = 8.82) and 47.35 (SD = 9.28) at week 52 and the mean change from baseline to week 52 of 0.62 (SD = 4.77).

Joint Health

HJHS: In arm A, the mean HJHS total score at baseline was 18.1 (SD = 18.4). The estimated mean change in the HJHS total score from baseline to week 52 was −1.54 (95% CI, −2.70 to −0.37; P = 0.0101). In arm B, the mean change from baseline to week 52 in HJHS total score was −4.1 (SD = 8.7). A sensitivity analysis performed using the data of patients in arm A who rolled over from the prospective observational OBS16221 study also showed an improvement in HJHS total score. The LS mean change from baseline to week 52 was −0.86 (95% CI, −2.38 to 0.66).

Table 15: Summary of Key Efficacy Results From the XTEND-1 Trial (Full Analysis Set)

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; aPTT = activated partial thromboplastin time; CI = confidence interval; FAS = full analysis set; FVIII = factor VIII; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; HJHS = Hemophilia Joint Health Score; IQR = interquartile range; NA = not available; PROMIS = Patient-Reported Outcomes Measurement Information System; QoL = quality of life; SD = standard deviation.

Note: All data are reported for FAS unless otherwise stated. Mean change from baseline is reported for mean change from baseline at week 52.

^aEstimated using a negative binomial model with the total number of treated bleeding episodes during the efficacy period as the response variable and log-transformed efficacy period duration (in years) as an offset variable.

^bEstimated using a repeated negative binomial model with treatment (Altuviiio prophylaxis versus historical prophylaxis) as covariate.

^cAchieving trough FVIII activity levels > x% are based on average trough samples from each scheduled visit using the aPTT-based 1-stage clotting assay. Patients with trough samples outside 168 ± 5 hours from previous dose are excluded from this analysis.

Source: XTEND-1 Clinical Study Report.⁵⁴

XTEND-Kids Trial

A summary of key efficacy outcomes in the XTEND-Kids trial is presented in Table 16.

FVIII Inhibitor Formation

Inhibitor development to FVIII: The primary end point of the XTEND-Kids study was the occurrence of inhibitor development against FVIII based on all patients who had reached at least 50 exposure days. Overall, 65 patients who had reached at least 50 exposure days were analyzed for inhibitors. The incidences of inhibitor development to FVIII were 0.0% (95% CI, 0.0 to 5.5) in patients with 50 or more days of exposure to Altuviiio and 0.0% (95% CI, 0.0 to 4.9) in all treated patients.

Bleeding Outcomes

Annualized bleeding rate: The overall mean ABR at week 52 was 0.89 (95% CI, 0.56 to 1.42) and a median ABR was 0 (IQR, 0 to 1.02). Of the 74 patients, 47 (63.5%) had an ABR of 0 and 25 (33.8%) had an ABR of greater than 0 to 5 at 52 weeks. Two patients in the cohort aged 6 years to younger than 12 years had a higher ABR with 7.2 in 1 patient and 21.4 in the other patient. A total of 64 bleeding episodes were treated with Altuviiio in 27 of the 74 patients (17 bleeding episodes in 14 patients in the cohort aged < 6 years and 47 bleeding episodes in 13 patients in the cohort aged < 12 years). Results of sensitivity analyses based on mean ABR at 52 weeks on the PPS or mean ABR on FAS including patients with data at week 26 were consistent with the primary analysis.

Annualized joint bleeding rate: In the FAS, there were a total of 42 treated joint bleeds throughout the study. The overall estimated mean AjBR was 0.59 (95% CI, 0.27 to 1.28), with 0.19 (95% CI, 0.06 to 0.62) in the cohort aged younger than 6 years and 0.99 (95% CI, 0.38 to 2.60) in the cohort aged 6 years to younger than 12 years. Of the 74 patients who had an efficacy period, 61 (82.4%) patients reported no joint bleeds, while 12 (16.2%) patients reported 1 to 5 joint bleeds. One (1.4%) patient had 21 joint bleeds as per analysis, 18 of which were not confirmed by the investigator nor reported by the patient. This patient received an intensive consolidation treatment regimen of Altuviiio 2 to 3 times per week for a total of approximately 4 months following the treatment of 2 traumatic hip bleeds. Consequently, the intensive consolidation therapy resulted in 18 derived “new” treated bleeds of unknown type as per statistical analysis A sensitivity analysis excluding the participant who did not receive the weekly prophylactic treatment for an extended period of time showed that the estimated mean AjBR in the cohort aged 6 years to younger than 12 years decreased to 0.41 (95% CI, 0.19 to 0.89) and the overall estimated mean AjBR to 0.30 (95% CI, 0.16 to 0.57)

Physical Functioning and Pain (QoL)

Haemo-QoL: QoL data were assessed using the Haem-A-QoL total score for patients between the age of 4 years and 7 years, and the Haemo-QoL Kids Short Version was used for patients of at least 8 years of age. For patients aged 4 years to 7 years, 8 years to younger than 12 years, and in respective caregivers, data were collected using 4 separated Haem-A-QoL. For patients between the age of 4 years and 7 years, the mean change from baseline to week 52 was −5.31 (SD = 10.83) in the cohort aged younger than 6 years and 4.69 (SD = 5.41) in the cohort aged 6 years to younger than 12 years. In patients aged 4 years to 7 years overall, the mean change from baseline to week 52 was −2.46 (SD = 10.49). Parents of children between the age of 4 years and 7 years were also asked to complete the Haem-A-QoL for a parent-proxy assessment of this outcome. For the overall group, the mean change from baseline based on the parent proxy was −2.85 (SD = 11.82), which is aligned with the patient-reported results. For patients aged 8 years and older, the mean change from baseline to week 52 was –9.79 (SD = 12.18).

PROMIS Pain Intensity and Physical Function: Similar to the XTEND-1 trial, pain intensity was assessed in the XTEND-Kids study using item “a” of the PROMIS Pediatric instrument as a change from baseline to week 52. For patients between the age of 5 years and 12 years, a parent or caregiver response was used as a proxy for the child. In the cohort of patients aged less than 6 years, the mean change from baseline was −0.44 (SD = 2.65) and for patients between the age of 6 years and 12 years, the mean change from baseline was −0.75 (SD = 2.53). Overall, the mean change from baseline was −0.62 (SD = 2.52). Patients between the age of 8 years and 12 years responded to this outcome independently. For patients aged 8 years or older in the cohort aged 6 years to 12 years, the mean change from baseline was 0.00 (SD = 2.98).

In the cohort aged younger than 6 years, 8 parents of participants aged 5 years or older completed the PROMIS Short Form Physical Function questionnaire at baseline, and 8 parents completed it at week 52. The mean change from baseline to week 52 was 3.96 (SD = 6.73; n = 7). In the cohort aged 6 years to younger than 12 years, 14 participants aged 8 years or older completed the PROMIS Short Form Physical Function questionnaire at baseline, and 16 participants at week 52. The mean change from baseline to week 52 was 0.78 (SD = 10.48; n = 10). In the cohort aged 6 years to younger than 12 years, 16 parents of participants aged younger than 12 years completed the questionnaire at baseline, and 16 parents at week 52. The mean change from baseline to week 52 was −1.36 (SD = 12.15; n = 10).

Joint Health

HJHS: In the XTEND-Kids study, the questionnaire primarily designed for children aged 4 years to 18 years was used. In the cohort aged younger than 6 years, 20 patients were aged 4 years or older and the mean change in HJHS total score from baseline to week 52 was 0.2 (SD = 8.3). In the cohort aged 6 years to younger than 12 years, the mean change in HJHS total score from baseline to week 52 was −1.1 (SD = 4.3) in 33 patients.

Response During Perioperative Management

Table 17 is a summary of the perioperative management outcomes of Altuviiio in the XTEND trials.

Number of injections and dose to maintain hemostasis during major surgery: A summary of the results available from both the XTEND-1 and XTEND-Kids studies for the use of Altuviiio for perioperative management of bleeding is available in Table 17.

Table 16: Summary of Key Efficacy Results From XTEND-Kids Trial (Full Analysis Set)

ABR = annualized bleeding rate; AjBR = annualized joint bleeding rate; aPTT = activated partial thromboplastin time; CI = confidence interval; FVIII = factor VIII; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; HJHS = Hemophilia Joint Health Score; IQR = interquartile range; NA = not available; PROMIS = Patient-Reported Outcomes Measurement Information System; QoL = quality of life; SD = standard deviation.

Notes: Mean change from baseline is reported for mean change from baseline at week 52.

Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aEstimated using a negative binomial model with the total number of treated bleeding episodes during the efficacy period as the response variable and log-transformed efficacy period duration (in years) as an offset variable.

^bAchieving trough FVIII activity levels > x% are based on average trough samples from each scheduled visit using the aPTT-based 1-stage clotting assay. Patients with trough samples outside 168 ± 5 hours from previous dose are excluded from this analysis.

Source: XTEND-Kids Clinical Study Report.¹⁷

In the XTEND-1 study, 11 of 12 major surgeries that occurred during the treatment regimen required a single injection of Altuviiio (i.e., the preoperative loading dose) to maintain hemostasis. The mean dose per injection was 41.65 IU/kg (SD = 15.21 IU/kg). For 1 surgery, conducted during routine prophylaxis, no preoperative loading dose was reported on the day before or the day of the surgery.

In the XTEND-Kids study, both major surgeries required a single injection of Altuviiio to maintain hemostasis. The mean dose per injection was 61.13 IU/kg (SD = 1.06 IU/kg).

Harms

XTEND-1 Trial

Harms data for the XTEND-1 trial are summarized in Table 18. The summary of harms is presented for arm A, arm B, and the overall population included in the XTEND-1 trial. CDA-AMC focused on reporting the harms results in the overall population rather than in different arms.

Table 17: Summary of Perioperative Management Outcomes (Surgery Subgroup) From XTEND-1 and XTEND-Kids Trials

SD = standard deviation.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aAnalysis is based on the major surgeries conducted during the treatment regimen, excluding the surgeries conducted after the last Altuviiio dosing.

^bThe number of injections to maintain hemostasis during surgery includes all injections, from loading dose (i.e., the preoperative injection, administered either on the day of surgery or one day before the surgery), to the end of surgery.

