Reimbursement Review

Vutrisiran (Amvuttra)

Sponsor: Alnylam Pharmaceuticals

Therapeutic area: Transthyretin-mediated amyloidosis

What Is Transthyretin Amyloidosis With Cardiomyopathy?

Transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM) is a rare disease that causes a protein called TTR to misfold and build up in the heart. This leads to heart failure, poor physical health, and early death. People with ATTR-CM often feel weak, dizzy, and short of breath. These symptoms can make daily life harder and affect relationships and finances. In Canada, about 33 out of every 100,000 people were estimated to have ATTR-CM in 2020. The average age of patients with ATTR-CM was approximately 80 years, most patients were older males, and most cases were not inherited.

What Are the Treatment Goals and Current Treatment Options for ATTR-CM?

The main goals of treating ATTR-CM are to slow the progression of disease, help patients live longer, and improve their quality of life. Input from patients and clinical experts also emphasized the importance of maintaining independence, reducing symptoms like fatigue and shortness of breath, and minimizing hospital visits and caregiver burden. Quality of life and daily functioning were identified as important outcomes in the patient group input for patients to maintain autonomy and the ability to participate in meaningful activities, such as employment, travel, and social engagement.

Tafamidis is currently the only approved treatment in Canada that modifies the course of ATTR-CM. Other therapies — like vutrisiran, eplontersen, and patisiran — are approved for hereditary TTR amyloidosis with polyneuropathy but not yet for cardiomyopathy. In addition, medications like diuretics, rhythm control drugs, and SGLT2 inhibitors are used to manage symptoms and heart-related complications.

What Is Amvuttra and Why Did Canada’s Drug Agency Conduct This Review?

Amvuttra is a ribonucleic acid interference therapy that is administered by subcutaneous injection. At the time this review was conducted, Health Canada was reviewing Amvuttra for the treatment of adult patients with wild-type ATTR-CM (wtATTR-CM) or hereditary ATTR-CM (hATTR-CM).

CDA-AMC reviewed Amvuttra to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the indication under review by Health Canada.

How Did CDA-AMC Evaluate Amvuttra?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, as well as the economic evidence, of Amvuttra versus other treatments used in Canada for the treatment of cardiomyopathy in adult patients with wtATTR-CM or hATTR-CM. Tafamidis was considered the relevant treatment to compare with vutrisiran for the review of the clinical evidence.

• CDA-AMC identified equity and ethical considerations relevant to vutrisiran and the treatment of adult patients with wtATTR-CM or hATTR-CM.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 1 patient group submission in response to our call for input and by input from the participating public drug programs around issues that may impact their ability to implement a recommendation. No clinician group input was submitted to CDA-AMC for this review.

• Three clinical specialists with expertise in the diagnosis and management of ATTR with representation from Ontario and Alberta were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed the following clinical evidence:

  • 1 phase III, double-blind, placebo-controlled trial (HELIOS-B) comparing Amvuttra with placebo in 654 patients with wtATTR-CM or hATTR-CM

  • 1 indirect treatment comparison (ITC) of vutrisiran versus tafamidis based on subgroups from the HELIOS-B study.

• For the comparison of Amvuttra versus placebo based on the HELIOS-B study:

  • In adults with ATTR-CM, treatment with vutrisiran demonstrated a clinically meaningful reduction in the cumulative incidence rate of all-cause mortality (ACM) and recurrent cardiovascular events over the course of up to 36 months when compared with placebo.

  • Overall, efficacy results suggested that vutrisiran leads to a clinically important improvement in ACM and likely less decline in functional status as determined by stabilization of New York Heart Association (NYHA) class.

  • Health-related quality of life, assessed via Kansas City Cardiomyopathy Questionnaire Overall Summary score, likely declined less with vutrisiran compared with placebo.

  • No notable safety concerns for vutrisiran were identified during the study period.

• Based on the sponsor-submitted ITC, the effects of vutrisiran on ACM, recurrent cardiovascular events, and NYHA class transitions compared with tafamidis are very uncertain.

Economic Evidence

• Amvuttra is available as a prefilled syringe containing 25 mg vutrisiran in a 0.5 mL solution for subcutaneous injection. At the submitted price of $143,041.00 per prefilled syringe, the annual cost of Amvuttra is expected to be $572,164 per patient, based on the Health Canada–recommended dosage.

• Clinical efficacy in the economic analysis was derived from the HELIOS-B trial. Specifically, data for Amvuttra were sourced from patients in the Amvuttra monotherapy arm without background tafamidis use, while data for tafamidis were obtained from patients in the placebo arm who received tafamidis as background therapy. As the HELIOS-B trial was not designed to directly compare these 2 treatment strategies, the sponsor conducted an ITC by using inverse probability of treatment weighting to adjust for baseline differences between the 2 groups and inform the model inputs.

• The CDA-AMC Clinical Review noted that, based on the sponsor-submitted ITC, the effects of Amvuttra on ACM, recurrent cardiovascular events, and NYHA class transitions compared with tafamidis are highly uncertain, and that the ITC does not support that Amvuttra has superior efficacy than tafamidis. This uncertainty arises due to methodological limitations, potential residual confounding despite statistical adjustment, and imprecise effect estimates. Furthermore, no conclusion can be drawn regarding the safety of Amvuttra relative to tafamidis, as safety outcomes were not assessed in the sponsor-submitted ITC.

• CDA-AMC estimated that the budget impact of reimbursing Amvuttra for use in the adult patients with ATTR-CM will be $779 million over the first 3 years, compared with the amount currently spent on tafamidis. The expenditure on Amvuttra over this period is predicted to be $1.2 billion. The actual budget impact of Amvuttra will depend on the prevalence of ATTR-CM in Canada and market uptake of Amvuttra in prevalent and incident populations. At the submitted price, the incremental budget impact of reimbursing Amvuttra is predicted to be greater than $40 million in each of year 1, year 2, and year 3, and the economic feasibility of adoption must be addressed. Additionally, the magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption, given the difference between the sponsor’s estimate and CDA-AMC’s estimate.

• Based on evidence reviewed for this submission, there is no robust evidence to suggest that Amvuttra provides greater health benefit than tafamidis. If there are no differences in health outcomes between Amvuttra and tafamidis, then the total cost of Amvuttra to the health system should not exceed that of tafamidis for the treatment of adult patients with wtATTR-CM or hATTR-CM to ensure cost-effectiveness.

Background

Introduction

The objectives of this report are as follows:

• Review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of vutrisiran, 25 mg, subcutaneous injection in the treatment of TTR amyloidosis with cardiomyopathy (ATTR-CM) in adult patients. The focus will be placed on comparing vutrisiran to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence. This focus is outlined in Table 1.

• Review and critically appraise the economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis (BIA). The focus of the Economic Review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, a Canada’s Drug Agency (CDA-AMC) base case is developed, informed by clinical expert input, the available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

The application was submitted by the sponsor before receiving a Notice of Compliance from Health Canada. This report reflects the anticipated indication and recommended dosage for vutrisiran during the initial CDA-AMC review period.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

6MWT = 6-minute walk test; ACM = all-cause mortality; AE = adverse event; AESI = adverse event of special interest; CDA-AMC = Canada’s Drug Agency; CV = cardiovascular; HRQoL = health-related quality of life; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary; NOC = Notice of Compliance; NYHA = New York Heart Association; RNA = ribonucleic acid; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aThe Economic Review aligns with the scope of the Clinical Review, unless otherwise stated.

^bCDA-AMC has previously issued a reimbursement recommendation for this drug for the same indication or a similar indication.

Submission History for the Drug Under Review

CDA-AMC previously reviewed Amvuttra (vutrisiran injection) through the Reimbursement Review process for stage I or stage II polyneuropathy in adult patients with hereditary TTR-mediated amyloidosis (hATTR) and issued a recommendation of “reimburse with clinical criteria and/or conditions.”

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input received from interested parties (i.e., patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each Reimbursement Review. One patient group submission from Transthyretin Amyloidosis Canada (TAC) was received, and no clinician group submission was received. A quantitative survey with 23 questions was administered to 30 patients and caregivers. Moreover, qualitative interviews were conducted with 12 patients, and a 2-hour round table discussion with patients and caregivers across Canada was held. In total, 51 patients and caregivers provided their input. The full submissions received are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the Reimbursement Review process by identifying issues that may impact their ability to implement a recommendation.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections in this report.

Each review team includes at least 1 clinical expert with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process. Three clinical experts with expertise in the diagnosis and management of TTR amyloidosis (ATTR) participated as part of the review team.

Disease Background

ATTR involves the deposition of amyloid fibrils formed from misfolded TTR protein in multiple organs and tissues, with corresponding clinical manifestations.¹ ATTR may be nonhereditary (wild-type [wtATTR]) or hereditary (hATTR) in origin. Cardiomyopathy is among the most severe and burdensome possible manifestations of ATTR. ATTR with cardiomyopathy (ATTR-CM) leads to rapid, irreversible, and progressive loss of cardiac function.^2-4 Specifically, ATTR-CM is characterized by the deposition of TTR-derived amyloid fibrils in the interstitial tissue of the myocardium, leading to progressive heart failure, physical impairment and decline in health-related quality of life (HRQoL), and, ultimately, premature death.^5-7 Also, it may result in cardiac conduction disorders, including irregular heartbeat, heart palpitations, fatigue and/or exercise intolerance, edema in the lower extremities, ascites, early satiety, nausea, dyspnea, and syncope.^7-11 Input from the patient group described a range of physiological symptoms that result in light-headedness, difficulty sleeping, low energy, and challenges with eating. Patients also reported instability while walking or climbing stairs, which often led to falls. These symptoms had broader impacts on their daily lives, often affecting relationships, financial stability, and well-being.

