FDA Approves Vutrisiran for ATTR-CM, Expanding Indication in Amyloidosis

The FDA has approved vutrisiran (Amvuttra; Alnylam Pharmaceuticals) for the treatment of cardiomyopathy associated with wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults.¹

This expanded indication makes vutrisiran both the first and the only FDA-approved therapy for both the cardiomyopathy and polyneuropathy manifestations of ATTR amyloidosis. Alnylam also noted it plans to offer patient access programs to minimize out-of-pocket costs, with the company anticipating that most patients will pay $0.

The approval decision was made based on positive findings from the HELIOS-B phase 3 clinical trial (NCT04153149), which evaluated the RNA interference (RNAi) therapeutic’s safety and efficacy in a patient population of 655 patients who were randomly assigned to 25-mg vutrisiran (n= 326) or placebo (n = 329), with a subgroup of monotherapy patients who were not receiving tafamidis (Vyndamax; Pfizer) at baseline. Those receiving vutrisiran demonstrated statistically significant reductions in cardiovascular mortality, hospitalizations, and urgent heart failure visits compared with those on placebo. Altogether, the study met all 10 of its prespecified primary and secondary end points.

Ronald Witteles, MD, one of the trial investigators and a professor of medicine at Stanford University School of Medicine as well as codirector of the Stanford Amyloid Center, said in a statement that the “approval provides an opportunity to further transform ATTR-CM treatment with a new mechanism of action,” noting that the trial demonstrated the treatment’s ability to allow “patients to live longer, experience fewer hospitalizations, and improve how they function and feel.”¹

“The trial enrolled patients who mirror the real-world population with this disease, and I am very encouraged by vutrisiran’s ability to demonstrate meaningful clinical benefits across both cardiovascular outcomes and multiple measures of disease progression. This is a very exciting day for patients with this challenging disease,” Witteles said.¹

HELIOS-B Efficacy Data

The trial data were published in the New England Journal of Medicine.² During the double-blind treatment period of HELIOS-B, lasting up to 36 months, vutrisiran treatment reduced the combined risk of all-cause mortality and recurrent cardiovascular events by 28% (overall population HR, 0.72 [95% CI, 0.56-0.93; P = .01]; monotherapy population HR, 0.67 [95% CI, 0.49-0.93; P = .02]). The treatment group also had a lower risk of death from any cause through 42 months (overall population HR, 0.65; 95% CI, 0.46-0.90; P = .01).

Among the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least 1 primary end point event. Treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4-39.6; P <.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4-9.2; P <.001) in the overall population.

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Additional analysis that included 6 months of open-label treatment showed a mortality risk reduction of 36%. Among patients in the monotherapy subgroup, the combined risk reduction reached 33%, with a 35% reduction in mortality through 42 months. The HELIOS-B trial data also showed those receiving vutrisiran preserved functional capacity and quality of life, with biomarkers predictive of cardiac outcomes used for assessment, including NT-proBNP and troponin I.

HELIOS-B Safety Data

Its safety profile remained consistent with prior studies, including the HELIOS-A trial (NCT03759379) which supported its initial FDA approval for hereditary ATTR polyneuropathy (hATTR-PN) in 2022. Common adverse events included extremity pain (15%), arthralgia (11%), dyspnea (7%), and decreased vitamin A levels (7%). No new safety concerns emerged in the ATTR-CM population. The incidence of adverse events was similar in the 2 groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and 67% of those in the placebo group.

“FDA approval of AMVUTTRA for ATTR-CM marks a major step forward, offering patients a new therapeutic option with proven clinical benefit,” Yvonne Greenstreet, MBChB, CEO of Alnylam, said in a statement.¹ “This milestone reflects nearly two decades of commitment to the ATTR amyloidosis community.”

Vutrisiran is designed to target TTR production, addressing the underlying cause of ATTR-CM by reducing circulating TTR levels. The therapy thereby limits amyloid deposition, thereby mitigating further cardiovascular damage. It is administered via subcutaneous injection every 3 months.

Prior Approval for ATTR Polyneuropathy

In June 2022, after the FDA first extended its review by an additional 3 months, the agency approved vutrisiran for the treatment of those with ATTR amyloidosis polyneuropathy.³

That decision was based on positive 9-month results from the phase 3 HELIOS-A study (NCT03759379). Those results showed that the treatment met the primary end point of change from baseline in the modified Neuropathy Impairment Score at 9 months (P <.001), with vutrisiran additionally achieving statistically significant results (P <.001) on secondary measures such as the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy and timed 10-meter walk test compared with historical placebo results.³

The HELIOS-A trial was a global, open-label, multicenter study that evaluated 164 patients with hATTR amyloidosis randomly assigned 3:1 to 25-mg vutrisiran (n = 122) or 0.3 mg/kg of patrisiran (Onpratto; Alnylam) (n = 42) via intravenous infusion once every 3 weeks for 18 months. Efficacy was assessed by comparing the results of the drug relative to placebo in HELIOS from the phase 3 APOLLO trial (NCT01960348) of patisiran, a randomized controlled study in a comparable patient population.

Post-Approval Data in Polyneuropathy

At the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, a new analysis of the phase 3 HELIOS-A trial was presented, showing that vutrisiran improved quality of life in patients with hereditary ATTR with polyneuropathy, through preserved functional activity and social participation.⁴

The analysis occurred over 18 months and included 122 patients on vutrisiran and 76 patients on placebo who had raw scores on the Rasch-built Overall Disability Scale (R-ODS), a patient-reported outcome measure.

The median R-ODS raw scores were recorded in 113 patients on vutrisiran and 54 patients on placebo, showing stable raw R-ODS and Logits among vutrisiran-treated patients (R-ODS: baseline = 35, month 18 = 36; Logit: baseline: 2.04, month 18 = 2.28), an indication of preservation of activity. This was reflected by patients’ ability to walk outdoors for less than 1 km, whereas investigators observed deterioration in the placebo arm (R-ODS: baseline = 30.5, month 18 = 19.5; Logit: baseline = 1.05, month 18 = 1.06).

REFERENCES
1. Alnylam Announces FDA Approval of AMVUTTRA® (vutrisiran), the First RNAi Therapeutic to Reduce Cardiovascular Death, Hospitalizations and Urgent Heart Failure Visits in Adults with ATTR Amyloidosis with Cardiomyopathy (ATTR-CM). Alnylam. News release. March 20, 2025. Accessed March 20, 2025. https://www.businesswire.com/news/home/20250319752041/en/Alnylam-Announces-FDA-Approval-of-AMVUTTRA-vutrisiran-the-First-RNAi-Therapeutic-to-Reduce-Cardiovascular-Death-Hospitalizations-and-Urgent-Heart-Failure-Visits-in-Adults-with-ATTR-Amyloidosis-with-Cardiomyopathy-ATTR-CM
2. Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134.
3. Alnylam announces FDA approval of Amvuttra (Vutrisiran), an RNAi therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. News release. Alnylam. June 13, 2022. Accessed March 20, 2025. https://investors.alnylam.com/press-release?id=26776
4. Kumar V, Doenges M, Duque DR, Bender S, Capocelli K. Impact of vutrisiran on activities of daily living and functional status in patients with hATTR amyloidosis. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; October 15-18, 2024; Savannah, GA. ABSTRACT 209