Source: XTEND-1 Clinical Study Report ⁵⁴ and XTEND-Kids Clinical Study Report.¹⁷

Adverse Events

Of the 159 patients in the safety analysis set, 123 (77.4%) patients experienced at least 1 TEAE, resulting in a total of 391 TEAEs in the study. The most frequently reported TEAEs in greater than 3% of patients overall were headache (20.1%); arthralgia (16.4%); fall (6.3%); back pain (5.7%); COVID-19 and fatigue (4.4% each); contusion, hemophilic arthropathy, and nasopharyngitis (3.8% each); and joint injury, pain in extremity, and toothache (3.1% each).

The majority of TEAEs were also assessed to be mild in severity. Of the 159 patients, 77 (48.4%) patients had no TEAEs classified as moderate or severe but at least 1 TEAE was classified as mild. In addition, 39 (24.5%) patients had no TEAEs classified as severe but at least 1 TEAE was classified as moderate, and 7 (4.4%) patients had at least 1 TEAE classified as severe. TEAEs classified as severe were reported in 1 (0.6%) of each of the 7 patients and included angina pectoris, CD4 lymphocytes decreased, pancreatic carcinoma metastatic, mobility decreased, migraine, status epilepticus, and device breakage. Of the 8 TEAEs assessed as severe, 6 were also classified by the investigator as SAEs.

Serious Adverse Events

A total of 18 TESAEs were experienced in 15 (9.4%) patients, of which 16 TESAEs were reported in 13 patients in arm A and 2 TESAEs in 2 patients in arm B. Hemophilic arthropathy was the most commonly reported SAE, which was reported in 2 (1.3%) patients in arm A. All other TESAEs were reported in 1 (0.6%) patient each. The majority of TESAEs were assessed by the investigator as mild to moderate in severity.

Withdrawals Due to AEs

Two TEAEs in 2 (1.3%) patients resulted in permanent treatment discontinuation. The reason for WDAE was due to a decrease in CD4 lymphocytes in 1 patient with a history of HIV infection (reported as a TESAE), and due to a combined tibia–fibula fracture in the other patient who withdrew due to an AE.

Mortality

Death was reported in 1 patient overall, in arm B. The patient had a medical history of hepatitis C virus and died of metastatic pancreatic carcinoma, which was reported as a TESAE. The TESAE was assessed by the investigator as not related to Altuviiio treatment.

AEs of Special Interest

AEs of special interest were chosen for their relevance to hemophilia A or treatment and were prespecified in the study protocols. These AEs included the development of inhibitors, grade 3 or higher allergic reactions or anaphylactic reactions, and embolic or thrombotic events (except for injection site thrombophlebitis). There were no reports of inhibitor development to FVIII during the study. There were no reports of grade 3 or greater allergic reactions or anaphylaxis in association with Altuviiio administration during the study. There were no reports of embolic and thrombotic events during the study.

Table 18: Summary of Harms Results From XTEND-1 Trial (Safety Analysis Set)

CD4 = clusters of differentiation 4; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event; WDAE = withdrawal due to adverse event.

Source: XTEND-1 Clinical Study Report.⁵⁴

XTEND-Kids Trial

A summary of harms for the XTEND-Kids study is available in Table 19.

Adverse Events

Of the 74 patients in the safety analysis set, 62 (83.8%) experienced at least 1 TEAE, resulting in a total of 255 TEAEs. The most frequently reported TEAEs (in > 5% of patients overall) were SARS-CoV-2 test positive and upper respiratory tract infection (14.9% each); pyrexia (12.2%); asymptomatic COVID-19 (9.5%); gastroenteritis viral, head injury, and nasopharyngitis (8.1% each); arthralgia, pain in extremity, and vomiting (6.8% each); and contusion, diarrhea, viral infection, and viral upper respiratory tract infection (5.4% each). The majority of TEAEs were assessed by the investigator as mild in severity. Of the 74 patients, 43 (58.1%) patients had at least 1 TEAE of mild intensity and 13 (17.6%) patients had at least 1 TEAE of moderate intensity. There were 6 (8.1%) patients with at least 1 TEAE classified as severe. Of those with severe TEAEs, 3 patients aged younger than 6 years reported bacteremia, circumcision, or a fear of injection and 3 patients aged 6 to less than 12 years reported an eosinophilic esophagitis, vascular device occlusion, or chest or head injury. All patients with severe events recovered except 1 patient with extreme fear of blood draw who prematurely withdrew from the study 4 months later.

Table 19: Summary of Harms Results From XTEND-Kids Trial (Safety Analysis Set)

MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event; WDAE = withdrawal due to adverse event.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: XTEND-Kids Clinical Study Report.¹⁷

Serious Adverse Events

A total of 10 TESAEs were experienced in 9 (12.2%) patients, of which 5 TESAEs were reported in patients aged younger than 6 years and 5 TESAEs in patients aged 6 years to younger than 12 years. All TESAEs were reported in 1 (1.4%) patient each, except vascular device infection, which was reported in 2 (2.7%) patients. The majority of TESAEs were assessed by the investigator as mild to moderate in severity. The 5 TESAEs assessed by the investigator as severe were TESAEs of circumcision and bacteremia, each in 1 patient aged less than 6 years and TESAEs of vascular device occlusion, head injury, and eosinophilic esophagitis, each in 1 patient aged 6 years to less than 12 years.

Withdrawals Due to AEs

Although 1 patient withdrew from the study after 4 months due to extreme fear of blood draw, no patients discontinued Altuviiio treatment due to a TEAE during the study.

Mortality

There were no deaths reported during the study.

AEs of Special Interest

An event of “hives around eyes, mouth, face, and chest” was reported in one 2-year-old patient. The event occurred approximately 3 months after the first dose of Altuviiio (used for weekly prophylaxis) and 3 days after the last injection. There were no reports of embolic and thrombotic events during the study.

Critical Appraisal

Internal Validity

The 2 pivotal trials identified in the sponsor-conducted SLR were phase III, single-arm, open-label clinical trials (XTEND-1 and XTEND-Kids). Patients enrolled in both trials were previously treated with FVIII products for at least 6 months before baseline. In the XTEND-1 trial, 92 patients (n = 82 in arm A and n = 10 in arm B) were rolled over from an observational prestudy (242HA201/OBS16221) that assessed treatment patterns and outcomes in patients with severe hemophilia A previously treated with marketed FVIII replacement products. There were missing data related to efficacy outcomes such as FVIII inhibitor formation (patients with ≥ 50 exposure days), HJHS, and pain and physical function outcomes. Missing data on such critical outcomes are a potential risk of bias or imprecision regarding the efficacy of Altuviiio. Although the nonrandomized, open-label, single-arm design limits the interpretation of the efficacy results for both the XTEND-1 and XTEND-Kids studies, the clinical experts consulted by CDA-AMC for this review indicated that while traditional RCTs remain the gold standard for many conditions, it is not feasible in hemophilia A due to ethical constraints, challenges in patient recruitment, and the availability of effective treatments. According to the clinical experts, alternative designs like intrapatient comparisons and historical controls provide practical evaluation of new therapies such as Altuviiio.

The clinical experts indicated that the exclusion and inclusion criteria for the XTEND-1 and XTEND-Kids trials aligned with the patients they treat in clinical practice. It was noted that participants in both trials were previously treated patients with hemophilia A without inhibitors. Although the XTEND-1 trial started after the completion of the prestudy observational study, only 92 out of 156 participants were rolled over to the XTEND-1 study. All rolled over patients from the prestudy observational study were previously treated (≥ 150 exposure days) with any recombinant FVIII or plasma-derived FVIII product (prophylaxis or on demand). Although an appropriate washout period of 96 hours or longer for the rolled over patients who previously received a marketed FVIII product was observed, the criteria for enrolling patients from the prestudy observational study to the XTEND-1 study were not provided by the sponsor. This was determined by CDA-AMC as a potential selection bias. Additionally, although the sponsor provided data on the baseline characteristics of all patients in the prestudy observational study and those of the XTEND-1 study, the baseline clinical characteristics of the rolled over patients alone were not provided. CDA-AMC notes that this limits the ability to identify preexisting differences, potentially introducing bias and confounding; however, although this is speculative, the clinical experts indicated that the rolled over patients and those in the XTEND-1 study were likely similar and were not systematically different.

Patient compliance with FVIII prophylactic treatment during the prestudy observational study remained unclear, as the sponsor did not provide summary-level statistics on compliance. Although CDA-AMC recognizes that in the XTEND-1 study, a patient was considered compliant if their compliance rate was at least 80%, the reliability of the intrapatient comparison of ABR remains a concern. Although retention and compliance in the XTEND-Kids study was reported to be high, CDA-AMC notes that the administration of FVIII in the XTEND-Kids study is particularly challenging because it can be difficult to obtain venous access in children, the time commitment required for infusion may hinder compliance, and the cost associated with frequent administration may be burdensome. In both trials, efficacy was measured using ABR, a widely accepted end point in hemophilia research that provides an objective outcome.⁷⁸ Joint health and QoL were measured using the HJHS and Haem-A-QoL, which are validated outcome measures although still subject to some patient-reported bias, especially in open-label trials. Both trials appear to be adequately powered for assessing ABR and joint health outcomes, with sample sizes of 159 in the XTEND-1 study and 74 in the XTEND-Kids study, which should provide a robust estimate of efficacy for this population. However, smaller subgroup analyses, such as surgery, perioperative management, or specific age groups, may not be fully powered to detect efficacy in subpopulations. Both trials included follow-up safety assessments for 2 weeks to 3 weeks after the last dose; however, a longer follow-up period is needed to sufficiently evaluate delayed effects, which is critical for assessing the long-term efficacy and safety of Altuviiio. Although an interim report on the LTE study concerning safety of Altuviiio is consistent with results from the XTEND trials, complete results are needed to evaluate long-term safety outcomes.

In the primary analyses, documentation of bleeding events in both trials via electronic patient diary or electronic case report form was reviewed and assessed by the investigator. CDA-AMC notes that investigator-reviewed documentation of bleeding events could overestimate the efficacy of Altuviiio, particularly on bleeding outcomes such as ABR, AjBR, and intrapatient comparison of ABR. This risk arises from potential reporting bias, subjective assessments, underreporting, and potentially inconsistent bleeding event verification. The absence of independent adjudication and differences in documentation methods is also of concern. While the XTEND-1 study included a historical control through intrapatient comparison of ABR based on patients’ prior prophylactic regimens in a previous study, this approach is inherently weaker compared to a concurrent randomized control group as the reliance on historical data may introduce variability due to changes in patients' characteristics or external factors unrelated to treatment efficacy. This may result in potential confounding, particularly due to temporal events. For example, the clinical experts consulted for the review noted that physical activity is an important indicator of hemophilia A disease outcome. Given that the XTEND-1 trial was conducted during the COVID-19 pandemic while the prestudy observational study was conducted some years before pandemic, impact from possible change in physical activities related to the social distancing that was required on many occasions during the pandemic (e.g., intensity, types of physical activities) on the risk of bleeding in patients with hemophilia is uncertain. However, the clinical experts consulted by CDA-AMC did not expect this to significantly impact the results. Additionally, although the study design was deemed appropriate for data collection across varied populations, the lack of blinding introduces bias, as both participants and investigators were aware of the treatment, which could influence patient-reported outcomes such as physical function and pain outcomes (Haem-A-QoL, Haemo-QoL, PROMIS Pain Intensity) and therefore reliable assessments of these outcomes could not be made.

