CADTH Reimbursement Review

Abrocitinib (Cibinqo)

Sponsor: Pfizer Canada ULC

Therapeutic area: Atopic dermatitis, moderate to severe

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Table 1: Submitted for Review

NOC = Notice of Compliance.

Introduction

Atopic dermatitis (AD) is the most common type of eczema. It is a chronic, relapsing, inflammatory skin condition characterized by severely itchy skin (pruritus) that results in red and swollen skin (rash). Lesions may appear as fluid-filled vesicles that ooze, crack, and crust. Pruritus of the skin can cause frequent scratching and may result in lichenification (thickening of the skin) and secondary skin infections. Atopic dermatitis typically involves the popliteal (skin folds behind the knees) and the antecubital (skin folds in front of the elbows) areas. It may also appear on the face, neck, and hands. Individuals with AD have skin with impaired barrier function and reduced water-holding capacity, resulting in dry skin that requires treatment with specific bathing, cleansing, and moisturizing practices.

The goals of AD management are to prevent flares (episodes of worsening of symptoms typically requiring escalation of treatment), and effectively manage flares when they occur by preventing disease progression. While there is no cure for AD, several therapeutic options are available to patients to manage the condition. The majority of patients treat AD by avoiding skin irritants and using general skin care methods and topical anti-inflammatory therapy. If these common methods fail to improve AD, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or other therapies such as phototherapy.

The most common pharmaceutical topical therapies include topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs). Topical corticosteroids act as anti-inflammatory therapy and are considered to be the first-line treatment for AD. Topical calcineurin inhibitors are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used long-term. In Canada, the 2 available second-line drugs are pimecrolimus and tacrolimus. Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available in Canada, although it is not recommended for reimbursement by CADTH. Phototherapy is another second-line therapy that is commonly used after failure of TCS, TCIs, and crisaborole.

Systemic therapy for the treatment of AD typically involves the use of antimicrobials, antihistamines, or immunomodulators. Immunomodulatory drugs, including methotrexate, cyclosporine, mycophenolate mofetil, azathioprine (listed in order of frequency of use in Canada), can be used in patients who are not responsive to other treatments. Dupilumab (Dupixent) is an interleukin-4 and interleukin-13 inhibitor indicated for use in adults and pediatrics with moderate to-severe AD whose disease is not adequately controlled with topical prescription therapies or for whom those therapies are not advisable. CADTH recommended that dupilumab be reimbursed with conditions and it is currently reimbursed by the participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure on or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine.

Abrocitinib is a selective Janus kinase-1 (JAK1) inhibitor indicated for the treatment of patients 12 years of age and older with refractory moderate-to-severe AD, including pruritus, who have had an inadequate response to other systemic drugs (steroid or biologic) or for whom these treatments are not advisable. The product monograph states that abrocitinib can be used with or without medicated topical therapies for AD. Abrocitinib is available as 50 mg, 100 mg, and 200 mg oral tablets. The dosage recommended in the product monograph is 100 mg or 200 mg orally once daily, based on individual goals of therapy and the potential risk for adverse reactions. For patients using the 200 mg once daily dosage, a reduction in the dosage to 100 mg once daily can be considered after symptom control is achieved at week 12. Relative to patients who maintained the 200 mg dose, the risk of occurrence of serious adverse reactions was lower in patients who reduced their dose to 100 mg beyond 12 weeks. If symptom control is lost after dose reduction, the dose can be increased to 200 mg. In patients with moderate renal impairment (an estimated glomerular filtration rate [eGFR] of 30 mL/min to < 60 mL/min) or severe renal impairment (an eGFR < 30 mL/min), the recommended dose of abrocitinib should be reduced by 50%.

The objective of this review is to evaluate the beneficial and harmful effects of oral abrocitinib 100 mg and 200 mg once daily for the treatment of patients 12 years of age and older with moderate-to-severe AD, including pruritus, who have had an inadequate response to prescribed topical therapy or for whom these treatments are not advisable.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from a clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Three patient groups responded to CADTH’s call for patient input: the Canadian Skin Patient Alliance (CSPA), Eczéma Québec, and the Eczema Society of Canada (ESC). Eczéma Québec and the CSPA developed and circulated a web-based survey through both organizations’ newsletters and other channels. The survey drew 56 respondents. The ESC gathered survey data from more than 3,000 Canadians who live with AD on topics including quality-of-life impact, experience with systemic treatments, the AD patient journey, and experience with itch related to AD.

The patient groups reported that AD negatively affects mood and the ability to work, attend school, and participate in social interactions, and can cause patients to experience psychological distress. Itch is frequently experienced by patients and is considered the most burdensome symptom of AD, often affecting the ability of patients to sleep. The patient groups are seeking treatments that will reduce itch, decrease the occurrence of flares, reduce inflammation and rashes, and improve their ability to sleep and overall quality of life. Patients, particularly those who are adolescents, want to be able to have the confidence to be more outgoing and social, and patients with skin of colour want to avoid the visible changes in skin pigmentation that can result from scratching, flares, and scarring associated with AD.

Patients affected by AD must often try multiple treatments to find the best option for their circumstances, and these circumstances can change over time. The patient groups emphasized the importance of multiple treatment options to ensure that the specific circumstances of each patient can be addressed.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical expert consulted by CADTH noted that abrocitinib is potentially a useful addition to the currently available therapeutic options for AD. Abrocitinib may be particularly useful for patients who have contraindications to, experience adverse effects from, or who are unresponsive to the use off-label immunosuppressive drugs. Abrocitinib could also provide another treatment option for patients who have been treated with dupilumab but have demonstrated a suboptimal response, developed severe conjunctivitis or other ocular side effects from dupilumab, are intolerant to injections (e.g., due to severe injection-site reactions), and/or would prefer an orally administered treatment.

The clinical expert noted that abrocitinib should be used as an add-on therapy and that all patients should continue regimens involving emollients, TCS, and/or TCIs. Abrocitinib should not be used in combination with off-label immunosuppressives or dupilumab. The clinical expert was of the opinion that many specialists would consider a trial of methotrexate and cyclosporine before initiating treatment with abrocitinib.

The clinical expert suggested that patients less suitable for treatment with abrocitinib would be those with AD who are well controlled with topical therapy, phototherapy, and/or intermittent off-label immunosuppressive therapy, as well as those who are currently well controlled with dupilumab. Abrocitinib should be avoided in patients with potential contraindications to Janus kinase (JAK) inhibitors. Such contraindications include severe active infections, malignancies, ongoing treatment with chemotherapy such as checkpoint inhibitors, severe hepatic disease, severe renal disease, pregnancy and/or lactation, a history of thromboembolic events, and pre-existing hematologic disease.

In general, the outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials of AD treatments. Of these outcome measurements, an improvement of 75% of greater in the Eczema Area and Severity Index total score (EASI-75) after 16 weeks of treatment is a reasonable measure of response. In the opinion of the clinical expert, patients who initiate treatment with abrocitinib would be re-evaluated after 16 weeks (depending on the ability to arrange appointments). Those judged to be responders at this visit would be seen subsequently at 6-month intervals. Those who do not reach response targets at 16 weeks could be re-evaluated after 20 weeks following initiation of drug.

The factors anticipated by the clinical expert to be used as criteria for discontinuation included failure to achieve a clinically meaningful response at 16 to 20 weeks; failure to maintain an adequate response on long-term maintenance; development of a hypersensitivity response judged to be due to abrocitinib; treatment-emergent adverse effects (TEAEs) such as lymphopenia, neutropenia, arterial thrombosis, or venous thromboembolism (VTE); and treatment-emergent severe infections or malignancies.

Administration of the drug involves no special challenges. However, a specialist would still be required to diagnose, treat, and monitor patients taking abrocitinib. Appropriate specialists include pediatric dermatologists, general dermatologists, or pediatricians with experience and interest in AD.

Clinician Group Input

No clinician groups responded to the call for input for the review of abrocitinib.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could affect the implementation of a CADTH recommendation for abrocitinib.

• Access to phototherapy may be limited in some areas of Canada. The clinical expert consulted by CADTH noted that phototherapy is typically accessible in urban areas, but access may be limited in rural areas. The expert noted that this barrier to phototherapy access should be considered in the reimbursement review decision-making process.

• Could abrocitinib be initiated in patients who have failed previous treatment with a biologic drug? The clinical expert noted that patients who have failed dupilumab (with or without prior exposure to an immunomodulator) could be candidates to receive abrocitinib. The clinical expert noted that there is limited evidence supporting the sequential use of abrocitinib after an adequate trial of dupilumab in patients with moderate-to-severe AD.

• Should patients be required to have a previous trial of (or be ineligible for) cyclosporine, methotrexate, and phototherapy before initiating treatment with abrocitinib? The clinical expert consulted by CADTH noted that a trial of 2 of the 4 immunomodulators (methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine) should be considered before initiating abrocitinib.

• Could the reimbursement criteria that were recommended for dupilumab (e.g., initiation and renewal criteria) be applicable to abrocitinib? The clinical expert consulted by CADTH noted that the criteria for dupilumab could be applicable for abrocitinib and could be implemented in clinical practice.

• Should patients be required to undergo an adequate trial with dupilumab before being eligible for treatment with abrocitinib? The clinical expert consulted by CADTH noted that prior therapy with dupilumab should not be required for a patient to be eligible for treatment with abrocitinib, as the 2 drugs have the same indication and potential place in therapy.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The evidence for this review was derived from the results of a systematic literature review of pivotal and phase III studies that was supplemented with additional studies to address important gaps in the evidence from randomized controlled trials (RCTs). The systematic review included 6 double-blind, phase III RCTs: a pair of 12-week placebo-controlled trials conducted with abrocitinib as monotherapy for AD (JADE MONO-1 [N = 387] and JADE MONO-2 [N = 391]); 2 placebo-controlled trials conducted with abrocitinib as combination therapy for AD (JADE COMPARE [N = 838 adults] and JADE TEEN [N = 287 adolescents]); 1 26-week active-controlled trial comparing abrocitinib and dupilumab as combination therapy (JADE DARE [N = 727]); and 1 placebo-controlled, responder-enriched, withdrawal trial (JADE REGIMEN [N = 789]). The evidence from these studies was supplemented with the interim results from 1 long-term extension-phase study (JADE EXTEND) and 3 indirect treatment comparisons (ITCs).

The included studies evaluated a range of outcomes that are important in the management of AD, including overall severity of AD (e.g., the Eczema Area and Severity Index [EASI] and Investigator’s Global Assessment [IGA]), severity of itching (e.g., peak pruritus numerical rating scale [PP-NRS]), symptoms (e.g., Patient-Oriented Eczema Measure [POEM] and Pruritus and Symptoms Assessment for Atopic Dermatitis [PSAAD]), health-related quality of life (e.g., Dermatology Life Quality Index [DLQI] and Children’s Dermatology Life Quality Index [CDLQI]), fatigue (e.g., Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F] scale), patient-reported anxiety and depression, and the need for additional AD medications (e.g., corticosteroid-free days). In addition, the JADE REGIMEN study investigated the use of abrocitinib (100 mg once daily or 200 mg once daily) as a maintenance therapy for patients who achieved an initial response to the abrocitinib 200 mg once daily dosage regimen by evaluating the time to acute worsening of the patient’s condition (i.e., development of a disease flare in accordance with standardized criteria).

The eligibility criteria for the included RCTs were similar except for the differences in the age ranges for the combination-therapy studies (i.e., the JADE COMPARE and JADE DARE trials were limited to adults and the JADE TEEN trial was limited to adolescents) and the need to establish a response to abrocitinib 200 mg once daily to be randomized in the JADE REGIMEN trial. All of the trials enrolled patients with moderate-to-severe AD and an inadequate response to topical AD therapies. This is reflective of the indication that was initially submitted to Health Canada and CADTH; however, the approved indication reflects a more restrictive population (i.e., those with refractory moderate-to-severe AD and an inadequate response to other systemic drugs). The proportions of patients with prior exposure to at least 1 systemic therapy for AD in the included trials were: 48.3% for JADE MONO-1, 41.4% for JADE MONO-2, 43.2% for JADE COMPARE, 47.9% for JADE DARE, 25.6% for JADE TEEN, and 59.5% for JADE REGIMEN (in both the open-label induction phase and the double-blind treatment phase).

Efficacy Results

In the active-controlled, combination-therapy trial (JADE DARE), treatment with abrocitinib 200 mg once daily was superior to dupilumab every 2 weeks in demonstrating an improvement of 90% or greater in the Eczema Area and Severity Index total score (EASI-90) and IGA responses in the initial 20 weeks after starting treatment, but there were no statistically significant differences between the 2 drugs at 26 weeks.¹

When used as monotherapy and combination therapy, abrocitinib 100 mg once daily and 200 mg once daily resulted in statistically significant increases in the proportion of patients who demonstrated an EASI-75 and IGA response at 12 weeks compared with placebo (i.e., the co-primary end points). The adjusted differences for abrocitinib 100 mg once daily and 200 mg once daily (respectively) compared with placebo for an EASI-75 response in each study were: 27.9% (95% confidence interval [CI], 17.4 to 38.3; P < 0.0001) and 51.0% (95% CI, 40.5 to 61.5; P < 0.0001) for the JADE MONO-1 trial; 33.9% (95% CI, 23.3 to 44.4; P < 0.0001) and 50.5% (95% CI, 40.0 to 60.9; P < 0.0001) for the JADE MONO-2 trial; 31.9% (95% CI, 22.2 to 41.6; P < 0.0001) and 43.2% (95% CI, 33.7 to 52.7; P < 0.0001) for the JADE COMPARE trial; and 26.5% (95% CI, 13.1 to 39.8; P = 0.0002) and 29.4% (95% CI, 16.3 to 42.5; P < 0.0001) for the JADE TEEN trial. Similar results were demonstrated for IGA responses at 12 weeks compared with placebo: 15.8% (95% CI, 6.8 to 24.8; P = 0.0037) and 36.0% (95% CI, 26.2 to 45.7; P < 0.0001) for the JADE MONO-1 trial; 19.3% (95% CI, 9.6 to 29.0; P = 0.0008) and 28.7% (95% CI, 18.6 to 38.8; P < 0.0001 for the JADE MONO-2 trial; 23.1% (95% CI, 14.7 to 31.4; P < 0.0001) and 34.8% (95% CI, 26.1 to 43.5; P < 0.0001) for the JADE COMPARE trial; and 16.7% (95% CI, 3.5 to 29.9; P = 0.0147) and 20.6% (95% CI, 7.3 to 33.9; P = 0.0030) for the JADE TEEN trial. The clinical expert consulted by CADTH noted that the results for EASI-75 and IGA responses compared with placebo are clinically meaningful.