Globally, the estimated number of patients with ATTR-CM is ███████ to ███████, including 40,000 patients with hATTR with cardiomyopathy (hATTR-CM), and ███████ to ███████ patients with wtATTR with cardiomyopathy (wtATTR-CM).¹ ATTR-CM is more commonly of wild-type origin than of variant (hereditary) origin. The 2020 Canadian Cardiovascular Society and Canadian Heart Failure Society joint statement on cardiac amyloidosis noted that the true prevalence of ATTR-CM in Canada is uncertain.¹² Nonetheless, the estimated prevalence rate of ATTR-CM is approximately 0.033 or 33 per 100,000 persons in Canada, according to the sponsor.¹³ The sponsor assessed the demographics of patients with ATTR-CM in Canada and reported that the average age of patients was approximately ██ years. It was estimated that ████% of patients were aged 85 years or older, ██% of patients were aged 75 years or older, and ████% of patients were aged 65 years or older; ██% of patients were male.^13,14

Diagnosis of ATTR-CM begins once clinical manifestations of the disease are observed, after which the diagnostic pathway includes bone scintigraphy for detection of TTR amyloid deposits in the myocardium (with the use of monoclonal protein testing to exclude light-chain amyloidosis) or a biopsy to confirm diagnosis of ATTR-CM.^15,16

Current Management

No clinician group input was submitted to CDA-AMC for this review.

Treatment Goals

According to the patient group input from TAC, patients identified improving quality of life and daily functioning as key treatment goals for ATTR-CM. They emphasized the importance of maintaining autonomy and the ability to participate in meaningful activities, such as employment, travel, and social engagement.

The clinical experts consulted by CDA-AMC identified the most important goals for an ideal treatment for ATTR-CM, including slowing disease progression, preserving functional status, and improving survival and quality of life. The clinical experts indicated that the focus for patients with ATTR-CM would be on reducing mortality and hospitalization, managing volume overload, and addressing diuretic resistance and cardiorenal complications. The clinical experts highlighted that maintaining functional ability, minimizing symptom burden (e.g., fatigue, shortness of breath), and reducing the burden for prescribing physicians. Late diagnosis remains a significant gap, particularly in small, rural centres without specialized access are key priorities.

Current Treatment Options

The clinical experts consulted by CDA-AMC highlighted that currently tafamidis is the only approved disease-modifying therapy for ATTR-CM. The clinical experts indicated that gene silencer therapies, such as patisiran, eplontersen, and vutrisiran are available for ATTR but currently they are approved only for hATTR with polyneuropathy in Canada. According to the clinical experts, symptom-targeted therapies, such as diuretics, rhythm control drugs, and SGLT2 inhibitors are used in combination to manage cardiac complications.

Key characteristics of vutrisiran are summarized with other treatments available for ATTR-CM in the Supplemental Material document (available on the project landing page), in the Key Characteristics table in Appendix 1.

Unmet Needs and Existing Challenges

According to the patient group input from TAC, patients identified several unmet needs, including logistical barriers to accessing care, such as the burden of frequent medical appointments, treatment infusions, and long travel, particularly in rural areas. They also expressed concerns about the high cost of therapies, which is especially challenging for individuals unable to maintain employment. Additionally, patients reported that their condition, combined with the effort required to access care, impacts their ability to maintain autonomy and engage in daily activities, including, work, travel, and social interactions.

The clinical experts consulted by CDA-AMC identified key unmet needs in ATTR-CM treatment, including the lack of therapies that improve symptoms or reverse disease progression. For ATTR-CM, challenges remain in managing fatigue, shortness of breath, and volume overload, especially in patients who do not respond to tafamidis or have advanced chronic kidney disease and/or end-stage renal disease. The clinical experts indicated that access to care is inconsistent, with delayed diagnosis more common in rural areas and among females due to subtler disease presentation. According to the clinical experts, funding criteria (e.g., Exceptional Access Program requirements) may prevent early intervention, and specialist care is not uniformly available, creating geographic disparities. Overall, the clinical experts indicated that these issues highlight the need for more effective, flexible, and accessible treatment options.

Considerations for Using the Drug Under Review

Contents within this section have been informed by input from the clinical experts consulted for the purpose of this review, as well as the reimbursement conditions proposed by the sponsor (refer to the Initiation, Renewal, Discontinuation, and Prescribing Conditions Proposed by the Sponsor table in Appendix 1). The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, in the Summary of Drug Program Input and Clinical Expert Responses table in Appendix 1. The following has been summarized by the review team. No clinician group input was submitted to CDA-AMC for this review.

Place in Therapy

The clinical experts consulted by CDA-AMC anticipated that the availability of vutrisiran for ATTR-CM will shift the current treatment paradigm by introducing a second effective disease-modifying option alongside tafamidis. While both drugs target the underlying disease process, the clinical experts do not expect combination therapy to be widely adopted due to cost and limited supporting evidence. According to the clinical experts, vutrisiran is expected to be used as a first-line treatment for patients with mixed cardiomyopathy-polyneuropathy phenotypes or those who do not tolerate or experience more rapid than expected disease progression on tafamidis. It may also serve as a second-line option for patients experiencing side effects or seeking a more convenient mode of administration. The clinical experts agreed that it would not be necessary for patients to try other treatments before initiating vutrisiran, provided they meet diagnostic and reimbursement criteria. However, the choice between tafamidis and vutrisiran remains unclear and may depend on individual patient characteristics and resource considerations.

Patient Population

The clinical experts consulted by CDA-AMC indicated that patients best suited for vutrisiran treatment are identified through a combination of clinical judgment, laboratory tests (e.g., monoclonal protein testing, genetic testing), and diagnostic imaging (e.g., echocardiography, 99mTc‑pyrophosphate scintigraphy), with underdiagnosis remaining a concern due to nonspecific symptoms. The clinical experts agreed that patients with confirmed ATTR-CM, particularly those with mixed cardiomyopathy-polyneuropathy phenotype, advanced chronic kidney disease and/or end-stage renal disease, or progression despite tafamidis, are most in need of treatment and likely to benefit from vutrisiran. The clinical experts indicated that patients in earlier stages of disease are expected to show the most meaningful clinical response. The clinical experts indicated that asymptomatic carriers are not considered suitable for treatment, patients with New York Heart Association (NYHA) class IV heart failure, significant liver impairment, vitamin A deficiency, or aversion to injections may be less suitable for treatment with vutrisiran. The clinical experts highlighted that patients living in rural areas may have particular challenges accessing treatment due to limited access to cardiologists.

The clinical experts generally agreed that the sponsor’s proposed initiation criteria were appropriate and aligned with clinical practice. The clinical experts supported the criteria overall but recommended refinements, including adjusting end-diastolic interventricular septal thickness thresholds to avoid missing females with earlier disease, revising biopsy and imaging criteria to exclude amyloid light chain rather than monoclonal gammopathy of undetermined significance, considering patients with monoclonal gammopathy of undetermined significance presented about 25% of all patients with ATTR-CM and should not preclude them from getting treatment. The clinical experts also clarified that patients with mixed ATTR-CM and ATTR-PN should be considered.

Assessing the Response to Treatment

The clinical experts stated that in clinical practice, treatment response is primarily assessed through stability of heart failure symptoms (e.g., NYHA class, diuretic requirements, absence of hospitalizations) and neurological function (e.g., examination, nerve conduction studies), with a clinically meaningful response generally defined as disease stability rather than improvement. Assessment frequency varied slightly among the clinical experts, but a consensus leaned toward evaluations every 6 to 12 months.

Discontinuing Treatment

The clinical experts generally agreed that treatment with vutrisiran should be discontinued in cases of advanced disease progression or when the patient is no longer expected to benefit. According to the clinical experts, objective parameters for discontinuation include development of NYHA class IV heart failure, major side effects, clinically significant hepatic impairment, clinically severe vitamin A deficiency despite supplementation, initiation of another disease-modifying therapy (e.g., tafamidis), or receipt of a heart or liver transplant. One clinical expert indicated that while heart transplant recipients are typically excluded from ATTR clinical trials, there is ongoing uncertainty regarding post-transplant treatment, and in practice, many clinicians may consider continued therapy for ATTR to be reasonable in this population, despite the current lack of supporting evidence. Prognosis of survival shorter than 12 months was also cited as a reasonable threshold for stopping therapy. The sponsor’s proposed discontinuation criteria were largely aligned with the clinical experts’ expectations and considered implementable. Overall, the clinical experts indicated that the discontinuation of treatment with vutrisiran should be guided by a combination of clinical judgment and objective markers of disease progression or lack of therapeutic benefit.

