Drugs, Health Technologies, Health Systems

Reimbursement Recommendation

Vutrisiran (Amvuttra)

Indication: For the treatment of cardiomyopathy in adult patients with wild-type or hereditary transthyretin-mediated amyloidosis (wtATTR or hATTR amyloidosis)

Sponsor: Alnylam Canada ULC

Recommendation: Reimburse with conditions

Summary

What Is the Reimbursement Recommendation for Amvuttra?

Canada’s Drug Agency (CDA-AMC) recommends that Amvuttra be reimbursed by public drug plans for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) in adult patients if certain conditions are met.

Why Did CDA-AMC Recommend Reimbursement?

The Canadian Drug Expert Committee (CDEC) determined that Amvuttra demonstrates acceptable clinical value versus placebo in adult patients with ATTR-CM. Evidence from a clinical trial showed that Amvuttra reduced the cumulative incidence rate of all-cause mortality and recurrent cardiovascular (CV) events over a follow-up period of up to 36 months compared to placebo. Indirect comparisons suggest that Amvuttra may lead to fewer deaths, fewer repeat CV events, and better functional exercise capacity than tafamidis. However, the available indirect evidence does not show that Amvuttra is more effective than tafamidis.

ATTR-CM is a rare disease that leads to heart failure and early death. Tafamidis is currently the only approved treatment in Canada, but coverage is limited and some patients do not benefit from it. Amvuttra could be useful for patients with mixed heart and nerve involvement or those who cannot tolerate or whose disease does not respond to tafamidis, offering an additional disease-modifying treatment option. CDEC concluded Amvuttra addresses a significant unmet clinical need with an acceptable level of certainty in clinical value.

Which Patients Are Eligible for Coverage?

Amvuttra should only be covered for adults with confirmed diagnoses of ATTR-CM (wild-type or hereditary). Amvuttra should only be covered for patients who have mild to moderate heart failure symptoms (i.e., New York Heart Association [NYHA] classes I to III), and a history of heart failure that required treatment or hospitalization. Amvuttra should not be covered for patients who have had a heart or liver transplant, use a mechanical heart support device, or are already receiving other disease-modifying treatment for ATTR-CM (e.g., tafamidis).

What Are the Conditions for Reimbursement?

Amvuttra should only be reimbursed if it is prescribed by a specialist experienced in diagnosing and managing ATTR-CM and if the cost of Amvuttra does not exceed that of tafamidis. Amvuttra should be discontinued in patients whose disease progresses to NYHA class IV heart failure, who undergo a heart or liver transplant, or who receive an implanted cardiac mechanical assist device.

Important budget impact considerations must be addressed for health systems to be able to adopt Amvuttra.

Review Background

Highlights of Input From Interested Parties

The patient group (Transthyretin Amyloidosis Canada) noted the following effects of the disease, unmet needs, and important outcomes:

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

The participating public drug programs raised potential implementation issues related to considerations for relevant comparators, initiation, discontinuation, prescribing of therapy, care provision issues, and system and economic issues.

Recommendation

With a vote of 13 in favour to 0 against, CDEC recommends that vutrisiran be reimbursed for the treatment of cardiomyopathy in adult patients with ATTR-CM only if the conditions listed in Table 1 are met.

Table 1: Reimbursement Conditions and Reasons

Reimbursement condition

Reason

Implementation guidance

Initiation

1. Treatment with vutrisiran should be reimbursed in adult patients with documented cardiac disease due to ATTR-CM (hATTR-CM or wtATTR‑CM).

1.1. Documented wtATTR‑CM consists of all the following:

1.1.1. absence of a variant TTR genotype

1.1.2. evidence of cardiac involvement by echocardiography with end diastolic interventricular septal wall thickness greater than 12 mm

1.1.3. positive findings on 99mTc PYP scintigraphy with SPECT scanning or presence of amyloid deposits in biopsy tissue (fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac)

1.1.4. TTR precursor protein identification by immunohistochemistry, scintigraphy, or mass spectrometry.

1.2. Documented hATTR‑CM consists of all the following:

1.2.1. presence of a variant TTR genotype associated with cardiomyopathy and presenting with a cardiomyopathy phenotype

1.2.2. evidence of cardiac involvement by echocardiography with end diastolic interventricular septal wall thickness greater than 12 mm

1.2.3. positive findings on 99mTc PYP scintigraphy with SPECT scanning or presence of amyloid deposits in biopsy tissue (fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac).