In the subgroup of patients with prior use of a systemic immunosuppressant for AD, the adjusted differences for abrocitinib 100 mg once daily and 200 mg once daily (respectively) compared with placebo for an IGA response were: 9.1% (95% CI, −1.2 to 19.4) and 36.2% (95% CI, 22.7 to 49.7) for the JADE MONO-1 trial; 20.4% (95% CI, 6.7 to 34.1) and 26.9% (95% CI, 12.1 to 41.6) for the JADE MONO-2 trial; 27.5% (95% CI, 14.4 to 40.6) and 43.9% (95% CI, 30.7 to 57.1) for the JADE COMPARE trial; and 18.6% (95% CI, −1.7 to 38.9) and 41.7% (95% CI, 18.0 to 65.3) for the JADE TEEN trial. For EASI-75 response, the adjusted differences for abrocitinib 100 mg once daily and 200 mg once daily (respectively) compared with placebo for IGA response were: 17.0% (95% CI, 2.6 to 31.4) and 49.3% (95% CI, 33.8 to 64.7) for the JADE MONO-1 trial; 30.9% (95% CI, 16.4 to 45.3) and 54.6% (95% CI, 39.4 to 69.7) for the JADE MONO-2; and 49.1% (95% CI, 35.5 to 62.7) and 63.0% (95% CI, 50.3 to 75.7) for the JADE COMPARE trial; and 24.7% (95% CI, −1.7 to 51.1) and 39.0% (95% CI, 12.4 to 65.7) for the JADE TEEN trial.

A statistically significantly greater proportion of patients in both the abrocitinib groups demonstrated an EASI-90 response at 12 weeks in the JADE MONO-1, JADE MONO-2, and JADE TEEN trials, and at 16 weeks in the JADE COMPARE trial. Similarly, a statistically significantly greater proportion of patients in both the abrocitinib groups demonstrated an improvement of 100% in the Eczema Area and Severity Index total score (EASI-100) response at 12 weeks in the JADE MONO-1 and JADE MONO-2 trials, and at 16 weeks in the JADE COMPARE trial. There was no statistically significant difference between the abrocitinib and placebo groups for EASI-100 response in the JADE TEEN trial.

Patient groups and the clinical expert consulted by CADTH identified itch as the most burdensome symptom of AD. In both the monotherapy and combination-therapy trials, both doses of abrocitinib resulted in a greater proportion of patients achieving a improvement of 4 or greater from baseline on the peak pruritus numerical rating scale (PP-NRS4). The adjusted differences for abrocitinib 100 mg once daily and 200 mg once daily (respectively) compared with placebo for a PP-NRS4 response in terms of least squares mean difference [LSMD] in each study were 22.5% (95% CI, 10.3 to 34.8; P = 0.0003) and 41.7% (95% CI, 29.6 to 53.9; P < 0.0001) for the JADE MONO-1 trial; 33.7% (95% CI, 22.8 to 44.7; P < 0.0001) and 43.9 (95% CI, 32.9 to 55.0; P < 0.0001) for the JADE MONO-2 trial; 18.1% (95% CI, 6.2 to 30.0; P = 0.0045) and 32.7% (95% CI, 21.0 to 44.4; P < 0.0001) for the JADE COMPARE trial; and 22.8% (95% CI, 8.0 to 37.7; P = 0.0035) and 25.6% (95% CI, 10.6 to 40.6; P = 0.0013) at 12 weeks for the JADE TEEN trial at 16 weeks. The results were statistically significant for all comparisons with the exception of the JADE TEEN trial (due to failure of the statistical testing hierarchy at a higher-order end point of PP-NRS4 at 4 weeks for the abrocitinib 100 mg group) and were considered to be clinically meaningful by the expert consulted by CADTH. No subgroup analyses were performed for PP-NRS4 in the placebo-controlled trials. In the JADE DARE trial, for the co-primary end point of PP-NRS4 at week 2, abrocitinib 200 mg once daily was superior to dupilumab 300 mg every 2 weeks (48.2% versus 25.5%, for a difference of 22.6% [95% CI, 15.8 to 29.5; P < 0.0001]). The difference between the groups that received abrocitinib 200 mg once daily and dupilumab every 2 weeks decreased over time and was similar between the 2 groups from week 12 onward.

Those living with moderate-to-severe AD can experience sleep disruption due to the symptoms of their condition, particularly persistent itch. Both 100 mg once daily and 200 mg once daily dosages of abrocitinib resulted in statistically significant improvements in FACIT-F compared with placebo in the JADE MONO-1 trial (LSMD = 3.6 [95% CI, 0.9 to 6.4; P = 0.0102] and 4.5 [95% CI, 1.8 to 7.3; P = 0.0013], respectively) and the JADE MONO-2 trial (LSMD = 3.3 [95% CI, 0.8 to 5.9; P = 0.0107] and 4.3 [95% CI, 1.8 to 6.9; P = 0.0010], respectively); there was no statistically significant difference between either abrocitinib group and placebo for the smaller subset of adolescent patients who completed the Pediatric Functional Assessment of Chronic Illness Therapy–Fatigue (Peds-FACIT-F). In the combination-therapy trials, the FACIT-F scale was not evaluated in the JADE COMPARE trial and there was no statistically significant difference between either dose of abrocitinib and placebo in the Peds-FACIT-F in the JADE TEEN study. No subgroup analyses were performed for FACIT-F and Peds-FACIT-F.

Patient groups and the clinical expert consulted by CADTH reported that AD can have a profound negative impact on the mental well-being of those living with the condition, and these patients are at risk of experiencing depression. The monotherapy studies and the combination-therapy study in adults demonstrated that both 100 mg once daily and 200 mg once daily dosages of abrocitinib resulted in statistically significant improvements in Hospital Anxiety and Depression Scale (HADS) anxiety scores and depression scores compared with placebo. There was no statistically significant difference in HADS scores between the abrocitinib and placebo groups in the JADE TEEN trial or the abrocitinib and dupilumab groups in the JADE DARE trial. No subgroup analyses were performed for the HADS.

Patient groups noted the importance of treatments that can improve quality of life for those living with moderate-to-severe AD. The included trials evaluated health-related quality of life using the DLQI and CDLQI instruments for adults and adolescents, respectively. Treatment with both abrocitinib 100 mg once daily and 200 mg once daily (respectively) was associated with a statistically significantly greater improvement (i.e., lower scores) in DLQI scores compared with placebo in the JADE MONO-1 trial (LSMD = −2.8 [95% CI, −4.8 to −0.8; P = 0.0072] and −4.9 [95% CI, −6.9 to −2.9; P < 0.0001] at 12 weeks), the JADE MONO-2 trial (LSMD = −4.4 [95% CI, −6.2 to −2.7; P < 0.0001] and −5.9 [95% CI, −7.7 to −4.2; P < 0.0001] at 12 weeks), and the JADE COMPARE trial (LSMD = −2.8 [95% CI, −3.9 to −1.7; P < 0.0001] and −5.6 [95% CI, −6.7 to −4.5; P < 0.0001] at 16 weeks). Similarly, treatment with both abrocitinib 100 mg once daily and 200 mg once daily was associated with a statistically significantly greater improvement in CDLQI scores compared with placebo in the JADE TEEN trial (LSMD = −2.3 [95% CI, −3.7 to −0.8; P = 0.0026] and −2.3 [95% CI, −3.8 to −0.9; P = 0.0018], respectively). For the adolescent subgroup of patients in the monotherapies, only the 200 mg once daily group demonstrated a statistically significant improvement in CDLQI scores compared with placebo. In the JADE DARE trial, the change from baseline in DLQI scores was greater in the abrocitinib 200 mg group compared with the dupilumab treatment group from week 2 to week 20; however, the difference between the abrocitinib and dupilumab groups decreased over time and was no longer statistically significant at 26 weeks. No subgroup analyses were performed for the DLQI and CDLQI.

As shown in Table 2 and Table 3, treatment with both doses of abrocitinib typically resulted in statistically significant improvements in the additional secondary end points compared with placebo, including PSAAD, Scoring Atopic Dermatitis (SCORAD), POEM, Short Form (36) Health Survey Version 2 (SF-36v2), and Patient Global Assessment (PtGA), although most of these end points were analyzed outside of the statistically testing hierarchy. The JADE DARE trial demonstrated that abrocitinib was superior to dupilumab for improving SCORAD and POEM results in the initial weeks after treatment initiation, but there were no statistically significant differences at week 26. No subgroup analyses were performed for these end points.

Exploratory analyses demonstrated that initiating treatment with the abrocitinib 200 mg once daily regimen was generally more efficacious than the 100 mg once daily regimen for establishing a response to treatment in the 12- to 16-week time frame that was used in the phase III clinical trials. The clinical expert consulted by CADTH noted that specialists are likely to initiate treatment with the higher dosage for most patients and then may consider reducing the dosage based on the patient’s response to therapy and/or tolerability. This approach for reducing the 200 mg dosage is aligned with the dosing recommendations in the product monograph (i.e., for patients using the 200 mg once daily dosage, a reduction of the dosage to 100 mg once daily can be considered after symptom control is achieved).

Harms Results

Abrocitinib 100 mg once daily and 200 mg once daily were generally well tolerated, with few serious adverse events (SAEs) or withdrawals due to adverse events (WDAEs) for up to 16 weeks in the phase III trials and 48 weeks in the interim analysis of the long-term extension-phase study (JADE EXTEND). No subgroup analyses based on prior exposure to at least 1 systemic therapy for AD were performed for adverse events (AEs).

In the monotherapy studies (JADE MONO-1 and JADE MONO-2), the proportions of patients who had at least 1 AE were greater in the abrocitinib 100 mg once daily (69.2% and 62.7%, respectively) and 200 mg once daily (77.9% and 65.8%, respectively) groups compared with the placebo groups (57.1% and 53.8%, respectively). Nausea, headaches, and acne occurred in at least 5% more abrocitinib-treated patients compared with the placebo group. The proportions of patients with at least 1 SAE were similar between abrocitinib groups (3.2% in both) and the placebo group (3.9%) in the JADE MONO-1 trial. In the JADE MONO-2 trial, the proportions with at least 1 SAE were 3.2% in the abrocitinib 100 mg once daily group, 1.3% in the abrocitinib 200 mg once daily group, and 1.3% in the placebo group. In the JADE MONO-1 trial, the proportions of patients who withdrew because of AEs were 9.1% in the placebo group, 5.8% in the abrocitinib 100 mg once daily group, and 5.8% in the abrocitinib 200 mg once daily group. In the JADE MONO-2 trial, the proportions of patients who withdrew because of AEs were 12.8% in the placebo group, 3.8% in the abrocitinib 100 mg once daily group, and 3.2% in the abrocitinib 200 mg once daily group. Withdrawals due to AEs included events categorized as worsening AD, which contributed to the high proportion of WDAEs within the placebo groups of the monotherapy studies. Serious infections and opportunistic infections were rare in the monotherapy studies. Elevated blood creatine phosphokinase (CPK) was reported for numerically more patients in abrocitinib groups compared with placebo. No malignancies, major adverse cardiovascular events (MACEs), or VTE events were reported during the trials.

When used as combination therapy in adults, the proportion of patients who had at least 1 TEAE was greater in the abrocitinib 200 mg group (61.9%) compared to the abrocitinib 100 mg (50.8%), dupilumab 300 mg every 2 weeks (50.0%), and placebo (53.4%) groups in the JADE COMPARE trial. In the JADE DARE trial, the proportion of patients who had at least 1 TEAE was greater in the abrocitinib 200 mg group (74.0%) compared to the dupilumab 300 mg every 2 weeks group (65.5%). Most events were mild or moderate in severity in both the JADE COMPARE and JADE DARE trials. Nausea, headaches, and acne were the most reported AEs in the abrocitinib groups, and conjunctivitis was the most frequently reported in the dupilumab group. The proportions of patients with at least 1 SAE were 3.8% in the placebo group, 2.5% in the abrocitinib 100 mg once daily group, 0.9% in the abrocitinib 200 mg group, and 0.8% in the dupilumab group of the JADE COMPARE trial and 1.7% in the abrocitinib 200 mg group and 1.6% in the dupilumab every 2 weeks group of the JADE DARE trial. The proportions of patients who withdrew because of AEs were 3.8% in the placebo group, 2.5% in the abrocitinib 100 mg once daily group, 4.4% in the abrocitinib 200 mg once daily group, and 3.3% in the dupilumab group of the JADE COMPARE trial and 3.3% in the abrocitinib 200 mg once daily group and 2.5% in the dupilumab group of the JADE DARE trial.

When used as combination therapy in adolescents (in the JADE TEEN trial), the proportion of patients who had at least 1 AE was greater in the abrocitinib 200 mg once daily group (62.8%) compared to the abrocitinib 100 mg once daily (56.8%) and placebo (52.1%) groups. Nausea and acne were more commonly reported with abrocitinib compared with placebo. Two SAEs were reported in the placebo group and 1 SAE was reported in the abrocitinib 200 mg once daily group. The proportions of patients who withdrew because of AEs were 2.1% in the placebo group, 1.1% in the abrocitinib 100 mg once daily group, and 2.1% in the abrocitinib 200 mg once daily group.