Prescribing Considerations

The clinical experts agreed that prescribing and monitoring of vutrisiran should be limited to specialists with expertise in ATTR, specifically cardiologists (ideally, though not exclusively, with heart failure specialization). According to the clinical experts, diagnosis and treatment initiation should occur in tertiary or well-equipped secondary care settings, where necessary diagnostic tools and multidisciplinary support are available. The clinical experts mentioned that while the drug is expected to be accessible across Canada, regional disparities in access to specialists may pose challenges, particularly in rural areas. The clinical experts supported the sponsor’s proposed prescribing conditions, noting they align with current practice and are feasible to implement. Restricting prescribing to experienced clinicians also helps ensure appropriate patient selection and reduces administrative burden on general practitioners.

Clinical Review

Methods

The review team considered studies in the sponsor’s systematic review (pivotal studies and randomized controlled trials [RCTs]), sponsor-submitted long-term extensions (LTEs), indirect treatment comparisons (ITCs), and studies addressing gaps in the evidence for inclusion. Eligible studies for the systematic review included published and unpublished pivotal studies and phase III and IV RCTs, interventional studies (e.g., head-to-head studies, long-term studies including open-label follow-up studies, and single-arm trials), brief reports, and research letters. Relevant patients and interventions were defined by the indication and the recommended dosage in the product monograph. The vutrisiran monotherapy subgroup was considered potentially important for informing the reimbursement recommendation. Relevant comparators were drugs used in clinical practice in Canada to treat patients described in the indication under review. These included tafamidis, patisiran, and eplontersen, which are indicated for the same indication (i.e., tafamidis for ATTR-CM) or a similar indication (i.e., patisiran and eplontersen for ATTR-PN). The sponsor-submitted ITC only included vutrisiran versus tafamidis, as tafamidis is the current standard of care for the treatment of ATTR-CM. No LTEs or studies addressing gaps in the systematic review evidence were included in the review.

The review team selected outcomes (and follow-up times) for review considering the sponsor’s Summary of Clinical Evidence, clinical expert input, and patient and clinician group input. Included outcomes are those considered relevant to expert committee deliberations, and they were selected in consultation with committee members. Evidence from the systematic review for the most important outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach as they addressed important treatment goals for ATTR-CM, were considered important to patients and clinicians according to patient group input and clinician input, and provided the source for a key input in the sponsor’s pharmacoeconomic model:

• composite of all-cause mortality (ACM) and recurrent cardiovascular (CV) events

• Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS)

• ACM

• NYHA class.

Methods for data extraction, risk of bias appraisal, and certainty of evidence assessment are in the Supplemental Material document in Appendix 2.

Clinical Evidence

In this report, the following sources of evidence submitted by the sponsor are reviewed and appraised:

• 1 phase III, double-blind, placebo-controlled RCT included in the systematic review (HELIOS-B study)

• 1 ITC using subgroups from the HELIOS-B study.

Systematic Review

Description of Studies

Study Characteristics

Characteristics of the HELIOS-B trial are summarized in Table 2. Details pertaining to the study objectives, design, eligibility criteria, interventions and comparators, and relevant outcome measures are in the Supplemental Material document in Appendix 3.

Table 2: Characteristics of Studies Included in the Systematic Review

6MWT = 6-minute walk test; ACM = all-cause mortality; ATTR = TTR amyloidosis; ATTR-CM = TTR amyloidosis with cardiomyopathy; CV = cardiovascular; eGFR = estimated glomerular filtration rate; hATTR = hereditary TTR amyloidosis; HF = heart failure; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary; NAC = National Amyloidosis Centre; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; RCT = randomized controlled trial; SC = subcutaneous; wtATTR = wild-type TTR- amyloidosis.

^aThe diagnosis of ATTR-CM is defined as the presence of TTR amyloid deposits in a tissue-biopsy specimen or fulfillment of validated scintigraphy-based diagnostic criteria for ATTR-CM in the absence of monoclonal gammopathy.

^bNAC stage III is classified as NT-proBNP > 3,000 ng/L and eGFR < 45 mL/min/1.73m².

Source: HELIOS-B Clinical Study Report (2024).¹⁷ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

The HELIOS-B study was a phase III, double-blind, placebo-controlled RCT that evaluated the efficacy and safety of vutrisiran compared with placebo in adult patients with ATTR-CM. Patients were randomized at a 1:1 ratio to receive either vutrisiran (n = 326) or placebo (n = 328). Randomization was conducted using interactive response technology and stratified by baseline tafamidis use (yes versus no), ATTR-CM disease type (hATTR versus wtATTR), and NYHA class (I or II and aged < 75 years versus all others). The HELIOS-B trial had 3 periods: the double-blind period, which lasted up to 3 years, followed by a 2-year open-label extension period (ongoing as of the May 8, 2024, data cut-off), and then patients who discontinued the study drug during the double-blind or open-label extension periods could remain in the study to complete safety follow-up for up to 2 years. The study was conducted at 87 sites in 26 countries in North America (including 2 sites in Canada with ██ patients enrolled), Europe, and Asia.

The main body of this report presents data from the double-blind phase for the HELIOS-B trial up to 36 months.

Statistical Testing and Analysis Populations

The primary composite end point of ACM and recurrent CV events in the overall population and the vutrisiran monotherapy subgroup was analyzed using a modified Andersen-Gill model with a robust variance estimator. The model included treatment, ATTR disease type (hATTR versus wtATTR), NYHA class (I/II versus III), age group (< 75 years versus ≥ 75 years), and log-transformed baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) as covariates. For the overall population analysis, the model was stratified by baseline tafamidis use (yes versus no). Patients were censored at the end of the double-blind period. In the analysis of the primary composite end point of ACM and recurrent CV events (CV hospitalizations and urgent heart failure visits), intercurrent events included treatment and study discontinuation, tafamidis initiation (applicable to vutrisiran monotherapy subgroup only), selected prohibited medications, SGLT2 inhibitor initiation, heart transplant and left ventricular assist device (LVAD) placement, and events due to COVID-19. Patients who underwent heart transplant and/or had an LVAD placement were treated in the same manner as death in the primary analyses of the primary end points and mortality-related end points.

The overall type I error rate for the 2 primary end points and the secondary end points were controlled at a 2-sided 0.05 significance level using a prespecified multiplicity testing procedure. The 2 primary end points was tested at a 2-sided 0.05 significance level using the Hochberg testing procedure (i.e., if the larger of 2 P values is ≤ 0.05, both null hypotheses were rejected; otherwise, the smaller of the 2 P values will have to be at most 0.025 for the corresponding null hypothesis to be rejected). If both primary end points were statistically significant, the full alpha of 0.05 was passed to test the secondary end points defined in both the overall population and the vutrisiran monotherapy subgroup using a prespecified multiple testing procedure. If 1 or both primary end points were not statistically significant, secondary end point tests were performed and the results summarized, but statistical significance was not inferred.

Details pertaining to the multiple testing procedure and intercurrent events handling strategies are in the Supplemental Material document in Appendix 3.

Analysis Populations

The efficacy end points in the HELIOS-B study were analyzed based on the full analysis set (FAS), which included all randomized patients who received any amount of study drug as randomized. The safety population included all randomized patients who received any amount of the study drug and were analyzed as treated.

A total of 654 patients randomized to receive vutrisiran or placebo comprised the FAS, which was also referred to as the “overall population.” This population included patients receiving background tafamidis at baseline, as well as those who were not. In addition to the overall population, a separate “monotherapy population” was defined, which comprised patients in the overall population who were not receiving tafamidis at baseline (N = 395; vutrisiran: n = 196; placebo: n = 199).¹⁸ All primary and secondary end points were assessed in both populations. This review focused on the FAS (overall population) as it aligned with the proposed indication. The vutrisiran monotherapy subgroup was also considered relevant based on clinician input, which indicated that they would tend to use vutrisiran without tafamidis. The vutrisiran monotherapy subgroup also comprised the vutrisiran therapy population in the sponsor-submitted ITC and was included in the sponsor-submitted pharmacoeconomic model.

Patient Disposition

A total of 655 patients with ATTR-CM were randomized to receive vutrisiran (n = 326) or placebo (n = 329), with 1 patient who was assigned to placebo withdrawing from the trial before receiving a dose of randomized treatment. During the double-blind period, fewer patients in the vutrisiran group discontinued treatment compared with the placebo group (78 [23.9%] versus 99 [30.2%] in the vutrisiran versus placebo groups). The commonly reported reasons for treatment discontinuation included death (11.3% versus 14.6%), which was reported less frequently in the vutrisiran group, and withdrawal by patients, which was similar in the 2 groups (7.1% versus 7.0%). A lower proportion of patients in the vutrisiran group stopped study participation during the double-blind period compared with the placebo group (21.2% versus 28.4%). The most commonly reported reasons for study discontinuation included death (15.0% versus 19.2%) and withdrawal by patients (3.4% versus 4.6%).

Details of patient disposition for the HELIOS-B trial are summarized in the Supplemental Material document.

Baseline Characteristics

Detailed baseline characteristics are available in the Supplemental Material document. In the overall population, the baseline characteristics were similar between treatment groups. The median age of all study patients was 77.0 years, with a range of 45 to 85 years. The HELIOS-B trial enrolled mostly male patients (92.5%) and those with wtATTR (88.4%). A total of 39.6% of patients had baseline tafamidis use and 77.7% of patients were categorized as NYHA class II.