In both trials, perioperative management outcomes were assessed based on the rating of response by the surgeon or study investigator, as well as the number of injections and mean dose needed to maintain hemostasis per major surgery. Specifically, the investigators or surgeons who completed the surgical procedures assessed the participant’s response to surgery with efanesoctocog treatment using a 4-point clinical scale: excellent, good, fair, and poor. This assessment was to be performed 24 hours after the surgery. The clinical experts consulted for this review noted that there is no available objective evaluation of perioperative outcomes. CDA-AMC notes that the reliance on the opinion of the surgeon seems subjective and likely a potential source of bias to inform decision-making especially given that several surgeons or investigators were involved in the study.

Concomitant medications were reported by 92.5% and 79.7% in the XTEND-1 and XTEND-Kids studies, respectively. In both trials, paracetamol was reported as the most frequently used concomitant medication followed by tozinameran and tranexamic acid. In the XTEND-1 trial, medication for hemophilia-related pain was taken by 115 (72.3%) patients and 4 patients took a prohibited concomitant medication (FVIII products other than Altuviiio in 3 patients and Aspirin in 1 patient), and this was reported as a major deviation to the protocol. In the XTEND-Kids trial, medication for hemophilia-related pain was taken by 6 (8.1%) patients within 14 days before study visits overall. According to the clinical experts consulted by CDA-AMC, there were no serious concerns with the use of these prohibited concomitant medications unless they were taken by accident or occurred in life-threatening emergency situations.

In the XTEND-1 trial, the primary end point, key secondary end point, and selected secondary end points of high clinical importance in hemophilia treatment were tested hierarchically to maintain the overall type I error rate of 0.05 or less. All analyses in the XTEND-Kids trial were descriptive and did not include adjustments for multiplicity. There were some concerns about the assumptions for the statistical model that were adopted to inform the relative efficacy of Altuviiio against historical prophylaxis. The use of a negative binomial regression model in the XTEND-1 trial to estimate intrapatient ABR, although considered appropriate by the clinical experts, presents specific challenges. While the approach reduces variability by using patients as their own controls, concerns include potential misalignment with model assumptions, such as overdispersion and handling of excess zeros, which could bias estimates. Additionally, unmeasured confounders, patient heterogeneity, and missing or incomplete prestudy data may limit the reliability of comparisons. The high proportion of zero ABRs during prophylaxis suggests that alternative models, like zero-inflated regression, might better capture the data distribution. Additionally, the assumption that a negative binomial model implies a constant bleed rate within each period of study, can make it challenging to interpret the magnitude of the effect estimates of Altuviiio compared to historical prophylaxis. This is of particular concern as the prestudy observational study and the trial were conducted before and during the pandemic, respectively, likely impacting the overall bleeding rate. Specifically, the reported estimates of the relative ABRs describe a weighted average of the rate of bleeding over time. CDA-AMC notes that this weighted average can be overly optimistic and fail to accurately capture waning efficacy over time.

External Validity

CDA-AMC identified several considerations related to the generalizability of the XTEND-1 and XTEND-Kids studies in evaluating the efficacy and safety of Altuviiio. All patients included in the XTEND-1 and XTEND-Kids trials were patients with severe hemophilia A (< 1 IU/dL [< 1%] endogenous FVIII activity) who had been on previous prophylaxis or on-demand treatment with any recombinant and/or plasma-derived FVIII or cryoprecipitate for at least 150 exposure days. According to the clinical experts, this is reflective of current Canadian clinical practice where the standard of care for patients with severe hemophilia A is treatment with FVIII prophylaxis. The inclusion of both adults and children and patients from 6 study sites in Canada and from multiple countries across Asia, Europe, North America, and South America enhances the generalizability of the findings. The clinical experts consulted by CDA-AMC indicated that selection of eligible patients for treatment with Altuviiio should follow the inclusion and exclusion criteria used in both pivotal trials.

The results of the XTEND-1 and XTEND-Kids studies may have limited generalizability to the population of patients living in Canada as the study population was restricted to patients (without inhibitors) with severe hemophilia A. According to clinical experts consulted for this review, there is a subset of patients with mild or moderate hemophilia who require prophylaxis. The design of the XTEND-1 and XTEND-Kids studies did not include these patients. CDA-AMC notes that the magnitude of treatment effect in patients with mild and moderate hemophilia A is unclear. Additionally, CDA-AMC notes that the exclusion of patients with FVIII inhibitors limits the applicability of findings to new patients who have a higher risk of developing inhibitors such as those who have not received previous FVIII therapies. However, the clinical experts noted that patients are generally closely monitored for inhibitor development during the first few weeks of starting treatment. The impact of including patients with severe hemophilia A with a history of at least 12 bleeding episodes within 12 months, although acceptable, may exaggerate the efficacy of Altuviiio compared to what is seen in clinical practice as data on patients with mild or moderate hemophilia A are not available and generalizability to those patients remains uncertain. As a result, the magnitude of treatment effect in patients with less than 12 bleeding episodes within 12 months, especially for patients receiving on-demand therapy, compared to those included in the trials is unknown. There is limited evidence from an intrapatient comparison that supports efficacy of Altuviiio in patients previously treated with FVIII prophylaxis. Although the clinical experts indicated the difficulty in the direct comparison of efanesoctocog with other FVIII therapies, CDA-AMC notes that the lack of direct head-to-head comparison with the current standard of care, such as EHL FVIII products or nonfactor therapies like emicizumab, limits external validity regarding the real-world effectiveness and safety of Altuviiio compared to these alternative treatments. The lack of baseline data from the rolled over participants from the prestudy observational study also limits the generalizability and robustness of intrapatient comparisons, which rely on baseline data.

All patients included in the XTEND-1 and the XTEND-Kids trials were male except the inclusion of 1 female in the XTEND-1 trial. This was not considered to be an issue for the external validity of the study as hemophilia A predominantly affects males. Because hemophilia A can affect females, the clinical experts indicated that there is no biological reason that the safety and efficacy of Altuviiio would differ in females. According to the clinical experts, the once-weekly dosing of 50 IU/kg used in the trials aligns with the standard of treatment in hemophilia treatment centres, making it applicable to clinical settings. Specific subgroups, such as patients with obesity or those participating in higher physical activity, may require adjusted dosing, which was not thoroughly explored in the trials, limiting the generalizability of Altuviiio to these populations.

Results from the prestudy observational study included patients treated with EHL or SHL agents. However, information based on the type of FVIII concentrate (e.g., EHL versus SHL) that patients were previously treated with was not available as all patients were included in the analyses regardless of prior treatment with an EHL or SHL agent. According to the clinical experts consulted by CDA-AMC, the key difference between EHL and SHL FVIII agents in treating patients is the frequency of infusion. Due to its half-life, EHL FVIII may be associated with a lower ABR. However, this was not considered a serious generalizability issue by the clinical experts.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^14,15

• High certainty: Very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: Moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. The word “likely” is used for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. The word “may” is used for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: Very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. Evidence of very low certainty is described as “very uncertain.”

Although GRADE guidance is not available for noncomparative studies, the CDA-AMC review team assessed pivotal single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The target of the certainty of evidence assessment was the presence of a clinically important improvement in bleeding outcomes (ABR, AjBR), joint health (HJHS), physical function and pain (Haem-A-QoL, Haemo-QoL), and perioperative management, which were considered the most important outcomes to treatment by the clinical experts consulted for this review, and the clinician group and patient group inputs. According to the clinical experts, the target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the ABR and AjBR due to the lack of a formal estimate of a MID. According to the clinical experts, the target of the certainty of evidence assessment for perioperative management was the opinion of the surgeon’s or investigator’s rating of response due to the lack of a formal estimate of MIDs. The certainty of evidence was summarized narratively for the HJHS, Haem-A-QoL (Physical Health score and total score), and perioperative management as well as harms outcomes due to lack of comparator.

Results of GRADE Assessments

Table 2 and Table 3 present the GRADE summary of findings for Altuviiio for routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding in adults and children with severe hemophilia A.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

One LTE study was submitted for review, the XTEND-ed study (NCT04644575).¹⁸ The XTEND-ed LTE study is an ongoing phase III, open-label, multicentre study to assess long-term safety and efficacy of Altuviiio in previously treated patients with severe hemophilia A. The study began in February 2021 and is estimated for completion in 2027.¹⁸ At the time of this submission, the available evidence was limited to interim analyses based on conference presentations.^19,20 The reported data cut-off for the interim analysis was June 8, 2023. The submitted interim analyses pertain only to patients rolled over from the XTEND-1 and XTEND-Kids studies into arm A of the XTEND-ed LTE study and report on efficacy and safety-related outcomes over 2 additional years of treatment with Altuviiio.

The study comprises 3 treatment arms. Arm A included patients rolled over from the XTEND-1 and XTEND-Kids studies, patients from arm B or C of the XTEND-ed LTE study who agreed to roll over, or patients from other Altuviiio studies. Enrolment in arm B was limited to patients living in China; arm C enrolled patients globally with an upcoming planned major surgery and included patients living in Canada. Key exclusion criteria across all study arms included a positive inhibitor test. Patients in all study arms were administered weekly IV doses of 50 IU/kg Altuviiio prophylactic treatment. Arm A participants received the study drug for up to 48 months.

Interim outcomes included in the analysis were occurrence of inhibitor development (primary outcome), ABRs, treatment of bleeding episodes, safety and tolerability, and perioperative management. Statistical analyses were descriptive in nature. No formal comparisons were planned, and no hypotheses were formally tested.

Results

Patient Disposition

A total of 217 patients rolled over to the LTE from the 2 parent studies: from the XTEND-1 study, 98% (n = 121 of 124) of patients from arm A and 100% (n = 25 of 25) of patients from arm B; as well as 96% patients (n = 71 of 74) from the XTEND-Kids study. During the LTE, 9 patients discontinued therapy, 8 patients from the XTEND-1 study arm and 1 patient from the XTEND-Kids study arm. Discontinuations were due to the use of prohibited medications due to medical needs (44%), consent withdrawal (33%), AE occurrence (11%), and “other” reasons (11%).