Serious infections and opportunistic infections were rare in the combination-therapy studies. Herpes zoster and elevated blood CPK were reported for numerically more patients in the abrocitinib groups compared with the placebo group in both the JADE COMPARE and JADE TEEN trials. No malignancies, MACEs, or VTE events were reported during the trials for patients treated with abrocitinib patients (a malignancy was reported for 1 patient treated with dupilumab in the JADE COMPARE trial).

Table 2: Summary of Key Results From Monotherapy Studies

AE = adverse event; BSA = body surface area; CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-75 = improvement of 75% or greater in the Eczema Area and Severity Index total score; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; LSM = least squares mean; LSMD = least squares mean difference; NR = not reported; POEM = Patient-Oriented Eczema Measure; PP-NRS4 = improvement of 4 or greater from baseline on peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.d. = once daily; SAE = serious adverse event; SCORAD-75 = improvement of 75% or greater in Scoring Atopic Dermatitis; SD = standard deviation; SF-36 = Short Form (36) Health Survey; vs. = versus.

Note: The full analysis set was used for all efficacy end points and the safety analysis set was used for all AE end points.

^aThe estimate and CI for difference were calculated based on the weighted average of difference for each randomization stratum using the normal approximation of binomial proportions. P values were calculated using the Cochran-Mantel-Haenszel method adjusted by randomization strata (baseline disease severity and age category).

^bThe mixed model for repeated measures contained fixed factors of treatment, visit, treatment by visit interaction, stratification factors, baseline value and an unstructured covariance matrix.

Source: Clinical Study Reports.^2,3

Table 3: Summary of Key Results From Placebo-Controlled Combination-Therapy Studies

AE = adverse event; BSA = body surface area; CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-75 = improvement of 75% or greater in the Eczema Area and Severity Index total score; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; LSM = least squares mean; LSMD = least squares mean difference; NA = not applicable; NR = not reported;; POEM = Patient-Oriented Eczema Measure; PP-NRS4 = improvement of 4 or greater from baseline on peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.2.w. = every 2 weeks; q.d. = once daily; SAE = serious adverse event; SCORAD-75 = improvement of 75% or greater in Scoring Atopic Dermatitis; vs. = versus.

Note: The full analysis set was used for all efficacy end points and the safety analysis set was used for all AE end points.

^aDifferences between abrocitinib and dupilumab were calculated, but no statistical comparisons were made between the groups.

^bThe estimate and CI for difference were calculated based on the weighted average of difference for each randomization stratum using the normal approximation of binomial proportions. P values were calculated using the Cochran-Mantel-Haenszel method adjusted by randomization strata (baseline disease severity and age category).

^cThe mixed model for repeated measures contained fixed factors of treatment, visit, treatment by visit interaction, stratification factors, baseline value and an unstructured covariance matrix.

Source: Clinical Study Reports.^4,5

Table 4: Summary of Key Results From Active-Controlled Combination-Therapy Study

AE = adverse event; CI = confidence interval; EASI-90 = improvement of 90% or greater in the Eczema Area and Severity Index total score; HADS = Hospital Anxiety and Depression Scale; LSM = least squares mean; LSMD = least squares mean difference; NA = not applicable; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.d. = once daily; SAE = serious adverse event; vs. = versus.

Note: The full analysis set was used for all efficacy end points and the safety analysis set was used for all AE end points.

Source: Clinical Study Reports.¹

Critical Appraisal

Randomization was stratified based on relevant prognostic factors in the JADE MONO-1, JADE MONO-2, and JADE TEEN trials (i.e., baseline AD severity [moderate or severe] in all 3 studies and age [< 18 years or ≥ 18 years] in the JADE MONO-1 and JADE MONO-2 trials). There was no stratification at the time of randomization in the JADE COMPARE trial, stratification was based only on age (< 18 years or ≥ 18 years) in the JADE REGIMEN trial, and stratification was based on disease baseline AD severity in the JADE DARE trial. The baseline and demographic characteristics were generally well balanced across the treatments of each of the studies. The study treatments were administered in a double-blind manner, and a double-dummy design was used to maintain blinding in the JADE COMPARE and JADE DARE trials to account for the oral administration of abrocitinib and the subcutaneous injection of dupilumab. The AE profile of abrocitinib and the comparators (placebo or dupilumab) was unlikely to compromise blinding in any of the included trials. As the trials were placebo-controlled, it is possible that some patients could have inferred their allocated treatment assignment due to improvement or lack of improvement in AD over the study period and the use of rescue medication, which occurred in a higher proportion of patients in the placebo groups of the included studies. Withdrawals due to AEs included events categorized as worsening AD, which contributed to the high proportion of WDAEs within the placebo groups of the monotherapy studies. Adherence to the study treatments was evaluated by counting the number of study drugs at each visit. Median compliance was 100% across all treatment groups. Few patients discontinued from the combination-therapy trials (completion rates ranged from 89.3% to 96.8% across the treatment groups), but the completion rates were considerably lower in the placebo groups of the monotherapy trials (79.2% and 66.7% in JADE MONO-1 and JADE MONO-2 trials, respectively) compared with the abrocitinib groups (range = 86.5% to 91.0%). True intention-to-treat analyses were not performed; however, the full analysis set (FAS) included nearly all randomized patients, and sensitivity analyses were performed to investigate the impact of missing data. Data were more commonly missing in the placebo arms of the studies, and this may have biased the results in favour of the active treatments as analysis approaches and imputation of missing data assumed the data were missing at random (MAR) (e.g., missing data were imputed as nonresponders); however, numerous sensitivities analysis were performed to investigate the impact of missing data and the results remained robust.

Hierarchies were statistically significant at all end points in the statistical testing in the JADE MONO-1, JADE MONO-2, JADE COMPARE, and JADE DARE trials. The statistical testing hierarchy was stopped at the first key secondary end point of the JADE TEEN trial (i.e., PP-NRS4 response); however, the sponsor continued to calculate and report P values for the remaining key secondary end point (i.e., nominal P values were considered to be descriptive). Subgroup analyses, secondary end points, and exploratory end points were tested without adjustment for multiple comparisons, and all P values are considered nominal. Subgroup analyses for patients with prior exposure to at least 1 systemic therapy for AD were limited to the primary and key secondary end points (e.g., IGA and EASI-75 responses). Imbalances in baseline disease severity were evident across the treatment groups in the subgroup analyses based on prior exposure to at least 1 systemic therapy for AD. The clinical expert consulted by CADTH indicated that, overall, these analyses suggest that the response to abrocitinib would likely be similar for those with and those without prior exposure to a systemic therapy for AD.

The diagnostic criteria used in the screening process for the included studies were consistent with Canadian clinical practice for identifying patients with moderate-to-severe AD. Overall, the clinical expert consulted by CADTH indicated that the populations enrolled in the included trials were a reasonable reflection of the target population in Canada. The clinical expert consulted by CADTH noted that the co-primary end points (EASI and IGA) are clinically relevant and can be evaluated in routine Canadian practice for determining response to treatment with abrocitinib (i.e., for the purposes of establishing renewal criteria for reimbursement by the public drug programs).

As AD is a chronic disease, abrocitinib would likely be used as a long-term treatment for patients who require systemic therapy. The placebo-controlled trials were short-term (12 and 16 weeks) with only limited data available from the longer-term studies (JADE EXTEND and JADE REGIMEN) at the time of this review. Complete reporting of the longer-term studies will help characterize the longer-term efficacy and safety of abrocitinib in the treatment of AD.

Indirect Comparisons

Description of Studies

CADTH summarized and appraised 3 ITCs: 2 unpublished comparisons submitted by the sponsor (1 network meta-analysis [NMA] and 1 matched-adjusted indirect comparison [MAIC]) and a published ITC by the Institute for Clinical and Economic Review (ICER). The NMAs compared abrocitinib against dupilumab (the only drug approved for use in the treatment of AD at the time of this review), upadacitinib and tralokinumab (currently under review by Health Canada and CADTH for use in the treatment of AD), and several drugs that were not listed as under review by Health Canada or CADTH at the time of this review (e.g., nemolizumab, lebrikizumab, and baricitinib). The MAIC compared abrocitinib 100 mg once daily and 200 mg once daily against cyclosporine and methotrexate (2 drugs that are not approved by Health Canada for use as systemic treatments for AD but are commonly used in Canada).

Efficacy Results

Population With Prior Exposure to a Systemic Therapy for AD (Subgroup Analysis From Sponsor’s Network Meta-Analysis

Subgroup analyses for patients reporting AD treatment failure with systemic immunosuppressants before study enrolment were limited to IGA response and EASI-75 for the monotherapy studies. Comparisons could only be conducted for abrocitinib 100 mg once daily, abrocitinib 200 mg once daily, dupilumab 200 or 300 mg every 2 weeks, and placebo. The odds ratios for IGA response were: ||||| |||| |||| |||| || |||||| for abrocitinib 200 mg once daily versus placebo, |||| |||| |||| |||| || |||||) for abrocitinib 200 mg once daily versus dupilumab 200 mg or 300 mg every 2 weeks, and |||| |||| |||| |||| || ||||| for abrocitinib 200 mg once daily versus abrocitinib 100 mg once daily. The odds ratios for EASI-75 response were: ||||| |||| |||| |||| || |||||| for abrocitinib 200 mg once daily versus placebo, ||||| |||| |||| |||| || ||||||) for abrocitinib 200 mg once daily versus dupilumab 200 mg or 300 mg every 2 weeks, |||| |||| |||| |||| || |||||| for abrocitinib 200 mg once daily versus dupilumab 300 mg every 2 weeks, and |||| |||| |||| |||| || ||||| for abrocitinib 200 mg once daily versus abrocitinib 100 mg once daily.

Subgroup analyses for patients reporting AD treatment failure with systemic immunosuppressants before study enrolment were limited to a single composite end point (improvement of 50% or greater in the Eczema Area and Severity Index total score [EASI-50] plus DLQI improvement of ≥ 4 points) in the combination-therapy NMA. Comparisons could only be conducted for abrocitinib 100 mg once daily, abrocitinib 200 mg once daily, dupilumab 300 mg every 2 weeks, and placebo. The odds ratios for achieving an EASI-50 response and a DLQI improvement of 4 or more points were: |||| |||| |||| |||| || |||||| for abrocitinib 200 mg once daily versus placebo, |||| |||| |||| |||| || ||||| for abrocitinib 200 mg once daily versus dupilumab 300 mg every 2 weeks, and |||| |||| |||| |||| || ||||| for abrocitinib 200 mg once daily versus abrocitinib 100 mg once daily.

Overall Population

The sponsor’s NMA reported that ||||||||||| ||| || |||| |||||| |||||||||||| || || ||| || || |||| |||||| ||| ||||||||| ||| || ||||| | ||||| were consistently the most efficacious treatments across the efficacy outcomes evaluated in the NMA. Based on improvements in the EASI, abrocitinib 200 mg once daily was superior to |||||||| ||||||||||| ||| || |||| |||||| ||| ||||||||| ||| || ||||| | ||||| |||| ||||| |||||||||| |||| |||| || |||||||||||. When used in combination with topical therapies, abrocitinib 200 mg once daily was |||||||| || |||||||| ||||||||||| ||| || |||| |||||| ||| |||||||||||| ||| || ||||| | |||||. The results of the NMA conducted by the ICER were generally similar to those reported by the sponsor with respect to the comparative efficacy of abrocitinib 200 mg once daily. The sponsor’s NMA did not compare abrocitinib 100 mg once daily against all of the comparators (only placebo). However, the ICER’s NMA reported that, for most efficacy outcomes, abrocitinib 100 mg was either inferior or occasionally comparable to upadacitinib (30 mg and 15 mg once daily), abrocitinib 200 mg once daily, and dupilumab 300 mg every 2 weeks, while it was superior (or occasionally comparable) to both tralokinumab 300 mg every 2 weeks and placebo.

The sponsor-submitted MAIC reported that abrocitinib at both 100 mg once daily and 200 mg once daily dosages ||| || |||| ||||||||||| |||| |||||||||||| ||| ||||||||||||.

Harms Results

In the NMAs, the TEAEs and discontinuations due to AEs were similar across abrocitinib and the comparators. The sponsor-submitted MAIC reported that abrocitinib at both 100 mg once daily and 200 mg once daily dosages ||| |||| | ||||||| || |||||| |||||| ||||||| |||| |||||||| || |||||||||||| ||| ||||||||||||. No subgroup analyses were conducted for the AE end points.

Critical Appraisal

Subgroup analyses for patients reporting AD treatment failure with systemic immunosuppressants before study enrolment were limited to IGA response and EASI-75 for the monotherapy NMAs and a single composite end point (EASI-50 plus DLQI improvement of ≥ 4 points) in the combination-therapy NMAs. Due to the small number of patients in the LIBERTY AD ADOL trial with prior exposure to at least 1 systemic therapy for AD (n = 11 for the dupilumab 200 mg every 2 weeks or 300 mg every 2 weeks group and n = 9 for the placebo group), there was considerable uncertainty in the estimates of effect for the monotherapy NMA for IGA response. Similar to the primary NMA analyses, abrocitinib 200 mg once daily was |||||||| || ||||||||| ||| || ||||| |||||| ||| ||||||| ||||||||. In the combination-therapy NMA, abrocitinib 200 mg once daily was ||||||| || ||||||||| ||| || ||| ||| ||||||||||||| | |||||||| ||||||| |||||||| ||| || ||||||||||| || || ||||| | |||||| || ||||.

The sponsor-submitted NMA did not report on the relative efficacy and safety of abrocitinib 100 mg when compared with other treatments. Most importantly, no conclusions regarding the long-term efficacy of abrocitinib compared to the active comparators relevant to this review can be drawn as the NMA used study results collected over a relatively short duration compared to the chronic nature of AD. The inherent heterogeneity across trials in the networks also introduces uncertain to interpretation of the results of the trials. The robustness of the comparative efficacy was further compromised by the lack of precision in some of the findings, and results from the sponsor-submitted ITC must be interpreted with caution. The conclusion for the MAIC must be weighed against the highly unstable nature of unanchored indirect comparisons which, while being improvements on naive comparisons, are still highly prone to potential biases. Until direct evidence is available, the efficacy and safety differences between abrocitinib and cyclosporine-methotrexate will remain inconclusive.