Treatment Exposure and Concomitant Medications

The median duration of treatment was ████ months (range, ███ to ████ months), with a cumulative treatment exposure of █████ person-years for the vutrisiran group and █████ (range, ███ to ████), with a cumulative treatment exposure of █████ person-years for the placebo group.

All patients in the HELIOS-B trial received concomitant medication. The most frequently used concomitant medications were antithrombotic drugs (████% and ████% in the vutrisiran and placebo groups, respectively) and high-ceiling diuretics (████% versus ████%).

At baseline, 130 patients (39.9%) in the vutrisiran group and 129 patients (39.3%) in the placebo group were taking tafamidis. In the vutrisiran monotherapy population (i.e., patients in either study arm who were not taking tafamidis at baseline), 85 of 395 patients (21.5%) initiated tafamidis during the double-blind period: 44 of 196 patients (22.4%) in the vutrisiran group and 41 of 199 patients (20.6%) in the placebo group. The median time from the start of vutrisiran to initiation of tafamidis was 17.7 months (range, 6.4 months to 39.1 months).

The proportion of patients taking SGLT2 inhibitors at baseline was similar between the vutrisiran and placebo groups (10 [3.1%] in the vutrisiran group and 11 [3.4%] in the placebo group). A total of 216 patients (33.0%) who were not taking an SGLT2 inhibitor at baseline initiated SGLT2 inhibitors during the double-blind period: 102 patients (31.3%) in the vutrisiran group and 114 patients (34.8%) in the placebo group.

The proportion of patients taking oral loop diuretics at baseline was similar between the vutrisiran and placebo groups (261 [80.1%] with vutrisiran versus 259 [79.0%] with placebo). A total of 155 patients (47.5%) in the vutrisiran group and 183 patients (55.8%) in the placebo group had oral diuretic intensification (initiation of use or increase in existing dose) during the double-blind period. Among them, 133 patients (40.8%) in the vutrisiran group and 146 patients (44.5%) in the placebo group increased the dose of oral loop diuretics; 22 patients (6.7%) in the vutrisiran group and 37 patients (11.3%) in the placebo group initiated oral loop diuretics.

Details of patients’ use of concomitant medications the HELIOS-B trial are in the Supplemental Material document, in Appendix 4.

Results

The key efficacy and harms results and findings from the GRADE assessment are presented in this section. Detailed efficacy and harms results can be found in Appendix 4 in the Supplemental Material document. The HELIOS-B trial’s efficacy and harms outcomes reported in this review were based on data from the overall trial population as of the data cut-off date of May 8, 2024.

Key efficacy results include the following:

• The cumulative incidence of the composite end point — comprising ACM and recurrent CV events — at 36 months was ████ events per year in the placebo group and ████ events per year in the vutrisiran group. This represents an absolute rate reduction of ████ events per year (95% confidence interval [CI], █████ to █████). The hazard ratio (HR) was 0.72 (95% CI, 0.56 to 0.93; P = 0.01) in favour of vutrisiran versus placebo.

• Results from the component analysis of ACM and recurrent cardiovascular events, planned sensitivity, and additional analyses to test modelling assumptions were consistent with the primary analysis. Subgroup analyses of composite ACM and recurrent CV events also favoured vutrisiran over placebo across all prespecified subgroups, including in the vutrisiran monotherapy population. However, heterogeneity in the magnitude of the estimated HRs was visible and wide CIs were observed, generally among the subgroups with smaller sample sizes. No results from test of interaction were reported.

• Treatment between-group difference of change from baseline to month 30 in KCCQ-OS score (least squares mean difference) was 5.8 points (95% CI, 2.4 to 9.2; P < 0.001) in favour of vutrisiran versus placebo.

• A total of 60 patients (18.4%) in the vutrisiran group and 85 patients (25.9%) in the placebo group died from any cause during the follow-up period (up to 42 months). The between-group difference in cumulative incidence percentage of ACM events was ███% less in the vutrisiran group compared with placebo.

• A total of 68% of patients in the vutrisiran group and 61% of patients in the placebo group remained stable or improved in NYHA class from baseline to month 30, the adjusted between-group difference was 8.7% (95% CI, 1.3% to 16.1%; P = 0.02).

• Across the end points of changes in KCCQ, occurrence of ACM, and NYHA class, similar results were observed in the vutrisiran monotherapy population as the overall population. However, as with the primary outcome, heterogeneity in the magnitude of the estimated treatment effects was visible and wide CIs were observed, generally among the subgroups with smaller sample sizes. No results from test of interaction were reported. Details of the results in the vutrisiran monotherapy population can be found in Appendix 4 in the Supplemental Material document.

Although 6-minute walk test (6MWT) and EQ-5D-5L scores were considered relevant end points for this review, they were not assessed using the GRADE approach as change in NYHA class and KCCQ were prioritized as more direct and disease-specific measures of functional capacity and HRQoL, respectively. Nonetheless, 6MWT and EQ-5D-5L scores remain supportive end points, particularly for contextual interpretation and pharmacoeconomic modelling. Detailed results of these outcomes can be found in Appendix 4 in the Supplemental Material document.

Harms

Key harms results include the following:

• At least 1 adverse event (AE) was reported for 98.8% of patients (322 of 326) in the vutrisiran group and 98.5% of patients (323 of 328) in the placebo group. The most common AEs (occurring in at least 20% of patients) in both groups were cardiac failure (31.0% versus 39.0% in the vutrisiran group versus the placebo group), COVID-19 (26.7% versus 30.2%), and atrial fibrillation (21.2% versus 20.7%).

• At least 1 serious adverse event (SAE) was reported for 61.7% of patients in the vutrisiran group and 67.1% in the placebo group (absolute difference of ████%; 95% CI, █████% to ███%). The most common SAEs (occurring in at least 5% of patients) in both groups were cardiac failure (11.7% versus 17.4% in the vutrisiran group versus the placebo group), atrial fibrillation (8.0% versus 6.1%), and cardiac failure acute (4.0% versus 5.5%).

• A total of 10 patients (3.1%) in the vutrisiran group and 13 patients (4.0%) in the placebo group reported an AE that led to study drug discontinuation.

• Overall, 112 patients (17.1%) had a fatal AE during the double-blind period: 49 patients (15.0%) in the vutrisiran group and 63 patients (19.2%) in the placebo group. None of the deaths were considered related to the study drug by the investigator. In general, the cause of death was the underlying disease or factors related to the natural history of the disease.

• Across the harms outcomes, similar results were observed in the vutrisiran monotherapy population. Details of the results in the vutrisiran monotherapy population can be found in Appendix 4 in the Supplemental Material document.

Summary of Findings and Certainty of the Evidence

Literature-based minimal important difference (MID) estimates were used as the thresholds for the change from baseline to month 30 in KCCQ-OS score (MID = 5 points). Refer to the summary of outcome measures in Appendix 3 of the Supplemental Material document. In the absence of literature-based MID estimates, thresholds suggested by the clinical experts were used for the following outcomes: cumulative incidence rate of ACM and recurrent CV events over the course of up to 36 months (threshold: any difference) and cumulative incidence rate of ACM at 42 months (threshold: any difference) and the proportion of patients with at least 1 SAE (threshold: any difference). In the absence of a known threshold and the clinical experts were unable to suggest a specific threshold for a clinically important effect, the certainty in the presence of a nonnull effect was rated for the proportion of patients who remained stable or improved in NYHA class at 30 months.

Table 3: Summary of Findings for Vutrisiran vs. Placebo for Patients With ATTR-CM

ACM = all-cause mortality; ATTR-CM = TTR amyloidosis with cardiomyopathy; CDA-AMC = Canada’s Drug Agency; CI = confidence interval; CV = cardiovascular; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary; MID = minimal important difference; NR = not reported; NYHA = New York Heart Association; RCT = randomized controlled trial; SAE = serious adverse event; vs. = versus.

Notes: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThis analysis was not part of the statistical analysis plan and was requested from the sponsor by CDA-AMC to facilitate the GRADE assessment.

^bImprecision was not rated down. There is no established between-group MID for the cumulative incidence rate of ACM and recurrent CV events over the course of up to 36 months and the cumulative incidence proportion of ACM at 42 months, but the clinical experts suggested that any difference between groups could be considered clinically meaningful. The point estimates and the 95% CIs for the difference between groups suggested a difference consistent with this threshold, supporting the conclusion that the observed treatment effects are clinically important.

^cRated down 1 level for serious imprecision. A 5-point MID for KCCQ-OS is supported in heart failure populations and was selected for this assessment; no established between-group MID is specific to patients with ATTR-CM. The clinical expert consulted by CDA-AMC considered a 5-point difference between groups a threshold of clinical importance. The 95% CI for the difference between groups included both clinically important benefit and no difference based on a 5-point threshold. Some concern due to attrition (approximately 25% not completing KCCQ-OS at 30 months); imputation was applied for approximately 91% of the study population. Imputation methods and sensitivity analyses were appropriate and not clear evidence of differential missingness after imputation. Overall risk of bias considered not serious.