Table 20: Patient Disposition in XTEND-ed Trial

^aPatients remaining in study as of data cut-off date June 8, 2023.

Source: Sponsor’s clinical evidence.⁵¹

Exposure to Study Treatments

As of the XTEND-ed study interim analysis cut-off date, the mean treatment exposure days for patients enrolled from the XTEND-1 and XTEND-Kids studies were 83.1 days (SD = 14.8) and 35.6 days (SD = 14.7), respectively. The mean treatment duration was 82.5 weeks (SD = 14.3) for the XTEND-1 study group and 36.2 weeks (SD = 14.3) for the XTEND-Kids study group. The XTEND-1 and XTEND-Kids study groups were both reported to have high adherence to both treatment dose and treatment interval. Data on co-interventions and subsequent interventions for patients who participated in the XTEND-ed study were not provided by the sponsor.

Efficacy

Annualized Bleeding Rate

In the first 2 years of the XTEND-ed study, the mean overall ABR was 0.72 (SD = 1.26) for patients in arm A of the XTEND-1 study (prophylaxis arm), 0.42 (SD = 0.89) for patients in arm B of the XTEND-1 study (on-demand switch to prophylaxis), and 0.70 (SD = 1.27) for patients from the XTEND-Kids study. The mean ABR for patients from the XTEND-Kids study was also comparable across age groups: for patients aged younger 6 years, the mean ABR was 0.63 (SD = 1.18), and for patients aged 6 years to 12 years of age, the mean ABR was 0.77 (SD = 1.37).

Harms

Over the first 2 years of the XTEND-ed study, up to the interim analysis cut-off date, 74% of patients from the XTEND-1 study group had at least 1 TEAE and 12% had at least 1 serious TEAE. Two patients had 1 or more related TEAEs, which included facial paralysis and decreased coagulation FVIII level. The most common TEAEs (in > 5% of patients) included COVID-19 (22%), arthralgia (13%), headache (9%), nasopharyngitis (8%), and influenza (6%). Two patients discontinued therapy due to TEAEs.

In the XTEND-Kids study group, 61% of patients experienced at least 1 TEAE and 3% had at least 1 serious TEAE. The most common TEAEs (in > 5% of patients) included pyrexia (9%), arthralgia (7%), cough (7%), upper respiratory tract infection (6%), viral upper respiratory tract infection (6%), and oropharyngeal pain (6%). There were no treatment discontinuations due to TEAEs in this group.

As of the XTEND-ed study interim analysis cut-off date, there was no development of FVIII inhibitors in either group and no patient deaths.

Critical Appraisal

At the time of submission, the available evidence was limited to interim analyses based on conference presentations, which may impact the ability to sufficiently review and critically appraise the evidence, as well as the robustness of evidence and conclusions. Statistical hypothesis testing was not part of the study design and there was no active comparator or placebo arm. The XTEND-ed LTE study was designed as an open-label extension to assess long-term efficacy and safety of Altuviiio for the treatment of patients with hemophilia A. This open-label design could bias the magnitude of treatment effect for subjective efficacy outcomes and reporting of safety parameters due to unblinded exposure to the study medication during the treatment period. In addition, the mean treatment duration in the XTEND-Kids study group was less than half of that of the XTEND-1 study group, at 36.2 weeks and 82.5 weeks, respectively. Clinical experts noted that while 36 weeks is likely sufficient to assess treatment efficacy, more time is needed to evaluate long-term safety outcomes, such as inhibitor development.

The XTEND-ed arm A study population for this interim analysis consisted of patients who took part in the XTEND-1 and XTEND-Kids studies, and therefore it is reasonable to expect that the same strengths and limitations related to generalizability apply to the LTE. Given that patients needed to complete XTEND-1 or XTEND-Kids studies before enrolling, the LTE population is inherently enriched and introduces some selection bias for responders.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

There were no studies that provided a direct comparison between Altuviiio, and relevant comparators were identified. In an effort to address this evidence gap, the sponsor conducted indirect comparison analyses (ITCs) that compared Altuviiio with currently available active treatments as prophylactic treatment for adult patients with hemophilia A. The objective of this section is to summarize and critically appraise the methods and findings of these studies.

Description of Indirect Comparisons

The sponsor submitted 1 ITC report²¹ comparing relative treatment effects of Altuviiio versus relevant comparator therapies as prophylactic treatment on patients with hemophilia A. Outcome measures assessed in this ITC included ABR, annualized spontaneous bleeding rate, and AjBR.

Study Selection Methods

To inform the ITC, a SLR was performed to identify phase III clinical trials of FVIII replacement therapies and nonfactor replacement therapies in patients with hemophilia A. The search was run in MEDLINE, Embase, and Cochrane clinical trials register through the OvidSP gate using a search strategy constructed based on the inclusion or exclusion criteria presented in the following. The last search was conducted February 10, 2021. The ITC was focused on selected comparators and outcomes in compliance with the inclusion or exclusion criteria specified in the population, intervention, comparator, and outcome (PICO) criteria for SLR. The feasibility analysis and the extractions were reviewed and critically assessed by an independent external reviewer. Additionally, a targeted literature review search was conducted aiming to identify further clinical evidence published up to the end of June 2022 (i.e., beyond the SLR timespan) from studies pivotal for registration of SLR-identified comparators. The targeted search included National Center for Biotechnology Information databases, the ClinicalTrials.gov registry, the drug registration documentation of the FDA and European Medicines Agency, and company websites containing information essential for product registration, not always found in the main publications.

According to the authors for this ITC report, all currently reimbursed drugs in the EHL and SHL classes are expected to have equivalent efficacy within their own classes. Therefore, ITCs were conducted to compare Altuviiio (from the XTEND-1 study) to emicizumab (from the HAVEN 3 study), EHL products such as efmoroctocog alfa (from the A-LONG study), and SHL products such as octocog alfa (from the LEOPOLD I study).

Details of selection criteria for these ITCs are provided in Table 21.

Table 21: Study Selection Criteria and Methods for ITCs Submitted by the Sponsor

EHL = extended half-life; FVIII = factor VIII: ITC = indirect treatment comparison; NICE = National Institute for Health and Care Excellence; q.w. = every week; RCT = randomized controlled trial; SHL = standard half-life; SLR = systematic literature review.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted ITC report.²¹

ITC Analysis Methods

The XTEND-1 trial assessing Altuviiio is a 2-arm, parallel-design, nonrandomized trial. Patients who had been previously receiving FVIII prophylaxis were allocated to Altuviiio prophylaxis for 52 weeks (arm A). Those receiving on-demand treatment were allocated to arm B, in which they received on-demand Altuviiio for 26 weeks followed by 26 weeks of prophylactic Altuviiio. Because the design of the XTEND-1 trial does not allow the creation of connected networks with any of the comparator trials, the anchored comparisons (such as Bucher indirect comparison or network metanalysis) are not feasible for the comparison between Altuviiio and alternative treatments.⁸⁰ Therefore, unanchored indirect comparison is considered when networks are disconnected and only single arms from respective trials can be used.⁸⁰

In this ITC report, 2 methods were used with an intent of reducing or minimizing the risk of bias through balancing of the between-treatment differences in baseline characteristics of the included studies.

• Unanchored MAIC, when only aggregated data regarding baseline characteristic and outcomes were available:^81,82 to compare the mean estimates between outcomes of treatments A and B using standard statistical methods; between-trial imbalances in patient characteristics should be adjusted for, including all effect modifiers and prognostic factors.

• An observational comparison using a PSM approach when patient-level data for both compared studies are available: the propensity score can be interpreted as the conditional probability of being assigned to the treatment, given the baseline characteristics. Propensity scores are generated using logistic regression with the treatment use as the outcome and the observed background characteristics as predictors. These propensity scores can then be applied to minimize the bias of the comparison by balancing baseline characteristics between groups.^81,82

The unanchored MAIC was conducted for the comparison between Altuviiio and emicizumab or octocog alfa to minimize the risk of bias associated with unanchored comparisons, while the PSM method was used in the comparison between Altuviiio (XTEND-1) and efmoroctocog alfa (A-LONG).

In all analyses using the MAIC method, the XTEND-1 study patient-level data were adjusted for every baseline characteristic provided that adequate data were reported in the comparator studies. The following variables were considered to be adjusted for:

• age (mean, median, SD)

• body weight or body mass index (mean, median, SD)

• race (proportion of Asian patients and white patients)

• prior treatment regimen (proportion of patients receiving prophylaxis before entry)

• prior frequency of bleeding (mean, median, SD)

• presence of target joints (mean, median, SD, proportion of patients with 0, 1, or ≥ 2)

• comorbidities (proportion of patients with HIV and or hepatitis C virus infections)

• baseline patient-reported outcome values (mean, SD).

In the MAIC analyses, the model used for bleeding rate estimation from the XTEND-1 study individual patient data depended on the method of estimation used in the comparator study (e.g., negative binomial, crude mean), so that the same measure was used for treatment effect comparison. In particular, the method of bleeding rate estimation also determined the method of outcome comparison. The rates for comparators estimated using a count model (e.g., negative binomial) are directly reported from the model as the log of the rates. The between-treatment comparison expressed on the log scale and exponentiated results in the estimate of IRR. On the other hand, the absolute difference in rates calculated from 2 mean values results in the comparison following normally distributed MD in the incidence rate. Refer to Table 22 for a comparison of definitions for bleeding outcomes in the sponsor’s ITC report.

The PSM method allowed for estimation of both IRR and MD for incidence rate comparison between Altuviiio and efmoroctocog alfa, due to availability of individual patient data from both studies. In the comparison between the XTEND-1 and A-LONG trials, all patients from the XTEND-1 study arms A and B and A-LONG study individualized prophylaxis arm were included, assessing treatment effect comparison after matching patients for baseline characteristics using a PSM full matching method. The following baseline characteristics in the 2 trials were adjusted for in the model:

• age (mean and SD)

• body weight (mean and SD)

• proportion of patients treated prophylactically before enrolment

• presence of target joints, including:

  • proportion of patients with 0 target joint

  • number of target joint per patient (mean and SD)

• prior bleeds (mean and SD)

• proportion of patients who are HIV positive

• proportion of patients who are hepatitis C positive

• baseline Haem-A-QoL scores (mean and SD), including:

  • total score for change from baseline in Haem-A-QoL total score

  • physical score for change from baseline in Haem-A-QoL Physical Health score

The sponsor noted that in the comparison between Altuviiio and efmoroctocog alfa, during matching an additional caliper was imposed on inferential units that discard the patients if the units are more than a set distance (in propensity score units) away from predefined radius of their closest match. Given the lack of clarity about the optimal caliper width, the caliper ranges were manually chosen for selected variables to maximize the covariates adjustment and minimize information loss.