Other Relevant Evidence

Description of Studies

The JADE EXTEND trial is an ongoing multi-centre, quadruple-masked, randomized phase III study of the long-term efficacy and safety of abrocitinib with or without topical medications in patients aged 12 years and older with moderate-to-severe AD. Patients who complete the JADE MONO-1, JADE MONO-2, JADE COMPARE, JADE TEEN, or JADE REGIMEN studies are eligible for enrolment in the JADE EXTEND trial. Only limited data for patients from the JADE MONO-1 and JADE MONO-2 trials were available at the time of the CADTH review. Patients in the JADE EXTEND trial remained on the same dose of abrocitinib that they received in the parent study, and patients in the placebo groups of the parent study were re-randomized to treatment with abrocitinib 100 mg once daily or 200 mg once daily. The end points reported for the JADE EXTEND trial included IGA, EASI-75, and PP-NRS4 response.

At the data cut-off date of April 22, 2020, for the interim analysis, 520 eligible patients who participated in the JADE MONO-1 and JADE MONO-2 trials were included in the JADE EXTEND trial. Abrocitinib monotherapy was maintained in 361 of 520 patients in the JADE EXTEND trial, while 159 patients received combination therapy of abrocitinib and topical medication. Approximately 25% of patients in both the 100 mg once daily and 200 mg once daily abrocitinib groups had discontinued from the JADE EXTEND trial by week 48.

Efficacy Results

The sponsor reported interim results for 48 weeks of treatment for patients who completed the JADE MONO-1 or JADE MONO-2 trials. The IGA response rate increased from 26.0% to 45.2% in the abrocitinib 100 mg once daily group and from 40.9% to 60.5% in the abrocitinib 200 mg once daily group between week 12 and week 48 of treatment. The EASI-75 response rate increased from 42.1% to 68.0% in the abrocitinib 100 mg once daily group and from 61.9% to 87.2% in the abrocitinib 200 mg once daily group between week 12 and week 48 of treatment. The PP-NRS4 response rate increased from 41.6% to 52.0% in the abrocitinib 100 mg once daily group and from 56.3% to 72.5% in the abrocitinib 200 mg once daily group between week 12 and week 48 of treatment.

The clinical expert consulted by CADTH noted that an important gap in the phase III evidence base is the use of abrocitinib in patients who experienced an inadequate response or whose condition is no longer controlled by treatment with dupilumab. As such, CADTH included the information available for this subgroup of patients from JADE EXTEND. The sponsor reported exploratory analyses to evaluate the efficacy of 12 weeks of abrocitinib treatment in patients who were previously treated with dupilumab for 16 weeks in the JADE COMPARE trial and failed to demonstrate IGA, EASI-75, and PP-NRS4 responses. Further subgroup analyses were conducted for primary nonresponders (defined as patients who did not achieve a response at any visit through week 16 of the JADE COMPARE trial) and secondary nonresponders (defined as patients who had achieved a response at any time before week 16 but were nonresponders at week 16). Responses for the IGA were reported for 34.3% and 47.2% of dupilumab nonresponders who received 12 weeks of abrocitinib 100 once daily and abrocitinib 200 once daily, respectively. Responses of an EASI-75 were reported for 67.7% and 80.0% of dupilumab nonresponders who received 12 weeks of abrocitinib 100 once daily and abrocitinib 200 once daily, respectively. Responses of a PP-NRS4 were reported for 37.8% and 81.0% of dupilumab nonresponders who received 12 weeks of abrocitinib 100 once daily and abrocitinib 200 once daily, respectively.

Harms Results

No harms data were reported for JADE EXTEND at the time of the submission to CADTH.

Critical Appraisal

The JADE EXTEND trial is an ongoing, double-blind extension study that enrolled patients from the phase III RCTs. Only interim data were available at the time of the submission to CADTH, and reporting was limited to an interim analysis with partial reporting (i.e., a clinical study report was not available to enable a thorough appraisal). Extension studies are often limited by selection bias, as only patients who are tolerant to treatment and complete the parent studies are eligible to enrol. At the time of interim analysis, a large proportion of patients had withdrawn from both the abrocitinib 100 mg once daily (22.9%) and abrocitinib 200 mg once daily (20.0%) groups at 48 weeks.⁶ Issues with the generalizability of these data are the same as for the parent double-blind studies. Patients were considered to be dupilumab nonresponders if they failed to demonstrate an IGA, EASI 75, and PP-NRS4 response after 16 weeks of treatment, which was likely insufficient time to fully realize the maximal treatment effects for dupilumab. The CADTH reimbursement recommendation for dupilumab for patients aged 12 years and older with moderate-to-severe AD advises evaluating the response to treatment after 6 months of treatment.

Conclusions

Four double-blind RCTs demonstrated that, compared with placebo, 12 or 16 weeks of treatment with abrocitinib was associated with statistically significant and clinically meaningful improvements in a range of outcomes that are important to the management of AD, including overall severity of AD (EASI and IGA response), severity of itching (PP-NRS4 response), symptoms (POEM and PSAAD), health-related quality of life (DLQI and CDLQI), fatigue (FACIT-F), and patient-reported anxiety and depression. These trials included the use of abrocitinib as monotherapy (JADE MONO-1 [N = 387] and JADE MONO-2 [N = 391]) and as combination therapy (JADE COMPARE [N = 838 adults] and JADE TEEN [N = 287 adolescents]). One active-controlled trial demonstrated that abrocitinib 200 mg once daily was superior to dupilumab for improving symptoms in the initial weeks after starting treatment, but no significant differences were seen between the 2 drugs at 26 weeks. All of the trials enrolled patients with moderate-to-severe AD and an inadequate response to topical AD therapies. This is reflective of the indication that was initially submitted to Health Canada and CADTH; however, the approved indication reflects a more restrictive population (i.e., those with refractory moderate-to-severe AD and an inadequate response to other systemic drugs). The sponsor conducted pre-specified subgroup analyses based on prior exposure to at least 1 systemic immunosuppressant for AD for the co-primary end points of each trial (i.e., EASI-75 and IGA response). The clinical expert consulted by CADTH indicated that the subgroup analyses suggest that the response to abrocitinib would likely be similar for those with and those without prior exposure to a systemic therapy for AD.

All of the included studies suggest that initiating treatment with abrocitinib using the 200 mg once daily regimen was generally more efficacious than the 100 mg once daily regimen for establishing a response to treatment in the 12- to 16-week time frame that was studied in the trials. In addition, the JADE REGIMEN study demonstrated that responders who continue to receive 200 mg once daily as maintenance treatment were less likely to experience a disease flare than those who received 100 mg once daily or placebo.

The product monograph states that there is a risk of serious infections, malignancies, and thrombosis with abrocitinib and other JAK inhibitors. Serious AEs and WDAEs were rare in the included studies. As AD is a chronic disease, abrocitinib would likely be used as a long-term treatment for patients who require systemic therapy. Abrocitinib was well tolerated in the target patient population (i.e., at least 12 years of age with moderate-to-severe AD) in the short term 12- and 16-week phase III studies. No safety data were reported for the interim analysis of the long-term extension study (JADE EXTEND) and only limited data were available from the 52-week JADE REGIMEN trial. Data on AEs in the JADE REGIMEN trial were generally consistent with those observed during the parent studies, but with a numerical increase in the incidence of SAEs per 100 person-years with abrocitinib 200 mg once daily (7.77; 95% CI, 4.25 to 13.04) compared with the abrocitinib 100 mg once daily (2.69; 95% CI, 0.73 to 6.88) and placebo (3.18; 95% CI, 0.39 to 11.49). The ongoing JADE EXTEND study will help better characterize the longer-term efficacy and safety of abrocitinib in the treatment of AD.

Network meta-analyses from the sponsor suggest that ||||||||||| ||| || |||| |||||| |||||||||||| || || ||| || || |||| |||||| ||| ||||||||| ||| || ||||| | ||||| |||| ||||||||| ||||||||||| across the outcomes that were evaluated. Subgroup analyses for patients reporting AD treatment failure with systemic immunosuppressants before study enrolment were limited to IGA response and EASI-75 for the monotherapy studies and a single composite end point (EASI-50 response and a DLQI improvement of ≥ 4 points) in the combination-therapy NMA. There was considerable uncertainty in the estimates of effect for the monotherapy NMA for IGA response; however, similar to the primary NMA analyses, abrocitinib 200 mg once daily ||| |||||||| || ||||||||| ||| || ||||| |||||| ||| ||||||| ||||||||. The NMA from the ICER suggests that abrocitinib 100 mg was either inferior or occasionally comparable to upadacitinib 30 mg and 15 mg once daily, abrocitinib 200 mg once daily, and dupilumab 300 mg every 2 weeks. The sponsor-submitted MAIC reported that abrocitinib at dosages of both 100 mg once daily and 200 mg once daily ||| || |||| ||||||||||| |||| |||||||||||| ||| ||||||||||||. No subgroup analyses were reported for the MAIC, and the ICER’s NMA did not report a subgroup analysis based on prior exposure to at least 1 systemic therapy for AD. No conclusions regarding the long-term efficacy of abrocitinib compared to the active comparators relevant to this review can be drawn as the NMA used study results collected over a relatively short duration compared to the chronic nature of AD. The inherent heterogeneity across trials in the networks also introduces uncertainty to interpretation of the results of the trials. The robustness of the comparative efficacy was further compromised by a lack of precision in some of the findings, and results from the indirect comparisons must be interpreted with caution.

Introduction

Disease Background

Atopic dermatitis is the most common type of eczema. It is a chronic, relapsing, inflammatory skin condition characterized by severely itchy skin (pruritus) that results in red and swollen skin (rash). Lesions due to AD may appear as fluid-filled vesicles that ooze, crack, and crust. Pruritus of the skin can cause frequent scratching and may result in lichenification (thickening of the skin) and secondary skin infections. The disease typically involves skin folds in the popliteal (behind the knees) and antecubital (front of the elbows) areas. It may also appear on the face, neck, and hands. Individuals with AD have skin with impaired barrier function and reduced water-holding capacity, resulting in dry skin that requires treatment with specific bathing, cleansing, and moisturizing practices.

Atopic dermatitis is a hereditary form of eczema that generally presents in infancy with most cases beginning before the age of 5 years. The majority of these children will outgrow the condition by adolescence. It is common for children with AD to develop asthma and/or hay fever. This process is referred to as the “atopic march,” and AD is often the first step in the sequential development of these other atopic conditions. The clinical manifestations of AD vary with age, with infants showing AD on the extensor surfaces of extremities, face, neck, scalp, and trunk. Children are typically affected on the flexural surfaces of the extremities, neck, wrists, and ankles, while adolescents and adults are generally affected on the flexural surfaces of the extremities and the hands and feet.

The Canadian Dermatology Association reports that the lifetime prevalence of AD is up to 17% in the Canadian population, and evidence suggests that the prevalence has increased over the past 30 years. Patients often experience worsening itching symptoms throughout the night, and this may result in sleep loss, which may result in detrimental effects pertaining to school or work. Individuals with AD may also suffer from the social stigma of having a highly visible condition. Overall, these patient experiences describe a physically and mentally exhausting condition that can result in anxiety, depression, and a decrease in the quality of life.

The goals of AD management are to prevent flares (episodes of worsening of symptoms typically requiring escalation of treatment), and effectively manage flares when they occur by preventing disease progression. While there is no cure for AD, several therapeutic options are available to patients to manage the condition. The majority of patients treat AD by avoiding skin irritants and using general skin care methods and topical anti-inflammatory therapy. If these common methods fail to improve AD, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or other approaches, such as phototherapy.

Standards of Therapy

General Skin Care

General skin care practices for patients with AD include irritant avoidance and managing dry skin. The symptoms of AD may be reduced or prevented through the avoidance of known skin irritants or triggers.^7-9 Some common irritants include temperature, humidity, dust, pets (animal dander), smoke, and grass. Using mild detergents with no bleach or fabric softener to wash clothing and double-rinsing clothing has been recommended to those with AD. Dry skin associated with AD can be countered through specific bathing, cleansing, and moisturizing practices. Baths using lukewarm water and emulsifying oils followed by the use of moisturizers area recommended. Limiting the use of soap and fragranced products may also help reduce symptoms.^7,8

Topical Therapy

While a number of nonpharmacological topical therapies exist for treating the symptoms of AD, the most common therapy is the use of moisturizers. The use of moisturizers is important to combat dry skin through hydration and the prevention of trans-epidermal water loss. Moisturizers, which are routinely used to provide some barrier protection for the skin from irritants or allergens, can soften skin, reduce itching, and minimize cracking, fissuring, and lichenification. Moisturizers are routinely used frequently throughout the day, preferably after bathing. Moisturizers can contain a combination of emollients, humectants, and occlusive drugs.^7,9,10 Emollients (e.g., glycol and glyceryl stearate and soy sterols) lubricate and soften the skin by smoothing out the surface of the skin and filling the spaces with droplets. Humectants (e.g., glycerol, lactic acid, and urea) attract water and increase the skin’s water-holding capacity. Humectants sting open skin and are not useful in children with AD. Occlusive drugs (e.g., petrolatum, dimethicone, and mineral oil) provide a layer of oil on the surface of the skin to slow trans-epidermal water loss, prevent water loss though evapouration, and increase the moisture content of the skin. The choice of moisturizer depends on the area of the body and the degree of dryness of the skin.^7,9,10

The most common pharmaceutical topical therapies include the use of TCS and TCIs. The former act as anti-inflammatory therapy and are considered to be the first-line treatment for AD.⁷ The more than 30 different types of TCS come in the form of lotions, creams, oily creams, ointments, or gels, and they can be combined with other drugs such as antibiotics. Topical corticosteroids vary in potency. In Canada, low-potency (1%) hydrocortisone is the most commonly prescribed type of TCS for the face. For the body, triamcinolone or betamethasone valerate (moderate potency) are most commonly prescribed. Topical corticosteroids are applied directly to the area of affected skin before the use of emollients, and a response is typically seen within 10 to 14 days. Side effects associated with the long-term use of TCS include striae (stretch marks), petechiae (small red and/or purple spots), telangiectasia (small, dilated blood vessels on the surface of the skin), skin thinning, atrophy, and acne.^7,9-11 Topical corticosteroids are also recommended for use in children according to the American Academy of Dermatology (AAD), with cautions regarding dosing, as children have a larger ratio of surface area to body mass, and there are mixed results from various studies suggesting that systemic absorption may have an impact on growth.^7,10

Topical calcineurin inhibitors are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used long-term. In Canada, the 2 available second-line drugs are pimecrolimus and tacrolimus. Pimecrolimus 1% cream can be used for short-term and intermittent long-term therapy for mild-to-moderate AD and is effective in controlling pruritus.^10,11 Topical tacrolimus, an ointment that can be used for short-term and intermittent long-term therapy of moderate-to-severe AD, demonstrates rapid and sustained AD symptom control. The most common AE associated with TCIs is application site–specific burning and irritation. A black-box warning remains for TCIs regarding lymphoma; however long-term 10-year surveillance studies have not found an increased risk of lymphoma over that of the general pediatric population.

Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available in Canada, although it is not recommended for reimbursement by CADTH.¹² The advantage of TCIs and crisaborole is that both can be safely applied to the face and creases, whereas TCS that are more potent than 1% hydrocortisone are inappropriate. Other topical therapies for AD include treatments with diluted bleach baths, which can help reduce the occurrence of secondary skin infections.^7,9

Systemic Therapy

Systemic therapy for the treatment of AD typically involves the use of antimicrobials, antihistamines, or immunomodulators.^7,11 Systemic antibiotic treatment can be used to counter widespread secondary bacterial infection. Many patients encounter infection with Staphylococcus aureus, and this may cause new inflammation and exacerbate AD symptoms. The choice of systemic antibiotic drug depends upon the skin culture and sensitivity profile. Sedating antihistamines have been used in cases in which patients are not achieving adequate sleep due to itching.¹⁰

Immunomodulatory drugs, including (in order of frequency of use in Canada) methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, can be used in patients who are not responsive to other treatments.^7,10,11 However, these commonly used off-label treatments are used at the lowest dose for the shortest possible duration due to side effects.^13,14 According to the AAD, cyclosporine is an effective treatment in pediatrics. The AAD noted the evidence for the use of methotrexate in pediatric AD is limited; however, a recent 12-week study showed it had a slower onset than low-dose cyclosporine but an increased time before relapse after discontinuation. Regarding azathioprine, the AAD noted there was evidence of efficacy in children; however, its use should be reserved for recalcitrant AD, or cases in which AD has a significant psychosocial impact.¹⁵ The AAD noted that mycophenolate mofetil was a relatively safe systemic therapy in pediatric AD, although its long-term (> 24 months) efficacy and safety in pediatrics have not been studied.¹¹ With respect to corticosteroids, there is a longstanding understanding that chronic use can affect growth in children. The AAD does not recommend corticosteroid use in children with AD except as part of a short-term transition to systemic immunomodulators.

Dupilumab (Dupixent) is an interleukin-4 and interleukin-13 inhibitor indicated for use in adults and pediatrics with moderate to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. CADTH recommended that dupilumab be reimbursed with conditions and it is currently reimbursed by the participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure on or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine.¹⁶

Other Therapy

Phototherapy is another second-line therapy that is commonly used after failure of TCS, TCIs, and crisaborole. This therapy includes several sessions and is guided by a number of factors, including patient skin type and skin cancer history. According to AAD guidelines, phototherapy is considered to be a safe and effective treatment for AD in children. There are no studies of the long-term consequences of phototherapy use in pediatric AD patients; however, an increased risk of nonmelanoma skin cancer has been reported in children receiving psoralen and UV A radiation for psoriasis.¹⁷

Drug

Abrocitinib is a selective JAK1 inhibitor. All JAKs are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Abrocitinib is indicated for the treatment of patients 12 years of age and older with refractory moderate-to-severe AD, including pruritus, who have had an inadequate response to other systemic drugs (e.g., steroid or biologic), or for whom these treatments are not advisable. The product monograph states that abrocitinib can be used with or without medicated topical therapies for AD. The sponsor has requested that abrocitinib be reimbursed in accordance with the indication approved by Health Canada.

Abrocitinib is available as 50 mg, 100 mg, and 200 mg oral tablets. The dosage recommended in the product monograph is 100 mg or 200 mg orally once daily, based on the individual goals of therapy and potential risks of adverse reactions. The product monograph recommends patients using the 200 mg once daily dosage consider reducing the dosage to 100 mg once daily after symptom control is achieved at week 12. Relative to patients who maintained the 200 mg dose, the risk of occurrence of serious adverse reactions decreased in patients who reduced their dose to 100 mg beyond 12 weeks. If symptom control is lost after dose reduction, the dose can be increased to 200 mg.

Recommended dosage adjustments for patients with renal impairment are summarized in Table 5. No adjustment is required in patients with mild renal impairment (i.e., an eGFR of 60 mL/min to < 90 mL/min). In patients with moderate renal impairment (eGFR of 30 mL/min to < 60 mL/min) or severe renal impairment (eGFR < 30 mL/min), the recommended dose of abrocitinib is to be reduced by 50%, as shown in Table 5. Abrocitinib has not been studied in patients with end-stage renal disease on renal replacement therapy. No dosage adjustment is recommended in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. The product monograph states that abrocitinib has not been studied in patients with severe hepatic impairment (Child Pugh C). For patients receiving concomitant treatment with a strong inhibitor of cytochrome P450 2C19 (e.g., fluconazole, fluvoxamine, or fluoxetine), the use of abrocitinib is not recommended concomitantly with strong inducers of CYP enzymes (e.g., rifampin). The product monograph also states that treatment with abrocitinib should not be initiated in patients with a platelet count less than 150 × 10³/mm³, an absolute lymphocyte count less than 0.5 × 10³/mm³, or an absolute neutrophil count less than 1 × 10³/mm³, or in those who have a hemoglobin value less than 8 g/dL.¹⁸

Table 5: Dosage Adjustments for Renal Impairment

eGFR = estimated glomerular filtration rate; q.d. = once daily.

Source: Product Monograph.¹⁸

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Groups and Information Gathered

Three patient groups responded to CADTH’s call for patient input: the CSPA, Eczéma Québec, and the ESC.

The CSPA is a national nonprofit organization advocating, educating, and supporting Canadians affected by skin, hair, and nail disorders. Their mission is to promote skin health and improve the quality of life of Canadians living with skin disorders through advocacy, education, and awareness, supporting research, and working with affiliate member organizations that serve specific patient communities such as those with eczema, melanoma, or psoriasis.

Eczéma Québec was created as a branch of the McGill University Hospital Network Centre of Excellence for Atopic Dermatitis. Eczéma Québec is a Patient Advisory Committee and registered nonprofit organization. It established a network of adult AD patients and health care practitioners in the field of AD (encompassing specialist clinician dermatologists, general practitioners, nurse practitioners, and others), with a goal of building resources based on international best-practice guidelines. Eczéma Québec works with the Centre of Excellence to build knowledge translation tools featuring validated information to improve education, experience of care, and promote awareness and the health outcomes of this population.

Eczéma Québec and the CSPA developed and circulated a web-based survey in English and French using the Survey Monkey platform. The survey was distributed through both organizations’ newsletters and other channels. The survey drew 56 respondents. Of the respondents, 91% resided in Québec, 3.6% in Ontario, 3.6% in New Brunswick, and 1.8% in Manitoba. About 3-quarters (43 or 76.8%) of the respondents were patients while 7 (12.5%) were a parent of a patient. Most (80.4%) of the surveyed patients were female (gender at birth) and 19.6% were male. Of these respondents, 11 identified as male, 43 as female, and 2 as non-binary. The age groups (numbers of respondents, percentage of each) were: 18 to 24 (2, 3.6%), 25 to 34 (13, 23.2%), 35 to 44 (15, 26.8%), 45 to 54 (12, 21.4%), 55 to 64 (3, 5.4%), and over 65 years of age (9, 16.1%).

The ESC is a registered Canadian charity dedicated to improving the lives of Canadians living with eczema with a mission of providing support, education, awareness, and research. The ESC gathered survey data from more than 3,000 Canadians who live with AD on topics including quality-of-life impact, experience with systemic treatments, the AD patient journey, and experience with itch related to AD. Respondents included adults living with AD and the caregivers of children living with AD. Information for this submission was also gathered via questionnaires and 1-on-1 interviews. Patients and caregivers who shared their experiences using abrocitinib accessed the drug through a clinical trial.

Disease Experience

Based on patients’ experiences shared by the 3 patient groups for this review, AD negatively affects the individual and their family and can lead to psychological distress. The disease is not only referred to as the most common chronic inflammatory skin disease, but also as 1 of the highest-ranking disorders that causes disability-adjusted life-years in patients worldwide. Patients frequently report that itch is the most burdensome symptom of AD. Some also experience pain or a burning sensation from their AD. The severity of AD correlates with impacts on health-related quality of life as well as lost productivity at school and burdens on health systems. All respondents experienced itching because of their condition. Some patients shared challenges due to the pain they are experiencing. For example, with respect to their clothing: “The symptoms come and go between seasons. My biggest outbreaks are on my right heel, and it makes wearing shoes (even the comfiest shoes I own) very uncomfortable.”

Other reported experiences included: “At my worst, I had to be hospitalized. My AD was seeping, oozing, and infected. I was only sleeping a couple of hours a night. It was a very tough time for me” and “It felt like my whole body was burning, especially on my neck and chest. […] Aside from that, the itchiness is uncontrollable and would wake me up at night.”

Nearly half (48.5%) of the joint survey respondents had symptoms for more than 10 years; 5 (15.2%) had lived with symptoms for 1 to 2 years, 4 (12.1%) for 3 to 5 years, and 4 (12.1%) for 5 to 10 years. These patients and their caregivers also reported on the severity of the condition: 3 (9.1%) reported having a mild form of the disease, 16 (48.5%) from a moderate form, and 14 (42.4%) were living with a severe form of the disease. One patient reported: “All my life, I have struggled with itch. The constant, debilitating itch that would never leave me alone.” Atopic dermatitis also has significant impacts in terms of the psychosocial burden of symptoms, as 1 respondent reflected: “If flaring, [it is] hard to do some things physically and [I’m] self-conscious so tend to stay home.”

Mood, work, school, and social interactions can all be affected by AD. In the ESC survey, 32% of adult respondents with moderate or severe AD had missed work events due to their condition, and 30% had to change careers or give up certain activities. A respondent to the CSPA–Eczéma Québec questionnaire shared their experience of AD by noting: “Work stoppage, Repeated Depression, Lack of Sleep. It’s hard to participate in social or seasonal activities.” Adult respondents of the ESC survey reported feeling itchy multiple times each day (reported by 72% of respondents with moderate AD and by 95% of respondents with severe AD); 71% of adult survey respondents with moderate or severe AD rated their overall itch as 7 out of 10 or greater, and at its worst, 42% of survey respondents rated it as 10 out of 10 — the worst itch imaginable.

From the joint survey, 6 (18.2%) of the respondents noted they would miss 1 to 2 days per month and 2 (6.1%) would miss more than 7 days each month to care for their condition. Some compared the sensation of itch to being bitten by thousands of mosquitoes at once. The respondents noted that the most prevalent areas where they experienced AD were the backs of their hands (63.64%) and their thighs and/or legs (54.55%), neck (51.52%), the inside the arms and/or the elbow folds (51.52%), the outside of the arms and/or the exterior part of the elbows (51.52%), scalp (48.48%), face (45.45%), ears (45.45%), abdomen (45.45%), the area around the eyes (39.39%), breasts, under breasts and/or nipples (39.39%), back (39.39%), backs of the knees (36.36%), the top of the feet (30.30%), the palms of their hands (30.30%), groin area and/or genitalia (24.24%), buttocks (21.21%), front of the knees (21.21%), soles of the feet (21.21%), and armpits (18.18%). Other symptoms included redness of the skin (87.88%), repeated rashes (84.85%), frequent scratching (84.85%), cracked skin (84.85%), dry and rough skin (78.79%), disrupted sleep (75.76%), bleeding (69.70%), flaking of the skin (69.70%), pain (69.70%), thickening of the skin (60.61%), oozing (48.48%), swelling (42.42%), lichenification (39.39%), and blistering (36.36%).

Experience With Currently Available Treatment

For many patients living with AD, frequent moisturizing, trigger avoidance, and the use of topical treatments work well to control their AD flares, but others are left suffering.

Patients affected by AD often have to try multiple treatments to find the right option for their circumstances, and these circumstances can change over time. Respondents considered it important that AD patients have multiple treatment options available for their specific circumstances: “I think that my problem is that I no longer have treatment options left” (translation). Another reported: “I have been a prisoner of my creams and ointments. My family has had to sit by powerlessly as I scratched my skin until [I was] bloody.”

Patients and caregivers can feel extremely frustrated when they follow their doctors’ instructions closely and still continue to experience treatment failure. Parents often feel it is their fault that the treatment is failing. In addition to experiencing debilitating and life-altering symptoms, patients and caregivers alike report often having difficulty accessing timely and appropriate care when they experience flares of their disease: “Accessibility to a competent health professional with regard to eczema is one of the biggest challenges” (translation).