^dImprecision was not rated down. There is no established between-group MID for the proportion of patients who remained stable or improved in NYHA class, and the clinical experts could not suggest a threshold of importance. The target of the certainty of evidence assessment was the presence or absence of any effect relative to the null. The point estimate and the 95% CI for the difference between groups suggested a difference between the 2 groups. Some concern due to imputation methods where missing NYHA class values due to death, heart transplant, and left ventricular assist device placement were imputed as NYHA class IV may overestimate disease severity if some deaths were unrelated to progression or occurred suddenly without prior NYHA class IV symptoms.

^eRated down 1 level for serious imprecision. There is no established between-group MID for the proportion of patients with at least 1 SAE, and the clinical experts suggested that any difference between groups could be considered clinically important. The 95% CI for the difference between groups included both clinically important benefit and no difference based on the threshold of any difference.

Sources: HELIOS-B Clinical Study Report (2024)¹⁷ and sponsor-provided additional information (dated August 21, 2025, and September 1, 2025).^19,20 Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Critical Appraisal

Internal Validity

The HELIOS-B trial was a phase III, double-blind, placebo-controlled RCT to evaluate the efficacy and safety of vutrisiran compared with placebo in adult patients with ATTR-CM. Patients were randomized centrally using interactive response technology, which is generally adequate for allocation concealment. Randomization was stratified by baseline tafamidis use, ATTR disease type (hATTR versus wtATTR), NYHA class, and age. These stratification factors are clinically relevant and increase the likelihood of balance across these key variables. However, while stratification increases the likelihood of balance across the variables in the FAS, it does not equate to independent randomization within subgroups. Specifically, the vutrisiran monotherapy subgroup — defined as patients not receiving tafamidis at baseline — was not separately randomized. Although tafamidis use was a stratification factor, randomization was conducted across the entire trial population, not independently within the monotherapy subgroup. As a result, randomization does not guarantee balance within this subgroup, and chance imbalances in prognostic factors may be more likely, particularly given the smaller sample size. This limitation was acknowledged in the published article of the HELIOS-B trial.²¹ The protocol does not describe the method of sequence generation (block randomization, permuted blocks, and so on), which limits full assessment of randomization integrity. Nonetheless, baseline characteristics were generally similar between arms in both the overall population and the vutrisiran monotherapy subgroup. Therefore, there appears to be a low risk of bias arising from the randomization process in the overall population due to appropriate allocation concealment and stratification. However, results from the monotherapy subgroup may be less reliable due to potential chance imbalances, residual confounding, and reduced precision.

The HELIOS-B trial did not restrict eligibility based on background tafamidis use, with approximately 40% of patients in each arm receiving tafamidis at baseline. Concomitant use of tafamidis was permitted during the trial. In addition, initiation of tafamidis after randomization was allowed, with about 1 in 5 patients in the vutrisiran monotherapy subgroup starting tafamidis during follow-up at similar rates across arms (22.4% in vutrisiran versus 20.6% in placebo). This design may introduce uncertainty in interpreting the trial results, particularly regarding attribution of treatment effects for patients who received tafamidis and vutrisiran concurrently. In such cases, the observed treatment effects may reflect additive or synergistic effects of combination therapy rather than vutrisiran alone.

Confounding by indication and other prognostic factors may be present, particularly in relation to tafamidis use. use. While baseline tafamidis use was similar between randomized arms, and randomization was stratified by baseline use, patients who initiated tafamidis during the trial may have differed systematically from those who did not. These differences could relate to disease stage, clinical care access, or socioeconomic factors that may independently influence outcomes. Tafamidis drop-in rates (20% placebo to 22% vutrisiran) and the distribution of timing from randomization to tafamidis initiation (median = 17.0 months [range, 1.5 months to 33.8 months] for placebo and median = 17.7 months [range, 6.4 months to 39.1 months] for vutrisiran) were similar between arms. The most common reason for initiation was potential clinical benefit rather than disease progression. However, the possibility of bias due to channelling or indication cannot be excluded. While clinician decisions to initiate tafamidis may represent their judgment about disease progression leading to a risk of bias, taken together, the observed similarities in baseline use, drop-in rates, and timing of tafamidis initiation suggest that the risk of bias is likely low.

Immortal-time bias and selection bias may also be a concern if patients had to survive long enough before trial enrolment, potentially inflating survival estimates. However, the risk of this type of bias is limited for the main randomized comparison because eligibility requirements applied equally to both trial arms. More important is the risk of effect modification cannot be concretely ruled out, as the efficacy of vutrisiran may differ depending on tafamidis use. In the FAS, the HR for the composite primary end point in patients who were not receiving tafamidis at baseline (vutrisiran monotherapy) was 0.67 (95% CI, 0.49 to 0.93), and in those who were receiving tafamidis at baseline, the HR was 0.79 (95% CI, 0.51 to 1.21). Both relative effects favoured vutrisiran over placebo. While these estimates are directionally similar, their precision differs, with a narrower CI that excludes unity in the subgroup not taking tafamidis at baseline and a wider interval that includes no benefit in the subgroup who received tafamidis at baseline. This pattern raises the possibility of effect modification, especially in the absence of prespecified interaction testing, meaning the magnitude of vutrisiran’s effects could vary depending on baseline tafamidis therapy. However, the differences between the subgroup HRs appear small, their CIs overlap substantially, and without formal statistical test for interaction, it cannot be concluded with confidence that outcomes truly differ by baseline tafamidis use in the overall population.

Other cointerventions also potentially affect internal validity. Concomitant use of SGLT2 inhibitors and diuretics was permitted during the double-blind period of the HELIOS-B trial. However, no statistical adjustments were made for these cointerventions, which may introduce bias, as both drug classes may independently influence CV outcomes. While the proportion of patients initiating SGLT2 inhibitors was similar across treatment groups, a higher proportion of patients in the placebo group (56%) had oral diuretic intensification compared with the vutrisiran group (48%). This imbalance may introduce bias against vutrisiran as diuretics are commonly used to manage symptoms and heart-related complications, potentially improving outcomes in the placebo group. Furthermore, differences in prescribing patterns or patient characteristics associated with co-intervention use could contribute to confounding by indication or effect modification. For example, patients requiring diuretic intensification may have had more advanced disease or differing clinical trajectories, which could influence outcomes independently of the study drug. These factors introduce some uncertainty as to what the true magnitude of effect of vutrisiran may be.

The handling of intercurrent events was clearly specified. In the primary composite outcome analysis, deaths occurring after study discontinuation were excluded, raising the possibility of underestimating risk among patients who discontinued therapy. This exclusion could bias results in favour of vutrisiran if dropout and death patterns differed by arm. A higher proportion of patients in the placebo group stopped treatment or discontinued study due to death than the vutrisiran group. However, in the component analysis of ACM, all deaths were included using a treatment policy strategy, partially mitigating this limitation and thus the risk of bias is likely low.

In the HELIOS-B study, missing data were handled using planned, end point-specific strategies. For the primary composite outcome, no imputation was performed in the primary analysis, but a sensitivity analysis using multiple imputation for postwithdrawal CV events yielded similar results (HR = █████; P = ██████ overall; HR = █████; P = ██████ in the monotherapy subgroup), suggesting robustness of the primary analysis to missing events. For NYHA class, missing data not due to death were assumed as missing at random and multiply imputed, using a model incorporating relevant covariates. For missing data due to death (including heart transplant and LVAD placement), missing NYHA class values were imputed as class IV. Assigning NYHA class IV to deceased patients or to patients who had advanced cardiac procedures relies on the assumption that these reflect maximal symptomatic burden or advanced status. While this is a conservative imputation strategy that aligns with clinical intuition, especially when death is related to worsening cardiac status, deaths occurring due to noncardiac causes or acute events unrelated to NYHA class progression may overestimate disease severity. This imputation strategy could inflate the apparent severity in the group with more deaths, potentially biasing comparisons. Missingness was ███% in the placebo group and ███% in the vutrisiran group overall, but ██████ in the monotherapy subgroup (████% versus ███%, respectively). The proportion of missingness imputed due to death or advanced procedures was not reported. The Clinical Study Report indicated that planned sensitivity analyses were done to test the robustness of the results after imputation, but the results were not included in the submission.

Attrition in the analysis of KCCQ-OS was notable, with approximately ██% of patients completing the assessment at month 30 and ████ patients in the vutrisiran group (████%) provided HRQoL data than the placebo group (████%). However, multiple imputations were performed for missing data, increasing the number of patients analyzed and yielding a statistically significant treatment effect. While the high rate of missingness and reliance on model-based assumptions pose a risk of bias, the imputation approach reduces bias from differential attrition and potentially missingness that is not random. Planned sensitivity analyses were conducted to assess the impact of missing data and the robustness of the primary analysis using other modelling approaches to test assumptions; however, the results were not reported in the submission. Overall, the missing data strategy was methodologically sound, but there is some concern for bias from missing data for the NYHA class and HRQoL end points.