Definition for Bleeding Outcomes

Two commonly used methods to compare incidence rates are the IRR and the MD in the incidence rates. Both methods produce qualitatively similar estimates and statistically consistent inference but differ in the interpretation of results. IRR gives clinically interpretable results on the relative scale (treatment results in percent change in risk relative to comparator), while MD gives clinically interpretable results on the absolute scale (mean change in risk).⁸³

Table 22: Comparison of Definitions for Bleeding Outcomes

ABR = annualized bleeding rate; IRR = incidence rate ratio; MD = mean difference; NA = not available.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted indirect treatment comparison report.²¹

Results

Summary of Included Studies

The XTEND-1 trial and another 12 publications of potential comparators contributed to the ITC analyses and 8 drugs were involved: Altuviiio, 1 nonfactor replacement therapy (emicizumab), 4 EHL therapies (efmoroctocog alfa, damoctocog alfa pegol, rurioctocog alfa pegol, and turoctocog alfa pegol), 2 SHL therapies (octocog alfa [2 different drugs]), and a gene therapy (valoctocogene roxaparvovec). These drugs were used as prophylactic therapy, on-demand therapy, or a mix of prophylactic and on-demand therapy. Among these studies, 3 evaluated the effect of prior prophylaxis regimen on bleeding outcomes, and 9 evaluated the effect of prior prophylaxis or on-demand regimen on bleeding outcomes and HRQoL. Outcomes of interest assessed in this ITC report included ABRs (all, treated, joint, and spontaneous), HRQoL (measured by Haem-A-QoL), and joint health scores (as measured by HJHS). ABR outcomes were evaluated in all 13 included trials, while HRQoL and joint health outcomes were less commonly reported. HRQoL was evaluated in 4 trials of Altuviiio, efmoroctocog alfa, turoctocog alfa, and emicizumab used as prophylaxis or for an on-demand regimen. Joint health outcome was evaluated in 2 trials of Altuviiio and emicizumab (every 4 weeks). Therefore, the current report primarily focused on the bleeding outcomes. Because gene therapy for hemophilia A is not currently available in Canada, the currently report summarizes the results for the comparisons between Altuviiio and EHL therapies, SHL therapies, and nonfactor replacement therapy.

As per the sponsor, all currently reimbursed drugs in the EHL and SHL classes are expected to demonstrate similar efficacy within their own classes. The sponsor also noted that to align with the Canadian pharmacoeconomic model as well as the submitted pharmacoeconomic deviation request which was accepted for this review, the comparators for Altuviiio in this ITC report included efmoroctocog alfa (to represent the EHL group) and octocog alfa (to represent the SHL group). Trial characteristics of the included studies are shown in Table 23. The primary outcome of the XTEND-1 trial was assessed at 52 weeks, which was similar to the LEOPOLD I and A-LONG studies. In the HAVEN 3 study, bleeding rates were assessed at 24 weeks. In the XTEND-1, LEOPOLD I, and A-LONG studies, the study drugs were used as prophylactically or on demand. In the HAVEN 3 study, emicizumab was used prophylactically only.

Baseline patient characteristics in the XTEND-1 trial before and after matching with the HAVEN 3 study (arm D) and LEOPOLD I study are presented in Appendix 3. The baseline patient characteristics before and after matching for the XTEND-1 and A-LONG studies are presented in Table 27.

All patients in the included studies were aged 12 years or older and had a diagnosis of severe hemophilia A. In all studies, severe hemophilia A was defined as less than 1 IU/dL (< 1%) endogenous FVIII activity. Before matching, there were some imbalances between the studies in proportion of patients treated prophylactically before enrolment, presence of target joints, history of prior bleeding, and proportion of HIV or hepatitis C virus infections.

Table 23: Assessment of Homogeneity

EHL = extended half-life; FVIII = factor VIII; q.w. = once a week; q.2.w. = every 2 weeks; RCT = randomized controlled trial; rFVIII-FS = sucrose-formulated recombinant factor VIII; SHL = standard half-life.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted indirect treatment comparison report,²¹ von Drygalski et al. (the XTEND-1 study),⁸⁴ Mahlangu et al. (2018) (the HAVEN 3 study),⁸⁵ Mahlangu et al. (2014) (the A-LONG study),⁷⁶ XTEND-1 Clinical Study Report, and Saxena et al. (the LEOPOLD I study).⁸⁶

Results

Efficacy

MAIC for Altuviiio compared to emicizumab once weekly (for patients with prior prophylactic therapy): Emicizumab once weekly was assessed in arm D of the HAVEN 3 trial in 63 patients, with severe hemophilia A, who had been receiving prophylactic treatment before enrolment. Based on the available publication, the age of patients ranged from 13 years to 68 years, while the body weight ranged from 52.8 kg to 139 kg. Arm A of the XTEND-1 trial was compared with arm D of the HAVEN 3 study, because both cohorts recruited patients receiving prophylactic treatment before enrolment. Fourteen of 133 patients in the XTEND-1 study arm A with age and/or body weight outside the ranges reported in the corresponding HAVEN 3 study cohort were excluded from the analysis, so that 119 patients receiving Altuviiio were finally included in the MAIC (Table 24).

Table 24: Preselection of XTEND-1 Patients With Comparable Baseline Characteristics in HAVEN 3 Trial

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted indirect treatment comparison report.²¹

For the comparison between prophylactic regimens of Altuviiio and emicizumab once weekly, the baseline variables that were adjusted for in the matching process included: age, body weight, presence of target joints (proportion of patients without target joints, with 1 target joint, or with at least 2 target joints), and most abundant racial group (proportion of white patients, proportion of Asian patients). The estimated ESS was reduced from 119 to 76 patients following matching, which corresponds to 63.8% of the initial sample.

All ABRs in the HAVEN 3 study were calculated using a negative binomial model with stratification for the history of previous bleeds (< 9 or ≥ 9 bleeding events in the previous 24 weeks). ABRs for the XTEND-1 study were estimated using the same regression model, but without stratification factor due to lack of data regarding history of bleeds within 24 weeks before enrolment. A summary of the results for the MAIC of Altuviiio to emicizumab is available in Figure 2. Based on estimated effects from the model, Altuviiio compared to emicizumab once weekly (prior prophylactic use) was associated with lower rate of any bleeding (treated and untreated) (IRR = 0.32; 95% CI, 0.19 to 0.56) and joint treated bleeding (IRR = 0.48; 95% CI, 0.24 to 0.95). There was no evidence for significant differences regarding frequency of treated spontaneous bleeding (IRR = 0.62; 95% CI, 0.25 to 1.50).

Figure 2: Incidence Rate Ratio for ABR of Altuviiio vs. Emicizumab

ABR = annualized bleeding rate; CI = confidence interval; IRR = incidence rate ratio; MAIC = matching-adjusted indirect comparison; vs. = versus.

Source: Sponsor-submitted indirect treatment comparison report.²¹

MAIC for Altuviiio compared to octocog alfa (SHL class) (for patients with prior prophylactic and on-demand therapy): Octocog alfa (Kovaltry) was assessed in arms A and B of the LEOPOLD I trial in 62 patients with severe hemophilia A, who had been receiving prophylactic and on-demand treatment before enrolment. Based on the available publication, the age of patients ranged from 12 years to 61 years, while the body weight ranged from 39 kg to 121 kg. Pooled arms A and B of the XTEND-1 trial were compared with the LEOPOLD I study, because both cohorts recruited patients receiving prophylactic and on-demand treatment before enrolment. Seventeen of 159 patients in the XTEND-1 study with age and/or body weight outside the ranges reported in the corresponding LEOPOLD I study cohort were excluded from the analysis, so that 142 patients receiving Altuviiio were finally included in the MAIC (Table 25). Data from the LEOPOLD II study were not included in this ITC as these patients exclusively received on-demand therapy and not had previously received prophylactic therapy.

Table 25: Preselection of XTEND-1 Patients With Comparable Baseline Characteristics in LEOPOLD I Trial

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted indirect treatment comparison report.²¹

The comparison between interventions was adjusted for the following baseline variables in the MAIC model: age, body weight, proportion of patients with 1 or more target joints, proportion of white patients, proportion of patients treated prophylactically before enrolment, and prior bleeds. After matching, the estimated ESS was reduced from 128 to 29 patients following matching, which corresponds to 22.7% of the initial sample.

All ABRs in the LEOPOLD I study were reported as mean and SD. ABRs for the XTEND-1 study were estimated analogously. A summary of the results for the MAIC of Altuviiio to octocog alfa is available in Figure 3. Altuviiio compared to octocog alfa was associated with lower frequency of any bleeding (MD = −2.97; 95% CI, –4.28 to −1.67), spontaneous bleeding (MD = −2.23; 95% CI, –3.10 to –1.35), and joint bleeding (MD = −2.67; 95% CI, –3.85 to –1.49).

PSM for Altuviiio compared to efmoroctocog alfa (EHL class) (individualized prophylaxis): Efmoroctocog alfa was assessed in the A-LONG trial in 165 patients with severe hemophilia recruited to individualized prophylaxis (n = 118), weekly prophylaxis (n = 24), or on-demand treatment (n = 23); only 117 patients with assessed individualized prophylaxis were included in the comparison with Altuviiio, as this treatment regimen corresponds to dosing specified in regulatory labels. Pooled arms A and B of the XTEND-1 trial were compared with the A-LONG study, because both cohorts recruited patients receiving prophylactic and on-demand treatment before enrolment. The age of A-LONG study patients ranged from 12 years to 65 years and the body weight ranged from 42 kg to 127 kg; thus, the population from the XTEND-1 study had a slightly wider range of age and body weight values compared to the A-LONG study. In the analysis, all patients from the XTEND-1 study arm A and B and the A-LONG study individualized prophylaxis arm were included, assessing treatment effect comparison after matching patients for baseline characteristics using the PSM full matching method.

Figure 3: Mean Difference of ABRs Between Altuviiio and Octocog Alfa

ABR = annualized bleeding rate; CI = confidence interval; MAIC = matching-adjusted indirect comparison; MD = mean difference; vs. = versus.