Most patients expressed their dissatisfaction with the treatment options available to them and how these treatments addressed the most important symptom of their disease. One respondent stated: “Nothing works” while another shared that: “Nothing has stopped the itch.” Another source of frustration for these participants was that they did not see these treatments as long-term options but rather “temporary” (translation).

Although most respondents of the joint survey did not have specific experience with targeted treatments for AD (only 8 [14.3%] respondents had experience with dupilumab, 8 [14.3%] had experience with TCIs, and 16 [28.6%] had experience with cyclosporine), few of the other treatment options stood out as very effective or somewhat effective, with the treatment perceived as the most generally effective being TCS (66.7%), followed by the use of a moisturizer, emollient and/or ointments (47.8%), and topical phosphodiesterase type 4 inhibitors (30.0%).

According to the ESC survey on the use of systemic treatments for AD, oral corticosteroids were the most frequently used systemic treatments, but they also rated highest in safety concerns for patients. Patients also reported that the rebound flares experienced after taking oral corticosteroids can be devastating. Phototherapy is also sometimes used; however, some patients reported that it does not adequately control their AD in the long-term. In addition, a lack of access to phototherapy clinics is a significant barrier for many patients depending where they are located in the country. Furthermore, the COVID-19 pandemic significantly affected patients’ access to phototherapy clinics across the country.

Improved Outcomes

Overall, patients expressed the strongest desire for improvements in their ability to manage the itch and reduce flares, inflammation, and/or rashes and improve quality of life and sleep, and they a placed a slightly lower value on the importance of the mode of administration or lichenification.

In the joint survey, patients agreed that new treatments should be able to manage itch (28 of 28 strongly or somewhat agreed), reduce flares (26 of 27), manage redness and inflammation (26 of 27), give rapid results (26 of 28), address lichenification (thickening) of the skin (25 of 27), be easy to use (25 of 28), be covered by insurance or be affordable (23 of 27), allow patients to stop using topical treatments (23 of 28), and not require injections by the patient or someone else (19 of 28). No respondent strongly or somewhat disagreed that these outcomes were important in a new treatment. When referring to the preferred mode of administration: 67.9% (19) preferred daily pills taken by mouth, 50% (14) preferred daily topical medications, and 42.9% (9) preferred injections every other week that they could do themselves or with help. On the subject of topical medications, 1 patient commented: “If you knew how many layers of creams, I had to slather on my body with help.... It was just inhumane” (translation).

Patients were generally unwilling to accept serious side effects from a new treatment. However, they also commented that they are living with the serious effects of their disease, and the negative impacts of their disease would be weighed against the side effects of a treatment option. Across the spectrum of AD severity, patients and caregivers consistently reported carefully weighing the risks and benefits of any medication, ranging from topical medications to systemic medications. For those living with uncontrolled moderate or severe AD, they expressed a willingness to accept some acceptable level of side effects associated with a new treatment and a clinical trial if it meant it would bring them relief from their symptoms.

Patients, particularly those who are adolescents, want to be able to have the confidence to be more outgoing and social, and patients with skin of colour want to avoid the visible changes in skin pigmentation that can result from scratching, flares, and scarring.

Experience With Drug Under Review

The ESC interviewed Canadian patients about their experiences with abrocitinib, which was accessed through the clinical trial. The treatment was reported as being extremely effective at controlling itch, while also reducing flares and subsequently, the cycle of open sores, and skin infections. One patient indicated that, after starting abrocitinib, they no longer had skin infections from open sores that would ooze and then lead to hospitalization and the need for IV antibiotics. It was also reported that, in addition to itch relief and skin improvement, abrocitinib improved stress, sleep, mood, and concentration at work.

Medication delivery was also noted as a benefit of this treatment, compared to experiences patients have reported with complex and often uncomfortable skin care routines and topical treatments.

At the time that the responses from the joint survey responses were received, between March 29 and April 23 of 2021, none of the individuals who took part had direct experience with abrocitinib.

Additional Information

According to the ESC, patients who live with moderate-to-severe uncontrolled AD may never experience periods of clear skin despite adherent use of their treatments, such as topical medications. For this patient population, there is a significant gap in treatments, and more options are desperately needed. The burden of disease, quality-of-life impact, and suffering associated with moderate or severe AD can be debilitating, as the itch, discomfort, and pain can disrupt sleep, affect mental health, and lead to absenteeism from work and/or school. Abrocitinib offers hope to patients with uncontrolled moderate or severe AD by providing rapid improvement of itch and skin lesions, which in turn improves their quality of life.

According to the CSPA and Eczéma Québec, skin disorders are often diminished, disregarded, and dismissed. They are more than “just a rash.” The development of better-tailored treatment options for skin disorders on the horizon provides new hope that treatments will address the underlying pathology of skin disorders, rather than only treating the symptoms. Those living with skin disorders deserve to be treated with respect and dignity by the health system, which includes its embrace of new and tailored treatment options.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in 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 a clinical specialist with expertise in the diagnosis and management of AD.

Unmet Needs

Presently, patients achieving suboptimal disease control with appropriate disease-specific skin care measures (irritant avoidance, emollients, and bleach baths), TCS and/or TCIs, crisaborole, and phototherapy are offered treatments with off-label immunosuppressive drugs. In Canada, the most commonly chosen immunosuppressive drug is methotrexate, followed by cyclosporine, azathioprine, and mycophenolate mofetil. Because of their potential toxicities, these drugs are generally prescribed as intermittent courses in the treatment of AD. There are patients for whom some or all of these drugs are contraindicated or for whom toxicities limit their use. There are also patients who do not respond to these drugs. Dupilumab is offered as second-line systemic therapy to the immunosuppressives, but reimbursement for dupilumab in Canada remains problematic.

Place in Therapy

Abrocitinib, a small-molecule reversible JAK1 inhibitor, is a potentially useful addition to the currently available therapeutic options for AD. It will, in the specialist’s opinion, be a useful drug in patients who have contraindications to, experience adverse effects from, or who are unresponsive to the off-label immunosuppressive drugs. It will also be useful in that subset of patients who respond to off-label immunosuppressive drugs but who require continuous long-term therapy to control their disease.

Abrocitinib will also potentially be of value in patients with AD who have been treated with dupilumab and had a suboptimal response, who develop severe conjunctivitis or other ocular side effects from dupilumab or are intolerant of injections and prefer an oral drug, and/or those who have severe injection-site reactions to dupilumab.

All patients with AD treated with abrocitinib would be expected to continue on with emollients, TCS, TCIs, and/or crisaborole. It is expected that abrocitinib would never be combined with off-label immunosuppressants or dupilumab (or the new biologics such as tralokinumab that are emerging treatments for AD).

Abrocitinib is unlikely to cause a significant shift in the current treatment paradigm for AD beyond its inclusion as another effective drug. It would be appropriate to recommend trials of methotrexate and cyclosporine before initiating treatment with abrocitinib. These older drugs are cost-effective and efficacious, and dermatologists are well versed in appropriate dosing, duration of therapy, and monitoring of patients for potential toxicities. Many patients can be managed with intermittent use of immunosuppressants. The clinical expert consulted by CADTH noted that immunosuppressants have likely been underutilized in clinical practice, partly due to the paucity of literature. As these are older drugs with low commercial value, adequate clinical trials are rare. This leads to a “low evidence” designation in reviews and treatment guidelines.

Patient Population

Although AD is not a diagnostic challenge for a dermatologist, the differential diagnosis includes psoriasis, ichthyoses, allergic contact dermatitis, irritant contact dermatitis, and cutaneous T-cell lymphoma. The barrier dysfunction of AD predisposes patients to superimposed allergic contact dermatitis and also dermatophytosis, and therefore patch tests and skin scrapings for potassium, oxygen, and hydrogen, and fungal culture may be of benefit in selected cases. A biopsy would usually be reserved for patients recalcitrant to all therapy for whom cutaneous T-cell lymphoma is a consideration, or occasionally, to differentiate AD from psoriasis. Abrocitinib would never be considered for pre-symptomatic patients.

All patients with moderate-to-severe AD could respond to treatment with abrocitinib. It is unclear whether abrocitinib can effectively treat those patients who have failed methotrexate, cyclosporine, and/or dupilumab. It is not currently possible to identify those patients who are most likely to exhibit a response to abrocitinib.

The patients with AD who could be considered least suited for treatment with abrocitinib include:

• those who are well controlled with topical therapy, phototherapy, and/or intermittent off-label immunosuppressive therapy

• those who are well controlled with dupilumab

• those with potential contraindications to JAK inhibitors such as: severe active infections acute or chronic including latent tuberculosis, deep fungal infections and opportunistic infections; potentially malignancy, including ongoing treatment with chemotherapy such as checkpoint inhibitors; severe hepatic disease; severe renal disease; pregnancy and lactation; a history of thromboembolic events, and pre-existing hematologic disease, including lymphopenia and neutropenia.

Assessing Response to Treatment

In general, the outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials. The clinical expert consulted by CADTH anticipated that the EASI score will be chosen as the benchmark for reimbursement. As such, this will be calculated and recorded at each patient visit. Many clinicians will also record a DLQI score, although this value may not be required for reimbursement. Reduction in pruritus will also be noted but not formally scored using a scale. The patient’s impression of their overall improvement will also be recorded.

The benchmark response will be an EASI-75 at 16 weeks. However, EASI score reductions of 50% to 75% would be anticipated to be clinically meaningful, particularly to those who have had severe disease recalcitrant to all previous therapies. It is anticipated that patients who initiate treatment with abrocitinib would be re-evaluated after 16 weeks. Those who are judged to be responders at this visit would be seen subsequently once every 6 months. Those who have not reached response targets at 16 weeks would be re-evaluated at 20 weeks following initiation of drug. A decision about whether to stop or continue would be made at the 20-week visit. Bloodwork, including complete blood count and differential liver-function tests, creatinine, lipids, and CPK, would be analyzed monthly before the first follow-up visit and, if there are no concerns, every 3 months thereafter.

Discontinuing Treatment

The following factors would be considered when deciding to discontinue treatment with abrocitinib:

• failure to achieve clinically meaningful response at 16 to 20 weeks

• failure to maintain an adequate response on long-term maintenance

• development of a hypersensitivity response judged to be due to abrocitinib

• TEAEs, such as lymphopenia, neutropenia, arterial thrombosis, or VTE

• treatment-emergent severe infection

• treatment-emergent malignancy.

Prescribing Conditions

A specialist would be required to diagnose, treat, and monitor patients taking abrocitinib. Appropriate specialists would include a pediatric dermatologist, a general dermatologist, or a pediatrician with an interest in AD.

Clinician Group Input

No input was received from clinician groups.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 7.

Table 7: Summary of Drug Plan Input and Clinical Expert Response

AD = atopic dermatitis; CDEC = CADTH Canadian Drug Expert Committee; DMARD = disease-modifying antirheumatic drug; EASI = Eczema Area and Severity Index; EASI-75 = improvement of 75% or greater in the Eczema Area and Severity Index total score; JAK = Janus kinase.

Clinical Evidence

The clinical evidence included in the review of abrocitinib is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of oral abrocitinib 100 mg once daily and 200 mg once daily for the treatment of patients 12 years and older with moderate-to-severe AD, including pruritus, who have had an inadequate response to prescribed topical therapy or for whom these treatments are not advisable.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria are presented in Table 8. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 8: Inclusion Criteria for the Systematic Review

AD = atopic dermatitis; AE = adverse event; CDLQI = Children’s Dermatology Life Quality Index; CPK = creatine phosphokinase; DFI = Dermatitis Family Impact; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment; MACE = major adverse cardiovascular event; q.d. = once daily; RCT = randomized controlled trial; SAE = serious adverse events; SCORAD = Scoring Atopic Dermatitis; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Cibinqo (abrocitinib). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on May 25, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on September 15, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁴ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix 1 provides more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

A focused literature search for NMAs dealing with Cibinqo (abrocitinib) and AD was run-in MEDLINE All (1946–) on May 18, 2021. No limits were applied.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Five studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 9. None of the potentially relevant studies were excluded.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 9: Details of Included Monotherapy Studies

AD = atopic dermatitis; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CFB = change from baseline; DLQI = Dermatology Life Quality Index; EASI-50 = improvement of 75% or greater in the Eczema Area and Severity Index total score; EASI-75 = improvement of 75% or greater in the Eczema Area and Severity Index total score; EASI-90 = improvement of 90% or greater in the Eczema Area and Severity Index total score; EASI-100 = improvement of 100% in the Eczema Area and Severity Index total score; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; JAK = Janus kinase; Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy–Fatigue; POEM = Patient-Oriented Eczema Measure; PP-NRS = severity of pruritus numerical rating scale; PP-NRS4 = improvement of 4 or greater from baseline on peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.d. = once daily; RCT = randomized controlled trial; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = an improvement of 50% or greater in Scoring Atopic Dermatitis; SCORAD-75 = an improvement of 75% or greater in Scoring Atopic Dermatitis; SF-36v2 = Short Form (36) Health Survey Version 2; WPAI-AD = Work Productivity and Activity Impairment Questionnaire–Atopic Dermatitis.

Source: Clinical Study Reports.^2,3

Table 10: Details of Included Combination-Therapy Studies

AD = atopic dermatitis; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CFB = change from baseline; DLQI = Dermatology Life Quality Index; EASI-50 = improvement of 75% or greater in the Eczema Area and Severity Index total score; EASI-75 = improvement of 75% or greater in the Eczema Area and Severity Index total score; EASI-90 = improvement of 90% or greater in the Eczema Area and Severity Index total score; EASI-100 = improvement of 100% in the Eczema Area and Severity Index total score; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; JAK = Janus kinase; MOS = Medical Outcomes Study; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; PP-NRS = severity of pruritus numerical rating scale; PP-NRS4 = improvement of 4 or greater from baseline on peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.2.w. = every 2 weeks; q.d. = once daily; RCT = randomized controlled trial; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = an improvement of 50% or greater in Scoring Atopic Dermatitis; SCORAD-75 = an improvement of 75% or greater in Scoring Atopic Dermatitis.