External Validity

Overall, the estimands, end points, and outcome measures used in the HELIOS-B trial were appropriate and aligned with the study objectives outlined in the protocol. The definition of the primary composite end point (i.e., ACM and recurrent CV events) was considered clinically relevant by the clinical experts for assessing efficacy in treating ATTR-CM. However, its applicability to real-world practice could be enhanced by including additional markers of worsening heart failure, such as oral diuretic adjustments. Although IV diuretic administration was captured within the primary end point, clinicians often manage heart failure progression in outpatient settings through oral diuretic titration, particularly due to funding and access considerations, as per feedback from the clinical experts. These adjustments, while not formally captured in the trial’s primary end point, still reflect meaningful clinical deterioration. Their exclusion may limit the sensitivity of the end point to detect disease progression as it occurs in routine practice.

According to the clinical experts consulted by CDA-AMC, the characteristics of the patients enrolled in HELIOS-B trial were mostly reflective of those in clinical practice in Canada with ATTR-CM, with a few exceptions. Generally, the clinical experts commented that the trial eligibility criteria of the HELIOS-B trial were standard but more restrictive than those used in current clinical practice in Canada. For example, the trial excluded patients aged 85 years and older, which the experts emphasized is an arbitrary cut-off not commonly used in clinical practice where older individuals may still be active and capable of benefiting from treatment. Similarly, the requirement for a minimum end-diastolic interventricular septal wall thickness of 12 mm excluded certain patients, such as older adults or patients with low body weight (e.g., females weighing less than 50 kg), who may present with clear clinical signs of ATTR-CM but septal thickness of 11 mm, who could still benefit from treatment with vutrisiran. The clinical experts also highlighted the exclusion of patients with more advanced disease, such as those with polyneuropathy disability scores of IIIa or higher, as inconsistent with clinical practice, where such individuals may still benefit from cardiomyopathy treatment. Overall, the experts stressed that determining eligibility for treatment of ATTR-CM requires more nuanced clinical judgment that may not be fully captured by trial eligibility criteria.

The clinical experts noted that patients in the HELIOS-B trial appeared somewhat healthier than those they typically treat for ATTR-CM in clinical practice in Canada. This was reflected in baseline measures, such as NYHA class, NAC stage, 6MWT distance, and KCCQ-OS score. For example, the mean KCCQ-OS score in the HELIOS-B trial was more than 70 compared with less than 60 in the clinical experts’ practice. As a result, the efficacy results observed in the trial may overestimate what would be expected in routine care.

In protocol amendment 1, the NT-proBNP inclusion threshold in the HELIOS-B trial was lowered (from > 600 ng/L to > 300 ng/L). The clinical experts noted that this eligibility criteria change was more representative of clinical practice and improved the external validity of the study results. The clinical experts indicated that increased disease awareness and improved diagnostic tools (e.g., nuclear scintigraphy) have led to earlier detection of ATTR-CM, often before patients develop overt heart failure. As a result, NT‑proBNP levels in patients who were newly diagnosed are frequently lower than historical norms, and maintaining a higher threshold could unnecessarily exclude patients who may still benefit from treatment. The clinical experts emphasized that, although measuring NT-proBNP made sense in the context of a RCT, it is less applicable in real-world settings when deciding who would be eligible for ATTR‑CM treatment, especially given its variability in certain populations, such as those who are obese or whose ATTR-CM is effectively managed with diuretics. Thus, excluding patients from treatment with vutrisiran based on NT‑proBNP levels excludes some who might otherwise benefit from treatment.

The choice of placebo as the comparator in the HELIOS-B trial may not be reflective of clinical practice. To address this, the sponsor conducted an ITC using IPD from the HELIOS-B trial to assess the comparative efficacy of vutrisiran versus tafamidis. The clinical experts noted that tafamidis was the standard of care for ATTR‑CM at the time the HELIOS-B trial was conducted. However, they acknowledged that access to tafamidis may have varied across regions and institutions, which could explain why a sizable proportion of patients were receiving it at randomization and were permitted to continue it — or had it added to therapy in those receiving vutrisiran monotherapy — during the trial given vutrisiran did not yet have confirmed efficacy. Although tafamidis was permitted as concomitant therapy during the HELIOS-B trial, the clinical experts noted this may not reflect current practice, where tafamidis and vutrisiran will typically be considered monotherapy options. The clinical experts highlighted the lack of clear clinical guidance on when to initiate 1 treatment over the other or whether dual therapy is appropriate as a key challenge. While the trial design captures some real-world variability, it does not provide a practical framework for clinicians navigating decisions around switching or combining therapies if both drugs are available and reimbursed.

Long-Term Extension Studies

At the time of this review, the interim or final results for the long-term extension studies of the HELIOS-B trial were not available.

Indirect Evidence

Direct comparative evidence exists between vutrisiran and placebo from the HELIOS-B trial, but there is a gap in evidence comparing vutrisiran with tafamidis, which is the current standard of care for treating ATTR‑CM in Canada. Indirect comparisons were required to address this gap.

Description of ITC

One ITC was submitted by the sponsor comparing vutrisiran with tafamidis for treating ATTR-CM on ACM, recurrent CV events, and NYHA class transitions in patients with ATTR-CM.

Study Selection and Review Methods

Based on results from a feasibility assessment, the sponsor concluded that an ITC between vutrisiran and tafamidis, using data from the HELIOS-B and ATTR-ACT trials, is not feasible due to significant differences inpatient populations between the 2 studies. These differences could not be adequately adjusted for using available quantitative methods, leading to potential bias.²² However, the HELIOS-B trial included subgroups of patients receiving vutrisiran or tafamidis as monotherapy, which were used for the ITC using individual patient data (IPD). This ITC was used to inform the pharmacoeconomic model.

ITC Analysis Methods

For additional information on the analysis methods for the ITC, refer to Appendix 6 in the Supplemental Material document.

In the HELIOS-B trial, patients were randomly assigned to treatment with either vutrisiran or placebo. Patients who had been receiving background tafamidis treatment at enrolment were allowed to continue receiving tafamidis together with their randomly assigned study treatment. As a result, the trial included a subgroup of patients receiving vutrisiran monotherapy (vutrisiran randomization group, subgroup with no background tafamidis, referred as vutrisiran monotherapy group) and a subgroup of patients receiving tafamidis monotherapy (placebo randomization group, subgroup with background tafamidis, referred as tafamidis monotherapy group).

Adjustment for baseline differences between the vutrisiran and tafamidis monotherapy groups was done using the stabilized inverse probability of treatment weighting (IPTW) approach. Specifically, a logistic regression model was fitted for the odds of being in the vutrisiran monotherapy group versus the tafamidis monotherapy group. The propensity score weighting of patient-level data were used to minimize bias due to differences in baseline characteristics, and the key primary and secondary end points of the trial were compared between the vutrisiran monotherapy group and the tafamidis monotherapy group within the HELIOS-B trial. Propensity scores were calculated through a logistic regression model of the odds of being in the vutrisiran monotherapy group versus being in the tafamidis monotherapy group, conditional on patients’ baseline characteristics. The following baseline parameters are included as covariates in the propensity score model: high-priority adjustment factors including age category, ATTR disease type, NYHA class, log-transformed troponin I, log-transformed NT-proBNP, KCCQ-OS, and other candidate adjustment factors, including average peak longitudinal strain, estimated glomerular filtration rate, sex, race category, history of antithrombotic drugs, polyneuropathy disability score, and 6MWT distance. In addition to propensity score weighting, to further ensure the robustness of the approach in accounting for differences in baseline characteristics between the 2 groups, the inferential statistical models used to compare patient outcomes between the vutrisiran monotherapy and tafamidis monotherapy groups also included key prognostic variables (log-transformed NT-proBNP, log-transformed troponin I, and 6MWT distance) as covariates.

Summary of Included Studies

The only study included in the IPTW analysis was the HELIOS-B trial.

A summary of baseline characteristics before and after stabilized IPTW weighting is provided in the Supplemental Material document, along with the standardized mean differences (SMDs) between groups for each parameter. An absolute SMD of less than 10% for high-priority baseline parameters and less than 25% for other baseline parameters is considered to indicate a good balance between the groups.^23-25

After propensity score weighting, sample size was 188.0 in the vutrisiran monotherapy and 130.6 in the tafamidis monotherapy groups. Generally, the baseline characteristics after stabilized IPTW weighting were balanced between the vutrisiran monotherapy and tafamidis monotherapy groups. None of the high-priority baseline parameters had an SMD greater than 10% between the vutrisiran monotherapy and tafamidis monotherapy groups after stabilized IPTW. Among all other baseline parameters, only serum TTR concentration, region, and heart rate had a standardized difference greater than 25% between the vutrisiran monotherapy and tafamidis monotherapy groups after stabilized IPTW.

Critical Appraisal of the Sponsor-Submitted ITC

A systematic literature for relevant comparators was not conducted, which is considered acceptable in this context given tafamidis is the only Health Canada–approved treatment option and current standard of care for ATTR-CM. The clinical experts consulted by CDA-AMC confirmed that patisiran, inotersen, and eplontersen are not standard options due to insufficient supporting evidence. Based on this, the rationale for conducting an ITC using IPD from the HELIOS-B trial was considered reasonable and reflective of clinical practice.