Source: Sponsor-submitted indirect treatment comparison report.²¹

Table 26: Preselection of XTEND-1 Patients With Comparable Baseline Characteristics in the A-LONG Trial

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Source: Sponsor-submitted indirect treatment comparison report.²¹

The following baseline variables were adjusted for in the comparison between Altuviiio and efmoroctocog alfa: age, body weight, proportion of patients treated prophylactically before enrolment, presence of target joints (proportion of patients with 0 target joint, number of target joints per patient), prior bleeds, proportion of patients living with HIV or hepatitis C virus infections, and baseline Haem-A-QoL scores (total score and physical score).

The estimated ESS in models for bleeding for the XTEND-1 study individual patient data was reduced from 145 to 87 patients following matching which corresponds to 60% of the initial sample, and for the A-LONG study individual patient data was reduced from 116 to 30 patients following matching which corresponds to 26% of the initial sample (Table 27). The number of patients analyzed may be less than the number of patients recruited due to removed patients with missing information on baseline characteristics or outcomes.

The comparison between prophylactic regimens of Altuviiio and the efmoroctocog alfa individualized prophylaxis arm in patients receiving prior prophylactic or prior on demand therapy was feasible for FVIII consumption, the ABRs for any treated bleeding episodes, spontaneous treated bleeding episodes, and joint treated bleeding episodes. Treatment effect estimate for ABRs between the XTEND-1 and A-LONG studies was estimated with a negative binomial model with treatment duration as offset. A summary of the results for the PSM analysis of Altuviiio to efmoroctocog alfa is available in Figure 4. Altuviiio compared to efmoroctocog alfa individualized prophylaxis was associated with favourable (less frequent) estimates for treated bleeding rate (IRR = 0.29; 95% CI, 0.17 to 0.51), spontaneous bleeding rate (IRR = 0.21; 95% CI, 0.09 to 0.49), and joint bleeding rate (IRR = 0.37; 95% CI, 0.20 to 0.71]). The estimated IRRs were statistically significant.

Additional results: compared to other comparator therapies: Altuviiio was also compared to damoctocog alfa pegol, rurioctocog alfa pegol, and turoctocog alfa pegol, and the results on ABR favoured Altuviiio (Table 28). The direction of the changes in these results are comparable to those with emicizumab, octocog alfa, and efmoroctocog alfa.

Table 27: Matching of Baseline Characteristics Between XTEND-1 Pooled Arms and A-LONG for Models Assessing Bleeding Outcomes and Factor VIII

ESS = effective sample size; HCV = hepatitis C virus; NR = not reported; PSM = propensity score matching; SD = standard deviation; TJ = target joint.

Notes: The statistical tests used were the 2-sample t test for continuous variables and the 2-sample test for equality of proportions for binary variables. PSM model = age + weight + prior regimen + TJ + prior bleeds + HIV + HCV (caliper: SD = 0.1, age = 20, weight = 20, TJ = 5, prior bleeds = 5).

Details included in the table are from the sponsor’s Summary of Clinical Evidence.

^aStatistically significant difference in baseline characteristic between studies.

Source: Sponsor-submitted indirect treatment comparison report.²¹

Figure 4: Incidence Rate Ratio for ABRS of Altuviiio vs. Efmoroctocog Alfa

ABR = annualized bleeding rate; CI = confidence interval; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; IRR = incidence rate ratio; PHX = prophylaxis; vs. = versus.

Note: Change from baseline in Haem-A-QoL total score or physical score in the comparisons between Altuviiio vs. efmoroctocog alfa as prophylactic therapy was −2.43 (95% CI, −8.48 to 3.62) and −7.01 (95% CI, −14.69 to 0.67), respectively.

Source: Sponsor-submitted indirect treatment comparison report.²¹

Table 28: Summary of Additional Efficacy Outcome Measures for Other EHL Therapies in the Sponsor-Submitted ITC (MAIC and PSM)

ABR = annualized bleeding rate; CI = confidence interval; EHL = extended half-life; Haem-A-QoL = Haemophilia Quality of Life questionnaire for adults; IRR = incidence rate ratio; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect treatment comparison; MD = mean difference; NA = not available; O-D = on demand; PHX = prophylactic; PSM = propensity score matching; vs. = versus.

Note: IRR < 1.0 or MD < 0 indicates favouring Altuviiio; IRR > 1.0 or MD > 0 indicates favouring comparators.

^aBased on the PROTECT VIII trial.

^bBased on the PROPEL and PROLONG-ATE studies.

^cBased on the PATHFINDER 2 study.

Source: Sponsor-submitted indirect treatment comparison report.²¹

Harms

Harms data were not collected as part of the SLR and thus not included as part of this analysis of indirect evidence.

Critical Appraisal of Sponsor-Submitted Indirect Evidence

In this ITC report including MAICs and propensity score analysis, indirect evidence was identified by searching multiple databases based on prespecified inclusion and exclusion criteria. It was unknown if the studies were selected by 2 independent reviewers. Appropriate methods and tools were used to reduce the risk of bias and error in data extraction and quality assessment of the included studies. However, it was unknown if the risk of bias of the included studies was assessed by 2 independent reviewers and the results of quality assessment were not provided. In addition, risk of bias might have been assessed at the level of the trial, rather than at the level of the reported results (i.e., per outcome), which ignores that risk of bias can vary by reported result within a trial. It is worth noting that hemophilia A is a rare disease, therefore the number of clinical trials of hemophilia A and the number of patients recruited in the available trials could be limited. In total, 4 studies were included in this ITC report. They are all small open-label trials, randomized or nonrandomized; therefore, the evidence base for indirect comparisons between Altuviiio and comparator therapies is small.

The relative efficacy of Altuviiio (as prophylactic treatment) compared to the currently available active treatments in the target population was examined in this ITC. One of the major concerns for ITCs is that the included trials could be highly heterogeneous in terms of study design and patient characteristics at baseline. The studies included in the ITC were published between 2014 to 2023. The selection criteria in these 4 studies were similar, where patients who were aged 12 years or older with severe hemophilia A were enrolled. With the goal of reducing the risk of bias in result interpretation, unanchored MAIC or a PSM method was used in balancing the baseline characteristics between the included trials. The selection of conducting a MAIC or PSM analysis was appropriately justified in the sponsor’s ITC report. In the MAICs, the sponsor noted that the following potential effect modifier or prognostic factors were adjusted for if adequate data were reported in the comparator studies: age, body weight or body mass index, race, prior treatment regimen, prior frequency of bleeding, presence of targeted joints, comorbidities, and baseline patient-reported outcome values. There was no information provided on how these variables were identified, if based on literature review or being identified through a deliberating process by the clinicians. In general, the clinical experts consulted for this review agreed that these are relevant effect modifiers and prognostic variables. In addition, the XTEND-1 trial coincided with the COVID-19 pandemic, where changes in the level of physical activity before or during the COVID-19 pandemic may have affected patients’ risk of bleeding due to changes in lifestyle and behaviour related to physical activity. As such, there is potential for risk of bias in the included studies due to potential confounding by the heterogeneity in physical activity level at baseline, and the time that patients were treated and evaluated (prepandemic versus during pandemic). However, the direction of bias is unclear, and the clinical experts consulted by CDA-AMC did not expect this to significantly impact the results.

According to the clinical expert consulted for this review, clinical practice and management of patients with hemophilia A have evolved considerably in the past 10 years. For example, because there has been an increase in the use of factor prophylaxis in patients of all ages and disease severities, factor prophylaxis dosing and frequency are tailored based on patient’s own PK profile, bleeding profile, activity levels, and potential impact of a bleeding event. Further, the risk of severe bleeding in patients with factor levels indicative of mild to moderate disease range is recognized and such patients can still benefit from prophylactic treatment (either factor or nonfactor). In addition, many clinicians in Canada have adopted the WFH clinical practice guidelines. All these improvements have not been considered in the analyses, and as a result, the reported study results may be confounded and biased. After weighting in the PSM analysis, most of the patient characteristics were balanced between the XTEND-1 and A-LONG studies, although remaining imbalance were still observed. According to the clinical experts consulted on this review, the remaining differences observed between the 2 studies were small and unlikely to have substantial impact on study results.

In this ITC report, the sponsor noted that all currently reimbursed drugs in the EHL and SHL classes are expected to have equivalent efficacy within their own classes, based on the key opinion leaders’ input. Therefore, ITCs were conducted to compare Altuviiio to emicizumab, efmoroctocog alfa (representing EHL products), and octocog alfa (representing SHL products). The clinical experts consulted for this review agreed that this assumption was reasonable. However, a rationale of why certain drugs were selected in the ITC analyses instead of others in a same drug class was not provided by the sponsor. The analysis was primarily focused on patients who had been receiving prophylactic regimens before study entry, which was consistent with the inclusion criteria for arm A of the XTEND-1 trial for Altuviiio. However, comparisons with patients receiving prior on-demand treatment and the mixed populations (e.g., prophylactic and on-demand treatments) were also attempted.

The estimated ESS was reduced to 63.8% of the initial sample of the XTEND-1 study in the comparison with emicizumab and to 22.7% of the initial sample of the XTEND-1 study in the comparison with octocog alfa. In the comparison with efmoroctocog alfa, the ESS was reduced to 60% of the initial XTEND-1 study sample and 26% of the initial A-LONG study sample. A significant reduction in sample size can contribute to imprecision and increase uncertainty of the results. A notable reduction in ESS also suggests that the study results may be heavily influenced by a subset of the sample in the trials which may not be representative of the full sample, thus limiting generalizability to the full population presented by the XTEND-1 trial. The ABR was the main outcome of interest in this ITC report. HRQoL (measured with Haem-A-QoL) was also assessed in patients receiving prophylactic treatment. The results were briefly reported for the comparisons between Altuviiio and 2 EHL therapies (efmoroctocog alfa and turoctocog alfa) without sufficient details, and the study findings were inconsistent for these 2 EHL therapies. Other important clinical outcomes of interest to patients and clinicians, such as harms or inhibitor development, were not assessed in this ITC report. Therefore, the relative treatment effect of Altuviiio versus relevant comparators on these outcomes remains unknown. Moreover, the comparative efficacy and safety of Altuviiio versus comparators in the pediatric population, or its use as on-demand treatment or perioperative management was unclear due to the lack of clinical evidence.

Studies Addressing Gaps in the Systematic Review Evidence

There were no relevant studies addressing the gaps in the systematic review evidence submitted for this review.