2. Treatment with vutrisiran should be reimbursed in adult patients who have all the following characteristics:

2.1. heart failure symptoms categorized as NYHA class I to III

2.2. a history of heart failure, defined as at least 1 prior hospitalization for heart failure or clinical evidence of heart failure that has required treatment with a diuretic

2.3. no history of heart or liver transplant

2.4. no current use of an implanted cardiac mechanical assist device

2.5. no current use of other disease-modifying treatments for transthyretin amyloidosis (e.g., tafamidis).

In the HELIOS-B trial, vutrisiran demonstrated clinically meaningful benefits in adults with ATTR-CM, resulting in a clinically meaningful reduction in the cumulative incidence rate of all-cause mortality and recurrent CV events over a follow-up period of up to 36 months compared with placebo. Compared with placebo, vutrisiran results in a clinically important reduction in all-cause mortality and likely less decline in functional status as determined by stabilization of NYHA classification. Patients’ HRQoL likely declined less with vutrisiran compared to placebo.

The clinical experts stated that although genotyping is not strictly required for the treatment of ATTR-CM, it is strongly recommended due to its importance in guiding other key clinical decisions.

Vutrisiran could be initiated similarly to tafamidis as per the reimbursement criteria for each public drug plan.

With respect to the criterion of end diastolic interventricular septal wall thickness (> 12 mm irrespective of sex), the clinical experts noted to CDEC that females tend to have thinner septal wall thickness than males and may take longer to reach a > 12 mm threshold. Therefore, a sex-specific septal wall thickness threshold (≥ 11 mm for females) may better align with clinical practice while ensuring appropriate patient selection.

Discontinuation

3. Treatment with vutrisiran should be discontinued for patients who:

3.1. experience disease progression to NYHA class IV

3.2. receive a heart or liver transplant

3.3. receive an implanted cardiac mechanical assist device.

There is no evidence that vutrisiran should be held to a different standard than tafamidis when considering discontinuation.

Vutrisiran could be discontinued similarly to tafamidis as per the reimbursement criteria for each public drug plan.

Prescribing

4. The patient must be under the care of a specialist with expertise in the diagnosis and management of ATTR-CM.

This is meant to ensure that vutrisiran is prescribed for appropriate patients and that adverse effects are managed in an optimized and timely manner.

Pricing

5. The total treatment cost of vutrisiran should be negotiated so it does not exceed the total treatment cost of tafamidis for the same indication.

Based on CDEC’s assessment of the evidence, the efficacy of vutrisiran may be comparable to that of tafamidis. Therefore, the total treatment cost of vutrisiran should be no more than that of tafamidis.

Feasibility of adoption

6. The economic feasibility of adoption of vutrisiran must be addressed.

At the submitted price, the incremental budget impact of vutrisiran is expected to be greater than $40 million annually in each of the 3 years.

Additionally, at the submitted price, 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 the CDA-AMC estimates.

ATTR-CM = transthyretin amyloid cardiomyopathy; CDEC = Canadian Drug Expert Committee; CV = cardiovascular; hATTR-CM = hereditary transthyretin amyloid cardiomyopathy; HRQoL = health-related quality of life; NYHA = New York Heart Association; PYP = pyrophosphate; SPECT = single-photon emission CT; wtATTR-CM = wild-type transthyretin amyloid cardiomyopathy.

Rationale for the Recommendation

Clinical Value

Evidence from 1 phase III, double-blind, randomized, placebo-controlled trial (HELIOS-B, N = 654) suggests that in adults with ATTR-CM, vutrisiran results in a lower cumulative incidence rate of all-cause mortality and recurrent CV events compared with placebo over a follow-up period of up to 36 months. Additionally, vutrisiran resulted in a statistically significant reduction in all-cause mortality compared with placebo; the certainty of evidence was rated as high using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Vutrisiran was also likely to result in less of a decline in functional status, as determined by stabilization of NYHA classification of heart failure symptoms, compared to placebo.