Source: Clinical Study Reports.^4,5

Table 11: Details of Included Withdrawal Study

AD = atopic dermatitis; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CFB = change from baseline; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; JAK = Janus kinase; NRS = numeric rating scale; Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy–Fatigue; POEM = Patient-Oriented Eczema Measure; PP-NRS4 = improvement of 4 or greater from baseline on peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.d. = once daily; SCORAD = Scoring Atopic Dermatitis; SCORAD-50 = an improvement of 50% or greater in Scoring Atopic Dermatitis; SCORAD-75 = an improvement of 75% or greater in Scoring Atopic Dermatitis.

Source: Clinicaltrials.gov,³³ Gubelin et al. (2021),³⁴ Sponsor’s clinical summary.³⁵

Description of Studies

Table 12 provides an overview of the studies that were summarized and appraised by CADTH for the current review of abrocitinib. Five double-blind, phase III RCTs were included in the CADTH systematic review: 2 placebo-controlled trials conducted with abrocitinib as monotherapy for AD (JADE MONO-1 and JADE MONO-2)^2,3; 2 placebo-controlled trials conducted with abrocitinib as combination therapy for AD (JADE COMPARE and JADE TEEN)^4,5; and 1 placebo-controlled withdrawal trial (JADE REGIMEN).^34,35 CADTH also reviewed additional studies that did not meet the eligibility criteria of the systematic review but may address important gaps in the evidence from the pivotal and supportive RCTs. These included the interim analysis from 1 long-term extension-phase study (JADE EXTEND)^35,36 and 3 indirect comparisons (2 filed by the sponsor and 1 from the ICER).^37-39

Table 12: Summary of Evidence Included in Review

ICER = Institute for Clinical and Economic Review; MAIC = matching-adjusted indirect comparison; NMA = network meta-analysis; RCT = randomized controlled trial.

Monotherapy Studies

The JADE MONO-1 and JADE MONO-2 trials were phase III, double-blind, placebo-controlled, parallel-group RCTs conducted to evaluate the efficacy and safety of abrocitinib monotherapy in patients aged 12 years and older with moderate-to-severe AD and a body weight of 40 kg or more. The studies consisted of a 28-day screening period, a 12-week double-blind treatment phase, and a 4-week safety follow-up period (or entry into the long-term extension study [EXTEND]).^2,3 During the screening period, treatments for AD will be washed out, as applicable, according to eligibility requirements. Eligible patients were randomized in a 2:2:1 ratio to receive 200 mg of abrocitinib once daily, 100 mg of abrocitinib once daily, or matching placebo. Randomization was stratified by baseline disease severity (moderate [IGA = 3] or severe [IGA = 4] AD), and age (< 18 years or ≥ 18 years).^2,3 The 2 trials were identically designed, except for an additional exclusion criterion in JADE MONO-2 (i.e., patients who had topical treatments for AD within 72 hours of the first dose of study medication) and the inclusion of the Work Productivity and Activity Impairment Questionnaire–Atopic Dermatitis (WPAI-AD) as an additional end point.³⁵

The JADE MONO-1 trial was conducted at 69 sites in 8 countries: the US (n = 114), Canada (n = 64), Germany (n = 64), Australia (n = 51), Poland (n = 49), the Czech Republic (n = 19), the UK (n = 14), and Hungary (n = 12).² The JADE MONO-2 trial was conducted at 102 sites in 13 countries: the US (n = 19), Poland (n = 14), Republic of Korea (n = 10), Japan (n = 8), Australia (n = 7), Bulgaria (n = 7), Canada (n = 7), Germany (n = 7), the UK (n = 6), China (n = 5), Latvia (n = 5), Hungary, (n = 4), and the Czech Republic (n = 3).³

Figure 2: Schematic of JADE MONO-1 and JADE MONO-2 Design

PF-04965842 = abrocitinib.

Source: Clinical Study Report.²

Combination-Therapy Studies

Placebo-Controlled Trial in Adults

JADE COMPARE was a phase III, double-blind, double-dummy, placebo-controlled, parallel group, multi-centre study investigating the efficacy and safety of abrocitinib and dupilumab in comparison with placebo in adult subjects on background topical therapy, with moderate-to-severe AD. The study consisted of a 28-day screening period, a 20-week double-blind treatment phase, and a 4-week safety follow-up period (or entry into the long-term extension study [EXTEND]). During the screening period, treatments for AD will be washed out, as applicable, according to eligibility requirements. Eligible patients were randomized in a 4:4:4:1:1 ratio to receive 100 mg or 200 mg of abrocitinib once daily with dupilumab-matching placebo every 2 weeks, dupilumab 300 mg every 2 weeks (with a loading dose of 600 mg at baseline) with abrocitinib-matching placebo once daily, or 1 of 2 sequences of abrocitinib-matching placebo administered once daily with dupilumab-matching placebo administered every 2 weeks from day 1 for 16 weeks followed by either 100 mg or 200 mg of abrocitinib once daily. The 20-week double-blind treatment phase consisted of 2 parts: 1) a 16-week randomized, double-blind, placebo-controlled, double-dummy treatment period with patients receiving both injectable and oral investigational product; and 2) a 4-week phase during which patients only received the oral investigational product. At week 16, all patients were to cease administering injectable dupilumab or the matching placebo. This 4-week phase was included in the study to facilitate the washout of dupilumab before eligible patients entering the long-term extension study. Following week 16, patients who received placebo during part 1 of the study were to cross over to receive abrocitinib at a 100 mg once daily or 200 mg once daily (in accordance with how they were randomized) and those who received abrocitinib in part 1 continued on their randomized treatment. Those who received dupilumab in part 1 continued to take the oral placebo to maintain blinding. Randomization was not stratified by any baseline characteristics.⁴

The JADE COMPARE trial was conducted at 194 sites in 18 countries, including sites in the US (n = 46), Poland (n = 36), Republic of Korea (n = 7), Japan (n = 12), Australia (n = 10), Bulgaria (n = 5), Canada (n = 11), Germany (n = 13), the US (n = 11), Latvia (n = 5), Hungary (n = 5), the Czech Republic (n = 7), Chile (n = 4), Spain (n = 5), Italy (n = 2), Mexico (n = 4), Slovakia (n = 5), and Taiwan (n = 6).⁴

Figure 3: Schematic of JADE COMPARE Design

PF-04965842 = abrocitinib.

^aAt week 2 and week 16, key secondary end points are measured.

^bAt week 12, primary end points are measured.

^cAt week 20, eligible subjects will enter the long-term extension study; ineligible subjects will instead enter the 4-week off-treatment follow-up period.

Source: Clinical Study Report.⁴

Active-Controlled Trial in Adults

The JADE DARE trial was a phase IIIb, double-blind, double-dummy, active-controlled, parallel group, multi-centre study investigating the efficacy and safety of abrocitinib compared with dupilumab in adult patients on background topical therapy, with moderate-to-severe AD. The study consisted of a 28-day screening period, a 26-week double-blind treatment phase, and a 4-week safety follow-up period (or entry into the long-term extension study [EXTEND]). During the screening period, treatments for AD will be washed out, as applicable, according to eligibility requirements. Eligible patients were randomized in a 1:1 ratio to receive 200 mg of abrocitinib once daily with dupilumab-matching placebo every 2 weeks or dupilumab 300 mg every 2 weeks (with a loading dose of 600 mg at baseline) with abrocitinib-matching placebo once daily. Randomization was stratified by baseline AD severity (moderate or severe).¹

Figure 4: Schematic of JADE DARE Design

LTE = long-term extension study; PF-04965842 = abrocitinib; Q2W = every 2 weeks; QD = once daily; TCS = topical corticosteroids.

Source: Clinical Study Report.¹

Adolescents

The JADE TEEN trial was a randomized, double-blind, placebo-controlled, parallel-group, phase III RCT to evaluate the efficacy and safety of abrocitinib in adolescent patients aged 12 to 18 years of age with moderate-to-severe AD. The study consisted of a 28-day screening phase, a 12-week double-blind treatment phase, and a 4-week follow-up period or entry into the open-label extension study. Eligible patients were randomized at a 1:1:1 ratio to receive abrocitinib 100 mg once daily, abrocitinib 200 mg once daily, or placebo for 12 weeks. Randomization was stratified by baseline disease severity (moderate [IGA = 3] versus severe [IGA = 4] AD).⁵

The JADE TEEN trial was conducted at 99 sites in 13 countries, including sites in the Australia (n = 4), China (n = 10), Czech Republic (n = 3), Germany (n = 4), Hungary (n = 6), Italy (n = 1), Japan (n = 7), Latvia (n = 2), Mexico (n = 8), Poland (n = 13), Spain (n = 6), Taiwan (n = 3), and the US (n = 32).⁵

Figure 5: Schematic of JADE TEEN Design

EOT = end of treatment; IgG = immunoglobin G; PF-04965842 = abrocitinib; QD = once daily.

Source: Clinical Study Report.⁵

Withdrawal Study

The JADE REGIMEN trial was a phase III multi-centre, randomized, responder-enriched, double-blind, placebo-controlled withdrawal study that evaluated the efficacy and safety of abrocitinib monotherapy in subjects aged 12 years and older with moderate-to-severe AD. The JADE REGIMEN trial consisted of an initial open-label induction treatment with abrocitinib 200 mg once daily for 12 weeks. Responders to treatment were subsequently randomized (1:1:1) ratio to receive abrocitinib 200 mg once daily, abrocitinib 100 mg once daily, or matching placebo in a double-blinded maintenance treatment period for 40 weeks. Responders were identified as patients that achieved an IGA score of clear (0) or almost clear (1), a reduction of 2 or more points from the baseline IGA score, and an EASI-75 response compared to baseline. Patients who experienced disease flares during the double-blind treatment period were provided with open-label rescue therapy with abrocitinib 200 mg once daily and topical medication for 12 weeks and assessed for disease improvement throughout the rescue therapy period. A patient was considered to experience a disease flare if a loss of response was observed. This loss of response was defined as a decrease of at least 50% of the EASI response compared to randomization and an IGA score of 2 or higher. Following the 40-week double-blind treatment period, patients could enter a 4-week untreated follow-up period or the JADE EXTEND extension study (if eligible).^6,35

The JADE REGIMEN trial was conducted at 235 sites in 21 countries: the US, Argentina, Belgium, Brazil, Bulgaria, Canada; Chile, China, Germany, Israel, Italy, Latvia, Mexico, Netherlands, Poland, Romania, Russia, Serbia, Slovakia; Spain, and Taiwan.³³

Figure 6: Schematic of JADE REGIMEN Design

PF-04965842 = abrocitinib; QD = once daily.

Note: A flare is defined as a loss of response associated with a decrease of at least 50% of the EASI response compared to randomization and an IGA score of 2 or higher.

Source: Common Technical Document Module 2.7.3.⁶

Populations

Inclusion and Exclusion Criteria

Monotherapy Studies

Patients were eligible for the JADE MONO-1 and JADE MONO-2 trials if they met the following criteria: a diagnosis of chronic AD for at least 1 year before day 1 and had confirmed AD using the Hanifin and Rajka criteria at the screening and baseline visits; documented recent history (within 6 months before the screening visit) of an inadequate response to topical medications for at least 4 weeks, or for whom topical treatments are otherwise medically inadvisable (e.g., important side effects or safety risks), or who have required systemic therapies for control of their disease. Enrolment was limited to patients with moderate-to-severe AD, defined as an affected body surface area (BSA) of 10% or greater, an IGA score of 3 or higher, an EASI score of 16 or higher, and a pruritus numeric rating scale (NRS) score of 4 or higher at the baseline visit. Patients were to agree to avoid prolonged exposure to the sun and not use tanning booths, sun lamps or other UV light sources during the study. Any patients receiving concomitant medications for any reason other than AD were required to have been receiving a stable therapeutic regimen, defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever was longer) before day 1, and remain on a stable regimen throughout the duration of the studies.^2,3

Patients were excluded if that had active forms of other inflammatory skin diseases or evidence of skin conditions at the day 1 visit that would have interfered with the evaluation of AD or the patient’s response to the study treatment, or if they had received prior treatment with any JAK inhibitors. Patients were also excluded if they had any psychiatric condition, including recent or active suicidal ideation or behaviour that met any of the following criteria: suicidal ideation associated with actual intent and a method or plan in the past year or previous history of suicidal behaviours in the past 5 years (both assessed using the Columbia Suicide Severity Rating Scale); any lifetime history of serious or recurrent suicidal behaviour; a total score of 8 or higher on the Suicidal Behaviours Questionnaire – Revised; or clinically significant depression, defined as a total score of 15 or higher on the Patient Health Questionnaire – 8 items. The JADE MONO-2 trial also excluded patients if they had topical treatments for AD within 72 hours of the first dose of study medication.³⁵

Combination-Therapy Studies

Adults

Patients aged 18 years and older were eligible for the JADE COMPARE trial if they met the following criteria: a diagnosis of chronic AD for at least 1 year before day 1 and had confirmed AD using the Hanifin and Rajka criteria at the screening visit; documented recent history (within 6 months before the screening visit) of an inadequate response to topical medications for at least 4 weeks, or who have required systemic therapies for control of their disease. Enrolment was limited to patients with moderate-to-severe AD, defined as an affected BSA of 10% or greater, an IGA score of 3 or higher, an EASI score of 16 or higher, and a pruritus NRS score of 4 of higher at the baseline visit). During the last 7 days before day 1, patients could only use non-medicated topical therapy (i.e., emollients) for the treatment of AD without other active ingredients indicated to treat AD, or other additives that could affect AD (e.g., hyaluronic acid, urea, ceramide, or filaggrin degradation products) at least twice daily, with response to treatment remaining inadequate at baseline. Patients were to agree to avoid prolonged exposure to the sun and not use tanning booths, sun lamps, or other UV light sources during the study. Any patients receiving concomitant medications for any reason other than AD were required to have been receiving a stable therapeutic regimen, defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever was longer) before day 1, and remain on a stable regimen throughout the duration of the studies.⁴