Discussion

Summary of Available Evidence

Two pivotal, nonrandomized, open-label, multicentre, phase III trials (XTEND-1, N = 159; XTEND-Kids, N = 74) were included in the SLR conducted by the sponsor. The XTEND-1 and XTEND-Kids studies evaluated the safety and efficacy of weekly Altuviiio for prophylactic use for 52 weeks in an adolescent and adult (aged ≥ 12 years) population and pediatric (patients aged < 12 years) population, respectively, with severe congenital hemophilia A (defined as < 1 IU/dL [< 1%] endogenous FVIII activity) without FVIII inhibitors. The XTEND-1 study also assessed the use of efanesoctocog as on-demand treatment compared to prophylactic use in terms of the ABR. Patients in the XTEND-1 trial were divided into 2 treatment groups based on the treatment regimen before entering the study: Altuviiio prophylaxis group (arm A) and Altuviiio on-demand treatment followed by prophylaxis (arm B). Arm A included participants who were on a current FVIII prophylactic treatment regimen and participated in an observational prestudy (242HA201/OBS16221) for at least 6 months before baseline of the XTEND-1 study. The XTEND-Kids study comprised 2 age cohorts, children aged less than 6 years (n = 38) and children aged 6 years to less than 12 years (n = 36), and all patients received once-weekly IV doses of 50 IU/kg Altuviiio prophylactic treatment. Lastly, Altuviiio for perioperative management of bleeds was also assessed in any patient from the XTEND-1 and XTEND-Kids studies who underwent major surgery after the first dose of the study drug.

In the XTEND-1 study, the primary efficacy outcome was ABR and in the XTEND-Kids study, the primary outcome was formation of FVIII inhibitors. Other efficacy outcomes in both trials were AjBR, physical function and pain (Haemo-QoL, Haem-A-QoL), HJHS, response to perioperative management (number of injections to maintain hemostasis before major surgery), and harms outcomes. In the XTEND-1 study, the mean age of patients was 35.4 years (SD = 15.1 years), ranging from 12 years to 72 years, and 78.6% of patients had no family history of FVIII inhibitors. Further, the mean number of bleeding episodes 12 months before the study was 3.2 (SD = 5.4) in arm A and 35.7 (SD = 22.2) in arm B. In the XTEND-Kids trial, the mean age was 5.99 years (SD = 2.91 years), 77% of patients had no family history of an inhibitor, and the mean number of bleeding episodes during the 12 months before the study was 2.1 (SD = 4.2).

The key limitations of the body of evidence were related to the open-label study design, absence of randomized, direct comparative evidence between Altuviiio and other FVIII prophylaxis, and the exclusion of patients with FVIII inhibitors and patients who have not received prior FVIII therapies.

The sponsor submitted indirect evidence comparing efanesoctocog to relevant comparator therapies as prophylactic treatment for adult patients with severe hemophilia A. This included 2 MAICs that compared Altuviiio with a nonfactor replacement therapy agent (emicizumab) and an octocog alfa agent (as a proxy for SHL products), and 1 observational study using a PSM method to compare Altuviiio with efmoroctocog alfa (as a proxy for EHL products). Outcome measures assessed in this ITC included ABRs for any bleeding, spontaneous bleeding, and joint bleeding.

Evidence for long-term efficacy and safety of Altuviiio for prophylactic use was included in the submission based on the ongoing phase III, open-label, multicentre study, XTEND-ed (N = 217) that enrolled patients who were previously enrolled in the Altuviiio trials. This submitted interim analyses pertains only to patients rolled over from the XTEND-1 and XTEND-Kids studies into arm A of the XTEND-ed study and reports on efficacy and safety-related outcomes over up to an additional 2 years of treatment with Altuviiio.

Interpretation of Results

Efficacy

Input from patients’ groups, clinician groups, Canadian Blood Services, and the clinical experts consulted for this review indicated that the most important treatment goals for patients with hemophilia A are to prevent bleeding, including spontaneous and traumatic bleeding events, reduce joint pain, improve HRQoL, and achieve unrestricted lifestyle comparable to the general population. With currently available treatments, achieving this goal requires frequent administration of high treatment doses to overcome short treatment half-lives. According to the clinical expert and clinician group input, treatment burden is particularly notable in patients who require elevated trough levels due to recent surgical procedures, have compromised joint health, or have high physical activity levels. Consistent with clinical expert input, the clinician group and patient group agreed that current existing therapies demonstrate variable efficacy.

The efficacy of Altuviiio as routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding in adults and children with hemophilia A was assessed using 2 pivotal trials, the XTEND-1 and XTEND-Kids studies. The results of the XTEND-1 and XTEND-Kids trials suggest that Altuviiio (50 IU/kg) prophylaxis for up to 52 weeks reduces bleeding associated with hemophilia A based on the number of bleeds per year and the number of joint bleeds per year, assessed with ABR and AjBR, respectively. Although all analyses in the XTEND-Kids study were descriptive, and no formal hypothesis testing was performed, bleeding rates following 52 weeks of Altuviiio for prophylactic use in the XTEND-Kids study were consistent with those observed in the XTEND-1 study and considered clinically relevant by the clinical experts consulted by CDA-AMC. Additionally, once-weekly prophylaxis with Altuviiio for 52 weeks may result in an improved ABR compared to a prestudy standard of care FVIII prophylaxis based on the intrapatient analysis, although the evidence is uncertain as the magnitude of effect may be overestimated based on limitations of external and internal validity as the prior observational study and the XTEND-1 trial were conducted before and during the pandemic, respectively. However, the differences in magnitude of efficacy results are not expected to invalidate the clinical significance of the bleeding outcomes in the XTEND-1 study, which are expected to address a gap in therapy experienced by patients currently treated with standard-care FVIII. The clinical experts were in agreement that the reduction in bleeding outcomes was clinically meaningful, albeit there are several limitations associated with the open-label, nonrandomized design, which are reflected by the GRADE assessment as low level of certainty for ABR and very low level of certainty for AjBR. In rare disease conditions like hemophilia A, challenges such as patient recruitment, and availability of effective treatment make it practically impossible to use traditional RCTs in evaluating treatment efficacy. The clinical experts consulted for this review indicated that although RCTs remain the gold standard, alternative designs like single-arm trials and intrapatient comparison are accepted in hemophilia A as being able to provide a practical evaluation of new therapies. Overall, the data for bleeding outcomes in the XTEND-1 study were considered robust by the clinical experts consulted for this review given the consistency of the primary results with various sensitivity analyses, as well as the proportion of patients who were reported as experiencing no bleeds requiring treatment during the trials. Specific subgroups, such as patients with obesity or those participating in higher-intensity physical activity who may require adjusted dosing, were considered relevant to the assessment of Altuviiio; however, these were not studied in the trials.

The current standard of care for patients with hemophilia A in Canada is primary prophylactic therapy. According to the clinical experts consulted for this review, the goal of prophylaxis is to increase a patient’s FVIII levels to normal or near-normal levels to prevent spontaneous bleeding, prevent arthropathy, and to attain an active lifestyle comparable to individuals without hemophilia A. However, current products do not provide these normal or near-normal FVIII levels. Apart from emicizumab, which provides a FVIII activity equivalence level of 10% to 15%, the trough levels of available SHL and EHL FVIII concentrates are between 3% to 5% immediately after infusion with subsequent clearance dependent on the product half-life (but generally 14 to 18 hours), resulting in less bleeding protection. For patients who participate in regular physical activities, infusions may be planned to coincide with physical activity, otherwise additional doses on top of their regular prophylaxis are needed before certain physical activities to mitigate the risk of provoked bleeding. According to the patient group input received for this review, patients reported that new therapies that can improve hemophilia A disease outcomes such as improved bleeding protection with a reduced administration frequency (fewer doses with longer half-life) are needed to improve disease outcomes. As described, in both the XTEND-1 and XTEND-Kids studies, once-weekly Altuviiio for prophylactic use in patients with severe hemophilia A resulted in an ABR that was considered clinically relevant. Further, FVIII activity was descriptively reported as being greater than 40% for the first 4 days of treatment, and greater than 10% for nearly 7 days. As noted by the clinical experts consulted by CDA-AMC, clinically, this is reflective of effective bleeding control without a trade-off in burden of treatment. This is consistent with the reported half-life for Altuviiio⁸⁷ as well as input received from a patient group for this submission, where 1 patient who had been treated with Altuviiio via a special access program indicated that Altuviiio has helped reduced her risk of bleeding due to the sustained high FVIII level even after several days post infusion.

Outcomes that assessed joint health (HJHS), physical function and pain outcomes (PROMIS instruments), and HRQoL (Haem-A-QoL) were also identified as outcomes of importance to patients based on the patient and clinician group input received for this review. The input from the patient and clinician groups noted that up to 46% of patients with hemophilia report living with chronic pain which negatively affect physical and psychological health. Regarding joint health, the evidence did not suggest an improvement in joint health based on the HJHS, but it also did not suggest a worsening of joint health. The clinical experts indicated that while this is an outcome of importance for patients and an unmet need, an improvement in joint health is not expected based on the mechanism of action for Altuviiio. In adults (the XTEND-1 study), the change from baseline to week 52 in HRQoL based on the Haem-A-QoL Physical Health score indicated an improvement in QoL; however, this within-group change was not considered clinically meaningful based on the within-group MID identified in the literature.⁵⁵ In the XTEND-Kids study, the results for Haem-A-QoL total score did suggest an improvement for children aged 8 years to 12 years, but these data are highly uncertain due to a small sample size. While the results suggest an improvement in PROMIS Pain Intensity scores at week 52 for adults in the XTEND-1 study, it is unclear whether this change corresponds to a clinically meaningful difference due to the absence of validated MIDs for this outcome. Additionally, the evidence was insufficient to support an improvement in pain intensity among pediatric patients based on the results from the XTEND-Kids study. Assessments of pain and physical function did not correspond to an improvement in either trial. In consultation with the clinical experts consulted for this review, assessments at week 52 may not be a sufficient amount of time to evaluate an improvement in these outcomes and long-term results are likely needed to for an adequate assessment of these outcomes.

In view of this, the sponsor submitted an interim analysis of the ongoing LTE study, XTEND-ed. Outcomes included in the interim analysis include: the occurrence of inhibitor development (primary outcome), ABR, treatment of bleeding episodes, safety and tolerability, and perioperative management. Evidence for ABR was included in this review report, and the results over 2 additional years of therapy were consistent with what was observed in the pivotal trials. However, the available evidence was only limited to analyses based on conference presentations, which likely impacts the robustness of evidence and conclusions. The XTEND-ed arm A study population for this interim analysis consisted of patients who took part in the XTEND-1 and XTEND-Kids studies, and therefore it is reasonable to expect that the same strengths and limitations related to generalizability apply to the LTE.