Patients’ health-related quality of life (HRQoL) likely declined less with vutrisiran compared to placebo. However, due to the lack of longer-term data, it is uncertain if the observed beneficial effects would persist. Compared with placebo, there is moderate-certainty evidence that vutrisiran likely results in a clinically important reduction in the proportion of patients who experience at least 1 serious adverse event.

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. In the absence of head-to-head studies comparing vutrisiran and tafamidis (the current standard of care for ATTR-CM), a sponsor-provided indirect treatment comparison (ITC) was submitted that suggested vutrisiran improves all-cause mortality, recurrent CV events, and NYHA class stabilization compared with tafamidis. However, the results were 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 compared to tafamidis. The ITC did not evaluate their comparative effects on HRQoL or harms.

Based on its assessment of the clinical evidence from the HELIOS-B trial and the ITC, CDEC concluded that vutrisiran demonstrates uncertain clinical value compared with appropriate comparators (tafamidis) in adult patients with ATTR‑CM.

Additional information on the committee’s discussion around clinical value is provided in the Summary of Deliberation section.

Considering Significant Unmet Clinical Need

ATTR-CM is a rare disease that causes the TTR protein to misfold and build up in the heart. This leads to heart failure, poor physical health, and early death. Tafamidis (a once-daily oral tablet) is the only approved disease-modifying therapy for ATTR-CM in Canada. It has restricted coverage in almost all provinces and territories (except in Yukon, where it is not a benefit). There are limited therapies that improve symptoms or reverse disease progression. Some patients’ disease does not respond to tafamidis. The clinical experts consulted by CDA-AMC considered vutrisiran to be a first-line treatment option for those with a mixed phenotype of cardiomyopathy and polyneuropathy, those whose disease does not respond to tafamidis, or those who cannot tolerate tafamidis. Vutrisiran is a second disease-modifying treatment option alongside tafamidis with the potential to help manage symptoms for patients whose disease does not respond to tafamidis or for those who have limitations with oral therapy.

CDEC concluded vutrisiran addresses a significant unmet clinical need with an acceptable level of certainty in clinical value.

Further information on the committee’s discussion around unmet clinical need is provided in the Summary of Deliberation section.

Developing the Recommendation

Due to the uncertainty in clinical value, CDEC could not recommend whether to reimburse vutrisiran or not based on clinical value alone. Therefore, the committee also considered whether vutrisiran addresses a significant unmet clinical need. CDEC concluded that vutrisiran addresses a significant unmet clinical need with an acceptable level of certainty. Based on the preceding considerations, CDEC recommended that vutrisiran be reimbursed. As part of the deliberation on whether to recommend reimbursement, the committee also considered unmet nonclinical need and health inequity. Information on this discussion is provided in the Distinct Social and Ethical Considerations domain in the Summary of Deliberation section.

Because CDEC recommended that vutrisiran be reimbursed, the committee also deliberated on whether reimbursement conditions should be added to address important economic considerations, health system impacts, or social and ethical considerations, or to ensure clinical value is realized. The resulting reimbursement conditions, with accompanying reasons and implementation guidance, are stated in Table 1.

Summary of Deliberation

CDEC considered all domains of value of the deliberative framework before developing its recommendation: clinical value, unmet clinical need, distinct social and ethical considerations, economic considerations, and impacts on health systems. For further information on the domains of value, refer to Expert Committee Deliberation at Canada’s Drug Agency.

The committee considered the following key discussion points, organized by the 5 domains of value.

Clinical Value

Unmet Clinical Need

Distinct Social and Ethical Considerations

Economic Considerations

Impacts on Health Systems

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information (links to the full documents for the review can be found on the project web page):

CDEC Information

Members of the Committee

Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice-Chair), Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Carla Velastegui, Dr. Edward Xie, and Dr. Peter Zed.

Meeting date: November 26, 2025

Regrets: Three expert committee members did not attend.

Conflicts of interest: None