The ITC compared patients receiving vutrisiran monotherapy with those receiving tafamidis monotherapy within the HELIOS-B trial. However, patients were not independently randomized to these 2 monotherapy groups. Instead, randomization in the HELIOS-B trial was stratified by baseline tafamidis use but not across these. As a result, the comparison of interest — vutrisiran monotherapy versus placebo plus background tafamidis — is a cross-stratum comparison and therefore observational in nature. Consequently, the benefit of randomization is lost, and the ITC must be interpreted as an observational contrast.

Additionally, baseline characteristics showed heterogeneity between treatment groups, which may introduce bias and uncertainty.

To mitigate confounding between treatment groups, the stabilized IPTW approach was used. This method is appropriate in adjusting for baseline differences between the vutrisiran monotherapy and tafamidis monotherapy groups. Postweighting regression models further adjusted for key covariates. Overall, the covariates identified for adjustment were clinically relevant and comprehensive, and the statistical methods were appropriate. The clinical experts noted that time-dependent exposure (i.e., tafamidis could be started at varying time points for patients based on investigator judgment) could have been a meaningful addition to the modelling but indicated its omission is unlikely to significantly impact results as its effects may be captured through other adjusted variables, such as NYHA class, NT-proBNP, and renal function in the IPTW model.

Despite a generally good balance in baseline characteristics after weighting, some residual imbalances persisted. Notably, serum TTR concentration, geographic region, and heart rate had SMDs exceeding specified thresholds, which may introduce bias and uncertainty in treatment effect estimates. These imbalances potentially reflect structural differences in patient populations and care pathways that may not be fully addressed through statistical adjustment.

A range of statistical models to estimate treatment effects were used, including a modified Andersen-Gill model for recurrent events, a Cox proportional hazards model, and Poisson regression. While these models incorporated relevant covariates (e.g., baseline log-transformed NT-proBNP, troponin I, and 6MWT), there are notable limitations. The proportional hazards assumption was not met in the Cox model, which undermines the validity of HR estimates and suggested that alternative modelling approaches may have been more appropriate. The use of Poisson regression for CV event rates assumes constant event rates and independence, which may not hold in this clinical context of ATTR-CM.

Missing data in the ITC were handled as per the HELIOS-B trial, primarily using multiple imputations. This is generally an appropriate method; however, the imputation strategy that assigned NYHA class IV to patients who died or underwent advanced interventions may introduce bias by overestimating disease severity. The use of a Markov chain Monte Carlo–based multiple imputation procedure for other missing values was methodologically sound, but its validity depends on the assumption that data are missing at random, which may not hold in the presence of heterogeneity between treatment groups.

These limitations collectively may reduce confidence in the robustness of the ITC and the reliability of conclusions regarding comparative treatment efficacy of vutrisiran versus tafamidis. Additionally, HRQoL was identified by patient groups as an important outcome. However, no indirect comparison was conducted for HRQoL.

No harms outcomes were assessed in the ITC.

Efficacy Results of ITCs

Key comparative efficacy results of the IPTW are in Table 4.

Table 4: Summary of IPTW Results for Vutrisiran vs. Tafamidis

6MWT = 6-minute walk test; ACM = all-cause mortality; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; IPTW = inverse probability of treatment weighting; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; vs. = versus.

Note: The estimated sample size (N) for each group was derived based on postweighting adjustments.

^aHRs were based on the modified Andersen-Gill model and included treatment, log-transformed NT-proBNP, log-transformed troponin I, and 6MWT as covariates.

^bAnalyzed using a Cox proportional hazards model with treatment group, log-transformed NT-proBNP, log-transformed troponin I, and 6MWT as covariates. Proportional hazards assumptions were not met.

^cCV event rate and relative rate ratio were determined via a Poisson regression model that included treatment group, log-transformed NT-proBNP, log-transformed troponin I, and 6MWT as covariates, with logarithm of the follow-up time as an offset variable.

^dAdjusted difference and 95% CI were derived from multiple imputation procedures by combining estimates per Rubin's rules based on 100 datasets where missing NYHA class values due to death, heart transplant, and left ventricular assist device placement are imputed as class IV, and the other missing NYHA class values are imputed using a Markov chain Monte Carlo procedure, including selected baseline variables and postbaseline NYHA class assessments. For each imputed dataset, adjusted proportions, odds ratios, and 95% CIs are based on a logistic regression model, including treatment group, log-transformed NT-proBNP, log-transformed troponin I, 6MWT, and baseline NYHA as covariates.

Source: HELIOS-B IPTW Analysis Technical Report.²² Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹³

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the systematic review evidence were included in the review.

Discussion

Efficacy

The HELIOS-B trial evaluated the effects of vutrisiran on outcomes prioritized by patients and clinicians, including survival (ACM), CV events, functional status (NYHA class), and HRQoL (measured by KCCQ-OS). These efficacy outcomes aligned with patients’ expectation of important outcomes, which included slowing disease progression, preserving functional status, and improving survival and quality of life.

Based on results of the HELIOS-B trial, vutrisiran reduced the rate of the primary composite end point of ACM and recurrent CV events compared with placebo, with a between-group difference of █████ events per year (95% CI, █████ to █████) over 36 months. There was no established MID for this outcome in this population. The clinical experts consulted by CDA-AMC emphasized that any reduction could be clinically important given the seriousness of ATTR-CM. Based on the GRADE approach, the observed difference represents a clinically meaningful benefit supported by high certainty evidence. Sensitivity analyses supported the robustness of the primary analysis. Results from the secondary end points (i.e., ACM as a standalone end point and stabilization of NYHA class) were directionally consistent with and supportive of the clinical benefits observed in the primary end point of composite of ACM and recurrent CV events.

The trial permitted background tafamidis use in both treatment arms. Also, patients were allowed to initiate tafamidis during the HELIOS-B trial at the discretion of the clinical team. This introduces interpretive challenges, as the trial was not designed or statistically powered to specifically assess combination therapy or isolate the effect of vutrisiran. To address potential confounding from background tafamidis use, randomization to vutrisiran or placebo were stratified by baseline tafamidis use. Additionally, a prespecified vutrisiran monotherapy subgroup (patients not on tafamidis at baseline) was analyzed for efficacy and safety. As identified in the critical appraisal of the HELIOS-B trial and in the ITC, imbalances in other covariates in the subgroups and residual confounding were possible. Results from the vutrisiran monotherapy group on the primary outcome largely mirrored those of the overall population analysis, with some signal of heterogeneity of treatment effect based on a greater relative reduction in events (lower HR) and greater precision in the estimates among those not receiving tafamidis versus those who were at baseline. However, smaller sample sizes and lack of formal interaction preclude firm conclusions about subgroup differences. The proposed Health Canada indication for vutrisiran is for adult patients with ATTR-CM, regardless of tafamidis use. According to the sponsor and the clinical experts consulted by CDA-AMC, vutrisiran is intended to be used as monotherapy.

Determining the true magnitude of the treatment and how it will generalize to real-world practice is further complicated by other concurrent medications. A lower proportion of patients in the vutrisiran group (47.5%) than the placebo group (55.8%) had oral diuretic intensification (initiation of use or increase in existing dose) during the HELIOS-B trial. The clinical experts indicated that oral loop diuretic therapy intensification could be a marker of disease progression in practice settings. The differences in diuretic intensification between treatment groups could reflect bias or differences in disease trajectory. The CDA-AMC reviewers assessed the risk of bias as low, given the difference between groups in diuretic intensification was less than 10% and its alignment with the expected progression in patients who were untreated.

Patient and clinical experts indicated that maintaining or improving HRQoL is an important goal of treatment for ATTR-CM. HRQoL was measured using the KCCQ-OS, a well-established instrument in cardiovascular research. Scores on the KCCQ-OS declined from baseline in both groups. The between-group difference suggested that there is likely a clinically important smaller decline of HRQoL with vutrisiran compared with placebo at 30 months, based on a 5-point threshold for increase identified in the literature.²⁶ However, there was a high proportion of missing data; therefore, these data are at risk of bias due to attrition. The risk of bias was notable but rated as low because of the multiple imputation strategy for missing data in the analysis.

In the absence of direct comparative evidence between vutrisiran and tafamidis, an ITC using IPD from the HELIOS-B trial to estimate the relative efficacy of vutrisiran compared with tafamidis in patients with ATTR-CM. Although the sponsor-submitted ITC employed appropriate statistical methods, including IPTW and models adjusting for key prognostic factors, differences in model selection and violations of key assumptions (e.g., the proportional hazards assumption in the Cox model) may raise concerns about the robustness and comparability of results. While the adjustment for confounders and prognostic factors was generally comprehensive, the omission of other variables (e.g., time-dependent exposure), evidence of persisting imbalances in covariates after weighting, and assumptions in the imputation of missing NYHA class values may introduce residual bias. The point estimates of effect favoured vutrisiran over tafamidis, but the wide 95% CIs for the treatment effect measures, which included the null value (i.e., 1), indicate imprecision. Therefore, there is low certainty regarding the comparative efficacy of these treatments for ATTR-CM, and the current evidence would not support a claim of superiority.