In the XTEND-Kids trial, the primary end point was a safety outcome, that is, the incidence of inhibitor development to FVIII which was 0.0% in all treated patients and 0.0% in patients with 50 or more exposure days to Altuviiio. The inclusion of previously treated patients with hemophilia A and inclusion of patients with no family history of FVIII inhibitors (the majority of the study population) limits the generalizability of these findings, which was supported by input from the clinical experts. CDA-AMC notes that a larger sample of previously treated patients followed over a longer period and assessments of previously untreated patients would be useful in understanding the immune response and the potential immunogenicity of Altuviiio. Although the clinical experts consulted for this review agreed that the inclusion of patients with no history of FVIII treatment is a limitation, they indicated that this was not a major concern, because in clinical practice, patients are closely monitored for inhibitor development during the first few weeks of starting treatment consistent with standards of care in the Canadian landscape.

The patient group input received for this review highlighted surgery complications as one of the challenges associated with hemophilia A. Based on the patient group input, surgery is normally required to break the cycle of chronic synovitis in patients with hemophilia A; however, patients who present for such invasive procedures are at increased risk of bleeding during surgery. As such, perioperative management of hemophilia A is an important need. In both trials, a single injection of 50 IU/kg Altuviiio was effective in terms of achieving a hemostatic response in the perioperative setting, in which the hemostatic response was rated as excellent by the investigators or surgeons for all 14 major surgeries that occurred during the XTEND-1 and XTEND-Kids studies. While both trials appear adequately powered for assessing bleeding and joint health outcomes, outcomes concerning perioperative management may not be fully powered to detect rare AEs or efficacy in subpopulations, limiting the interpretation of this outcome.

No studies were identified in the sponsor’s systematic review that provided a direct comparison between Altuviiio and relevant comparators. As such, indirect evidence that compared Altuviiio with efmoroctocog alfa, octocog alfa, and emicizumab as prophylactic treatment for adult patients with hemophilia A was submitted. An anchored comparison was not feasible; therefore, 2 unanchored MAICs and a PSM analysis were conducted. Results from these indirect comparisons suggested that prophylactic treatment with Altuviiio was associated with improved bleeding outcomes (any bleeding, spontaneous bleeding, and joint bleeding) compared with comparator therapies currently available in clinical practice for adult patients with severe hemophilia A, such as EHL agents, SHL agents, or emicizumab. However, a definite conclusion on the magnitude of the clinical benefit of Altuviiio cannot be drawn due to limitations of the available indirect evidence, such as a sizable reduction in ESS, and inadequate or lack of adjustment for potential prognostic factors (e.g., physical activity level at baseline and the impact of the COVID-19 pandemic) that may introduce unmeasurable confounding in the relative treatment effect estimates. The effect of Altuviiio relative to other active therapies on patients’ HRQoL is also unknown.

Harms

In both pivotal trials, safety analyses were conducted for all patients who received at least 1 dose of Altuviiio. In both studies, AEs and SAEs were reported by the patient (or, when appropriate, by a caregiver, surrogate, or the patient's legally authorized representative). Overall, Altuviiio was well tolerated and reported TEAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A. There were no reports of serious allergic reaction, anaphylaxis, or vascular thrombotic events. In addition, no clinically meaningful patterns or trends were identified in the laboratory or vital sign parameters.

In the XTEND-1 trial, the most frequently reported TEAEs in greater than 3% of patients were headache (20.1%); arthralgia (16.4%); fall (6.3%); back pain (5.7%); COVID-19 and fatigue (74.4% each); contusion, hemophilic arthropathy, and nasopharyngitis (3.8% each); and joint injury, pain in extremity, and toothache (3.1% each). A total of 18 TESAEs were experienced by 15 (9.4%) patients. Hemophilic arthropathy was reported in 2 (1.3%) patients. The majority of TESAEs were assessed by the investigator as mild to moderate in severity. Two TEAEs in 2 (1.3%) patients resulted in permanent treatment discontinuation. Death was reported in 1 patient, in arm B. This patient had a medical history of hepatitis C virus and died of pancreatic carcinoma metastatic, which was reported as a TESAE. The TESAE was assessed by the investigator as not related to Altuviiio treatment. There were no reports of inhibitor development to FVIII, or embolic or thrombotic events during the study.

In the XTEND-Kids trial, the most frequently reported TEAEs (in < 5% of patients overall) were SARS-CoV-2 test positive and upper respiratory tract infection (14.9% each); pyrexia (12.2%); asymptomatic COVID-19 (9.5%); gastroenteritis viral, head injury, and nasopharyngitis (8.1% each); arthralgia, pain in extremity, and vomiting (6.8% each); and contusion, diarrhea, viral infection, and viral upper respiratory tract infection (5.4% each). The majority of TEAEs were assessed by the investigator as mild in severity. A total of 10 TESAEs were experienced in 9 (12.2%) patients. All TESAEs were reported in 1 (1.4%) patient each, except vascular device infection which was reported in 2 (2.7%) patients. The majority of TESAEs were assessed by the investigator as mild to moderate in severity. The 5 TESAEs assessed by the investigator as severe were TESAEs of circumcision and bacteremia. No patients discontinued Altuviiio treatment due to a TEAE during the study and no deaths were reported.

The 52-week assessment period of the XTEND-1 and XTEND-Kids studies were determined to be sufficient duration according to input provided by the clinical experts consulted in this review. Both trials included follow-up safety assessments for a few weeks after the last dose, but a longer follow-up period is needed to evaluate delayed adverse effects, which is critical for assessing the long-term safety of Altuviiio. Overall, the safety profile of Altuviiio compared to FVIII prophylaxis remains unknown based on the absence of direct, comparative evidence. An assessment of harms data was not conducted in the ITCs submitted by the sponsor.

Conclusion

Two pivotal phase III, nonrandomized, open-label clinical trials, the XTEND-1 (N = 159) and XTEND-Kids (N = 74) studies, were included in the sponsor’s systemic review to provide evidence on the efficacy and safety of Altuviiio in adult and pediatric patients with severe hemophilia A. Based on the inputs from patients, clinicians, and clinical experts, the most important treatment goals for patients with hemophilia A are to prevent bleeding, including spontaneous and traumatic bleeding events, reduce joint pain, improve HRQoL, and to achieve an unrestricted lifestyle comparable to the general population. In the XTEND-1 and XTEND-Kids studies, patients who received once-weekly Altuviiio administered as weekly prophylaxis for 52 weeks experienced an annual rate of treated bleeds that was considered clinically meaningful, with a mean ABR of 0.71 (95% CI, 0.52 to 0.97) and 0.89 (95% CI, 0.56 to 1.42) in the 2 trials, respectively. Further, the proportion of patients who did not report experiencing a treated bleed was 64.7% and 63.5% in the XTEND-1 and XTEND-Kids studies, respectively. Additionally, the XTEND-1 study included an intrapatient comparison that suggests that Altuviiio may result in an improved ABR compared to the patients’ historical prophylactic therapy, although the evidence is still uncertain. Patients enrolled in the pivotal trials also experienced an annual rate of joint bleeds that was considered clinically meaningful, and although the change from baseline to week 52 in HJHS indicated an improvement in joint health, the magnitude of this effect is unclear due to the small within-group differences and the lack of validated MIDs for this outcome. In adults (the XTEND-1 study) the change from baseline in HRQoL based on the Haem-A-QoL Physical Health score indicated an improvement in QoL; however, the change was not considered clinically meaningful based on the within-group MID identified in the literature. Results for Haem-A-QoL total score in the XTEND-Kids study suggest an improvement for children aged 8 years to 12 years, but these data are highly uncertain due to a small sample size. Although we observed improvement in PROMIS Pain Intensity scores at week 52 in the XTEND-1 study, the magnitude of this effect is unclear given the small within-group differences and the lack of MIDs for this outcome. Perioperative management of bleeds was also assessed and although the evidence is limited by a small sample size, all surgeries were reported as having a good or excellent hemostatic response to perioperative use of Altuviiio. Regarding safety, Altuviiio was well tolerated and the reported TESAEs were generally consistent with what is anticipated in an adult, adolescent, and pediatric population with severe hemophilia A. The majority of TESAEs across both pivotal studies were assessed to be mild in severity. There was no development of inhibitors to FVIII detected in either study, and there were no reports of serious allergic reactions, anaphylaxis, or embolic or thrombotic events.

It should be noted that the certainty of evidence was assessed as very low for all outcomes identified as clinically relevant for this review, with the exception of ABR in adults, which was considered to be of low certainty due to the intrapatient comparison and proportion of patients reporting no bleeds. The review team acknowledges that there are challenges associated with conducting a traditional RCT for rare diseases such as hemophilia A, and that the study design used in the XTEND trials is consistent with other trials for this condition. Nonetheless, the study design limits the interpretation of the safety and efficacy of Altuviiio, particularly as it relates to any comparator. The sponsor submitted indirect evidence to address this gap in the evidence, which suggested that prophylactic treatment with Altuviiio was associated with improved bleeding outcomes compared with the other treatments currently available in practice, such as EHL agents, SHL agents, or emicizumab. However, the magnitude of the clinical benefit of Altuviiio versus these comparator therapies is uncertain and likely overestimated by the study findings due to the limitations of the available indirect evidence, such as a sizable reduction in the ESS from the original sample size after the propensity score weighting analyses, and inadequate or lack of adjustment for potential prognostic factors, which may introduce unmeasurable confounding in the relative treatment effect estimates. Overall, Altuviiio used prophylactically resulted in clinically meaningful rates of bleeding outcomes over 52 weeks of use. Additionally, due to the prolonged half-life relative to other standard and EHL FVIII molecules that is noted in the product monograph, the evidence suggests that Altuviiio represents an additional option that supports a patient-centred approach to the management of hemophilia A.

In the perioperative setting, hemostatic response by Altuviiio was rated as excellent by the investigators and surgeons for all major surgeries. The clinical experts consulted for this review were in agreement that alternative designs like single-arm trials and intrapatient comparison provide practical evaluation of new therapies. Further, concerns with generalizability of the results included no control for multiplicity in the XTEND-Kids study and potential biases introduced by assumptions in the statistical models used to make the comparisons. In addition, the lack of control for physical activity and the potential temporal trends due to the pandemic limits the interpretation of the efficacy outcomes.

References

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