Patients were excluded if that had active forms of other inflammatory skin diseases or evidence of skin conditions at the day 1 visit that would have interfered with the evaluation of AD (e.g., psoriasis, seborrheic dermatitis, or lupus) or the patient’s response to the study treatment. Patients could not have had received prior treatment with any systemic JAK inhibitor or dupilumab. Patients were also excluded if they had any psychiatric condition, including recent or active suicidal ideation or behaviour that met any of the following criteria: suicidal ideation associated with actual intent and a method or plan in the past year or previous history of suicidal behaviours in the past 5 years (both assessed using the Columbia Suicide Severity Rating Scale); any lifetime history of serious or recurrent suicidal behaviour; total score of 8 or higher on the Suicidal Behaviours Questionnaire – Revised; clinically significant depression, defined as a total score of 15 or higher on the Patient Health Questionnaire – 8 items.⁴

Adolescents

Patients aged 12 to 18 years of age were eligible for the JADE TEEN trial if they had a body weight of at least 25 kg and met the following criteria: a diagnosis of chronic AD for at least 1 year before day 1 and had confirmed AD using the Hanifin and Rajka criteria at the screening and baseline visits, documented recent history (within 6 months before the screening visit) of inadequate response to topical medications for at least 4 weeks, or for whom topical treatments are otherwise medically inadvisable (e.g., important side effects or safety risks), or who have required systemic therapies for control of their disease. Enrolment was limited to patients with moderate-to-severe AD, defined as an affected BSA of 10% or greater, an IGA score of 3 or higher, an EASI score of 16 or higher, and a pruritus NRS of 4 or higher at the baseline visit). Patients were to agree to avoid prolonged exposure to the sun and not use tanning booths, sun lamps, or other UV light sources during the study. During the last 7 days before day 1, the patient must have used only non-medicated topical therapy for the treatment of AD (i.e., emollients) at least twice daily, without other active ingredients indicated to treat AD, or other additives that could have affected AD (e.g., hyaluronic acid, urea, ceramide, or filaggrin degradation products), with response to treatment remaining inadequate at baseline. Any patients receiving concomitant medications for any reason other than AD were required to have been receiving a stable therapeutic regimen, defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever was longer) before day 1, and remain on a stable regimen throughout the duration of the studies.⁵

Patients were excluded if that had active forms of other inflammatory skin diseases or had evidence of skin conditions at the day 1 visit that would have interfered with the evaluation of AD or the patient’s response to the study treatment or had received prior treatment with any JAK inhibitors. Patients were also excluded if they had any psychiatric condition, including recent or active suicidal ideation or behaviour that met any of the following criteria: suicidal ideation associated with actual intent and a method or plan in the past year or previous history of suicidal behaviours in the past 5 years, both assessed using the Columbia Suicide Severity Rating Scale; any lifetime history of serious or recurrent suicidal behaviour; total score of 8 or higher on the Suicidal Behaviours Questionnaire – Revised; or clinically significant depression, defined as a total score of 15 or higher on the Patient Health Questionnaire – 8 items. The JADE MONO-2 trial also excluded patients if they had used topical treatments for AD within 72 hours of the first dose of study medication.³⁵

Withdrawal Study

Patients were eligible for the JADE REGIMEN trial if they had a diagnosis of moderate-to-severe AD for at least 1 year and were aged 12 years and older. Patients had moderate-to-severe AD, a BSA of 10% or greater, an IGA score of 3 or higher, an EASI score of 16 or higher and a PP-NRS score of 4 or higher. Within 6 months of screening patients had to have documented inadequate response to treatment with medicated topic therapy for 4 weeks or longer or required use of a systemic therapy to control their AD.^34,35

Patients were excluded if they met any of the following criteria: were unwilling to discontinue current AD medications before the study or required treatment with prohibited medications during the study; had experienced prior treatment with JAK inhibitors; had other active non-AD inflammatory skin diseases or conditions affecting skin; had a medical history including thrombocytopenia, coagulopathy or platelet dysfunction, Q-wave interval abnormalities, current or history of certain infections, cancer, lymphoproliferative disorders or other medical conditions (at the discretion of the investigator); or were pregnant, breastfeeding, or a woman of childbearing potential who was unwilling to use contraception.³³

Baseline Characteristics

Monotherapy Studies

Baseline characteristics for the JADE MONO-1 and JADE MONO-2 trials are summarized in Table 13 and Table 14, respectively. The majority of patients in the JADE MONO-1 trial were men (57%) and the mean age of patients in the study was 32.5 years (standard deviation [SD] = 16.0). The proportion of patients with moderate disease (59%) was higher than the proportion of patients with severe disease (41%) as measured by IGA scores.³⁵ The characteristics were well balanced across the 3 treatment groups in the JADE MONO-1 trial, with the exception of differences in the proportion of females (which ranged from 36.4% in the placebo group to 47.4% in the abrocitinib 200 mg once daily group), the proportion of White patients (which ranged from 67.5% in the abrocitinib 200 mg once daily group to 80.5% in the placebo group), and the median EASI score at baseline, which ranged from 22.9 in the placebo group to 27.3 in the abrocitinib 100 mg once daily group. For the subgroup of adolescent patients, the median EQ-5D Youth (EQ-5D-Y) Visual Analogue Scale (EQ VAS) scores were lower in the placebo group (45.0; interquartile range [IQR] = 32.0 to 77.5) compared with the abrocitinib 100 mg once daily (70.0; IQR = 48.0 to 87.5) and abrocitinib 200 mg once daily groups (66.0; IQR = 40.0 to 82.5]). Prior treatments for AD are summarized in Table 15, and 48% of those in the JADE MONO-1 trial had received topical drugs only (48.3% had prior exposure to at least 1 systemic therapy). Prior exposure to dupilumab was reported by 7.8% of the patient population (exposure to other biologics was not reported). Patients with prior exposure to at least 1 systemic immunosuppressant for AD had more severe disease at baseline relative to the overall study population within the abrocitinib groups of the JADE MONO-1 trial (e.g., those with severe disease based on baseline IGA ranged from 54.3% to 57.1% across the abrocitinib groups in the subgroup and from 40.9% to 41.% in the overall study population). The proportion of patients with severe disease at baseline was considerably lower in the placebo group of the subgroup analysis (32.1%) compared with overall study population (40.3%).⁴⁰

Table 13: Summary of Baseline Characteristics for JADE MONO-1 (Safety Analysis Set)

AD = atopic dermatitis; BMI = body mass index; BSA = body surface area; CDLQI = Children's Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator's Global Assessment; IQR = interquartile range; NRS = numeric rating scale; Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy–Fatigue; POEM = Patient-Oriented Eczema Measure; PP-NRS = peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.d. = once daily; SCORAD = Scoring Atopic Dermatitis; SF-36 = Short Form (36) Health Survey; VAS = Visual Analogue Scale.

Source: Clinical Study Report² and additional data provided by sponsor.⁴⁰

The majority of patients in the JADE MONO-2 trial were men (59%) and the median age of patients in the study was 31.0 years. The proportion of patients with moderate disease (67.8%) was higher than the proportion of patients with severe disease (32.2%) as measured by IGA scores.³⁵ Characteristics were well balanced across the 3 treatment groups in the JADE MONO-2 trial, with the exception of differences in race (e.g., the proportion of White patients ranged from 51.3% in the placebo group to 63.9% in the abrocitinib 100 mg once daily group). Prior treatments for AD are summarized in Table 15, and 57.8% of those in the JADE MONO-2 trial had received topical drugs only (41.4% had prior exposure to at least 1 systemic therapy). Prior exposure to dupilumab was reported in 3.6% of the patient population, and 2.8% had exposure to a biologic other than dupilumab. Patients with prior exposure to at least 1 systemic immunosuppressant for AD had more severe disease at baseline relative to the overall study population in the JADE MONO-2 trial (e.g., those with severe disease based on baseline IGA ranged from 43.3% to 48.8% across the 3 treatment groups in the subgroup and from 31.6% to 33.3% in the overall study population).⁴⁰

Table 14: Summary of Baseline Characteristics for JADE MONO-2 (Safety Analysis Set)

AD = atopic dermatitis; BMI = body mass index; BSA = body surface area; CDLQI = Children's Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator's Global Assessment; IQR = interquartile range; NRS = numeric rating scale; Peds-FACIT-F = Pediatric Functional Assessment of Chronic Illness Therapy–Fatigue; POEM = Patient-Oriented Eczema Measure; PP-NRS = peak pruritus numerical rating scale; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.d. = once daily; SF-36 = Short Form (36) Health Survey; SCORAD = Scoring Atopic Dermatitis.

Source: Clinical Study Report³ and additional data provided by sponsor.⁴⁰

Table 15: Summary of Prior Medications for JADE MONO-1 and JADE MONO-2 (SAS)

CS = corticosteroids; NR = not reported; q.d. = once daily; SAS = safety analysis set; TCIs = topical calcineurin inhibitors.

Source: Clinical Study Reports.^2,3

Combination-Therapy Studies

Placebo-Controlled Trial in Adults

Baseline characteristics for the JADE COMPARE trial are summarized in Table 16. The overall proportion of female patients was 51.1%, a majority (64.6%) of the patients had moderate AD, and the median age of patients in the study was 34.0 years.³⁵ Characteristics were well balanced across the 4 treatment groups in the JADE COMPARE trial, with the exception of differences in sex (ranging from 41.2% female in the placebo group to 55.4% in the dupilumab group), race (e.g., the proportion of White patients ranged from 66.4% in the placebo group to 76.5% in the abrocitinib 100 mg once daily group), and PtGA (ranging from 42.5% in the abrocitinib 200 mg once daily group to 51.9% in the placebo group).⁴ Prior treatments for AD are summarized in Table 17, and 56.5% of patients in the JADE COMPARE trial had received topical drugs only (43.2% had prior exposure to at least 1 systemic therapy). Only a minority of patients had prior exposure to a biologic (no patients had prior exposure to dupilumab and 2.3% of patients had prior exposure to a biologic other than dupilumab).³⁵ Patients with prior exposure to at least 1 systemic immunosuppressant for AD had more severe disease at baseline relative to the overall study population in the JADE COMPARE trial (e.g., those with severe disease based on baseline IGA ranged from 41.7% to 69.0% across the treatment groups in the subgroup analysis and from 31.8% to 38.9% in the overall study population). The proportion of patients with severe disease at baseline was greater in the abrocitinib 200 mg group (69.0%) of the subgroup analysis compared with the other treatment groups (range = 41.7% to 47.3%).

Table 16: Summary of Baseline Characteristics for JADE COMPARE (Safety Analysis Set)

BMI = body mass index; BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator's Global Assessment; IQR = interquartile range; NRS = numeric rating scale; POEM = Patient-Oriented Eczema Measure; PSAAD = Pruritus and Symptoms Assessment for Atopic Dermatitis; PtGA = Patient Global Assessment; q.2.w. = every 2 weeks; q.d. = once daily; SCORAD = Scoring Atopic Dermatitis; VAS = Visual Analogue Scale.

Source: Clinical Study Report⁴ and additional data provided by sponsor.⁴⁰

Active-Controlled Trial in Adults

Baseline characteristics for the JADE DARE trial are summarized in Table 17. The overall proportion of female patients was 45.4%, a majority of the patients had moderate AD (60.0%), and the median age of patients in the study was 33.0 years. Characteristics were well balanced across the 2 treatment groups in the JADE DARE trial. Prior treatments for AD are summarized in Table 18, and 51.9% of those in the JADE COMPARE trial had received topical drugs only (47.9% had prior exposure to at least 1 systemic therapy). Only a minority of patients had prior exposure to a biologic (no patients had prior exposure to dupilumab and 2.2% in each treatment group of patients had prior exposure to a biologic other than dupilumab).¹

Table 17: Summary of Baseline Characteristics for JADE DARE (Safety Analysis Set)

BMI = body mass index; BSA = body surface area; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = EQ-5D 5-Levels questionnaire; EQ-5D-Y = EQ-5D Youth Scale; HADS = Hospital Anxiety and Depression Scale; IGA = Investigator’s Global Assessment; IQR = interquartile range; PP-NRS = severity of peak pruritus numerical rating scale; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.d. = once daily; SCORAD = Scoring Atopic Dermatitis; VAS = Visual Analogue Scale.

Source: Clinical Study Report.¹

Adolescents

Baseline characteristics for the JADE TEEN trial are summarized in Table 18. The overall proportion of females was 49.1%, the median age of patients was 15.0 years, and the proportion with moderate AD was 61.4% based on IGA scores.³⁵ Characteristics were well balanced across the 3 treatment groups in the JADE TEEN trial, with the exception of differences in sex (ranging from 40.4% female in the abrocitinib 200 mg group to 54.2% in the placebo group), and percentage BSA (ranging from 38.2% in the placebo group to 48.0% in the abrocitinib 100 mg once daily group). Prior treatments for AD are summarized in Table 19, and 73.3% of those in the JADE TEEN trial had received topical drugs only (25.6% had prior exposure to at least 1 systemic therapy). Only a minority of patients had prior exposure to a biologic (1 patient in each group had prior exposure to dupilumab and 1 patient in the 200 mg abrocitinib group had prior exposure to a biologic other than dupilumab).⁵ Patients with prior exposure to at least 1 systemic immunosuppressant for AD had more severe disease at baseline relative to the overall study population in the JADE TEEN trial (e.g., those with severe disease based on baseline IGA ranged from 45.5% to 59.3% across the treatment groups in the subgroup analysis and from 35.1% to 40.6% in the overall study population). The proportion of patients with severe disease at baseline was greater in the abrocitinib 100 mg group (59.3%) of the subgroup analysis compared with the other treatment groups (range: 54.2% to 45.5%).

Table 18: Summary of Baseline Characteristics for JADE TEEN (Safety Analysis Set)