Harms

Vutrisiran has been available in Canada for the treatment of ATTR-PN since 2024, providing some clinical experience with its use. In the HELIOS-B trial, no new safety signals were identified for vutrisiran. There is moderate certainty that vutrisiran likely results in a clinically important reduction in the proportion of patients with at least 1 SAE when compared with placebo. Cardiac failure was the most frequently reported SAE and occurred more often in the placebo group. Although this finding may suggest a potentially favourable safety profile for vutrisiran in patients with ATTR-CM, the review team noted that the frequency of cardiac failure may be underestimated in the trial due to the concomitant use of tafamidis, SGLT2 inhibitors, and diuretics. Furthermore, this finding may be confounded by the higher use of beta-blockers and oral diuretic intensification in the placebo group, potentially biasing the results against vutrisiran. Additionally, the clinical experts noted that the proportion of patients who developed heart failure while receiving vutrisiran (31.0%) compared with placebo (39.0%) was consistent with expectations in clinical practice, given the advanced age of patients with ATTR-CM and natural anticipated disease manifestations and progression. Overall, the AEs and SAEs reported in the HELIOS-B trial were predominantly cardiac in nature. The clinical experts emphasized that these events are likely attributable to the natural progression of ATTR-CM and the advanced age of the study population, rather than to the drug itself. This interpretation aligns with the known disease course and the baseline risk profile of older patients with ATTR-CM, according to the clinical experts.

However, key gaps remain in the evidence as long-term safety data are lacking and results from an LTE study have not yet been made available at the time of this review. Additionally, safety outcomes were not assessed in the sponsor-submitted ITC, limiting the ability to contextualize vutrisiran’s safety profile relative to tafamidis. These limitations constrain a comprehensive understanding of the drug’s long-term risk-benefit profile, particularly in the context of chronic use in older patients with ATTR-CM.

Ethics and Equity Considerations

Patients with ATTR-CM often experience symptoms such as fatigue, light-headedness, difficulty sleeping, and instability while walking, which can lead to falls and limit independence. These symptoms may result in reliance on caregivers for daily activities, travel to appointments, and emotional support. Access to care for patients with ATTR-CM is uneven across Canada, with the clinical experts consulted by CDA-AMC noting delayed diagnosis in rural areas and among women due to subtler disease presentation. Geographic disparities in access to specialist care (e.g., cardiologists and neurologists with diagnostic capabilities) may limit timely intervention, especially in regions with limited access to cardiologists. The clinical experts stated that funding criteria, such as Exceptional Access Program requirements, may further restrict early treatment, raising concerns about equitable access. The high cost of therapy also presents a potential barrier, particularly for patients facing out-of-pocket expenses or limited financial resources. Given the age and comorbidities of the patient population, multidisciplinary care is often required, yet not consistently available across Canada, adding to treatment burden. Loss of autonomy is 1 of the most profound quality-of-life impacts reported by patients and caregivers, affecting career prospects, travel, and social engagement. For example, 66.7% of patients surveyed reported having to stop working, retire early, or reduce work hours due to the disease, and 80% noted a significant impact on their ability to travel. Patients also described how their identity and daily life became centred around managing medical and infusion appointments. These factors highlight ethical considerations related to autonomy, dignity, and equity, especially for people who live in rural areas and who are systematically marginalized for treatment of ATTR-CM. Although vutrisiran is expected to be widely available across Canada, systemic and logistical challenges, such as uneven access to specialists and diagnostic services, may limit its acceptability and appropriateness for some patients, emphasizing the need for careful implementation planning. Patients and caregivers expressed hope that vutrisiran may improve HRQoL and non–health-related quality of life by slowing disease progression, preserving functional status, and improving survival and quality of life, thereby supporting greater autonomy and preserving dignity.

Conclusion

One phase III, double-blind, placebo-controlled RCT (the HELIOS-B trial) suggested that in adults with ATTR-CM, vutrisiran results in a clinically meaningful reduction in the cumulative incidence rate of ACM and recurrent CV events over the course of up to 36 months compared with placebo. Additionally, compared with placebo, vutrisiran results in a clinically important reduction in ACM and likely less decline in functional status as determined by stabilization of NYHA class. Patients’ HRQoL likely declined less with vutrisiran compared with placebo. However, it is uncertain whether the observed beneficial effects would persist due to the lack of longer-term data.

Compared with placebo, there is moderate certainty of evidence that vutrisiran likely results in a clinically important reduction in the proportion of patients with at least 1 SAE. Overall, no new safety signals were identified in the HELIOS-B trial, and the observed safety profile of vutrisiran is as expected based on the product monograph and input from clinical experts.

There are no head-to-head studies between vutrisiran and tafamidis, the current standard of care for ATTR-CM. A sponsor-provided ITC suggested vutrisiran improves ACM and recurrent CV events, and NYHA class stabilization compared with tafamidis. However, the results are uncertain due to methodological limitations, potential residual confounding despite statistical adjustment, and imprecise effect estimates. The ITC does not support that vutrisiran has superior efficacy to tafamidis. The ITC did not evaluate the comparative effects on HRQoL or harms.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of vutrisiran compared with tafamidis for the treatment of ATTR-CM.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of vutrisiran from the perspective of a public health care payer in Canada over a lifetime horizon (24 years). The modelled population comprised adult patients with wtATTR-CM or hATTR-CM, which is aligned with the Health Canada indication and was based on the participants in the HELIOS-B trial. The sponsor’s base-case analysis included costs related to drug acquisition, administration, background supportive care therapies for management of symptoms, transient events, nonhospitalization disease management, SAEs, and terminal care.

In the sponsor’s base case, vutrisiran was associated with incremental costs of $3,519,742 and 1.33 incremental quality-adjusted life-years (QALYs) relative to tafamidis. This resulted in an incremental cost-effectiveness ratio of $2,648,299 per QALY gained. Of the incremental benefit compared to tafamidis (1.33 incremental QALYs), approximately 100% of benefit was predicted to be accrued after the treatment duration of the HELIOS-B trial (maximum treatment period = ████ ██████), because the sponsor’s model predicted lower survival for vutrisiran during the trial period but more favourable survival outcomes in the extrapolated period. Additional information about the sponsor’s submission is summarized in the Supplemental Material document, in Appendix 10.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 5; full details are provided in Appendix 11 of the Supplemental Material document).

Table 5: Key Issues With the Sponsor’s Economic Submission

ATTR-CM = TTR amyloidosis with cardiomyopathy; CDA-AMC = Canada’s Drug Agency; ITC = indirect treatment comparison; NYHA = New York Heart Association.

Note: Full details of the issues identified by CDA-AMC are provided in Appendix 11 of the Supplemental Material document.

CDA-AMC Assessment of Cost-Effectiveness

Based on the CDA-AMC Clinical Review of the sponsor-submitted ITC comparing vutrisiran monotherapy and tafamidis monotherapy, the results for ACM, recurrent CV events, and NYHA stabilization are uncertain due methodological limitations, potential residual confounding despite statistical adjustment, and imprecise effect estimates. Therefore, the ITC does not support that vutrisiran has superior efficacy to tafamidis for the treatment of adult patients with wtATTR-CM or hATTR-CM (refer to Table 5). Additionally, the ITC did not evaluate the comparative effects on HRQoL or harms. Additional limitations in the economic analysis were identified, including uncertainty in the long-term treatment effects and in the assumption of postdiscontinuation efficacy for vutrisiran. These limitations in the clinical evidence and economic model could not be addressed through reanalysis owing to the lack of supporting data. These limitations also bias the model results in favour of vutrisiran, meaning health outcomes for patients receiving vutrisiran is likely overestimated in the submitted analysis. Therefore, no reanalyses were performed.

Summary of the Budget Impact

The sponsor submitted a BIA to estimate the 3-year (2027 to 2029) budget impact of reimbursing vutrisiran for use in adult patients with wtATTR-CM or hATTR-CM.²⁷ The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach. The price of vutrisiran was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Appendix 10 of the Supplemental Material document.

CDA-AMC identified limitations with the sponsor’s estimated budget impact and made changes to model parameters and assumptions in consultation with clinical experts to derive CDA-AMC’s base case (Supplemental Material document, Appendix 12). CDA-AMC estimated that by year 3 of reimbursement, 2,319 patients would be eligible for treatment with vutrisiran; of these, 931 are expected to receive vutrisiran. The estimated incremental budget impact of reimbursing vutrisiran is predicted to be approximately $779 million over the first 3 years, with an expected expenditure of $1.2 billion on vutrisiran.

Conclusion

Based on the CDA-AMC Clinical Review of the sponsor-submitted ITC, the comparative efficacy of vutrisiran relative to tafamidis is highly uncertain due to several limitations, including methodological limitations, potential residual confounding despite statistical adjustment, and imprecise effect estimates. Additionally, no conclusion can be drawn regarding the safety of vutrisiran relative to tafamidis because safety outcomes were not assessed in the sponsor-submitted ITC. Given the uncertainty in the comparative clinical evidence, there is insufficient evidence to determine whether vutrisiran provides greater health benefit than tafamidis. If there are no differences in health outcomes between vutrisiran and tafamidis, then the total cost of vutrisiran to the health system should not exceed that of tafamidis.

The budget impact of reimbursing vutrisiran to the public drug plans in the first 3 years is estimated to be approximately $779 million. The 3-year expenditure on vutrisiran (i.e., not accounting for current expenditure on comparators) is estimated to be $1.2 billion.

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