New RNAi therapeutic offers a novel mechanism to address both cardiomyopathy and polyneuropathy manifestations of the disease.
The US Food and Drug Administration (FDA) has granted approval for AMVUTTRA (vutrisiran), an RNA interference (RNAi) therapeutic developed by Alnylam Pharmaceuticals, for the treatment of cardiomyopathy associated with both wild-type and hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults; this approval aims to reduce cardiovascular mortality, hospitalizations and urgent heart failure visits.
ATTR is an underdiagnosed and potentially fatal disease caused by misfolded transthyretin (TTR) proteins that form amyloid deposits in various organs – most commonly the nerves and heart. The wild-type form (wtATTR) primarily affects older adults and is considered age-related, with an estimated 200,000 to 300,000 people impacted. As the population ages, the prevalence of ATTR is expected to increase, and it is increasingly recognized as a significant, yet overlooked, contributor to heart failure.
AMVUTTRA operates by silencing the gene responsible for producing transthyretin (TTR), thereby reducing the accumulation of misfolded TTR proteins that form amyloid deposits in cardiac tissue; it is an RNAi mechanism that addresses the disease at its source. The therapeutic is administered via subcutaneous injection once every three months, offering a less frequent dosing regimen compared with existing daily oral treatments.
Clinical trial outcome
The FDA’s approval is based on the results of the HELIOS-B Phase 3 clinical trial, which evaluated the efficacy and safety of vutrisiran in patients with ATTR-CM. The study demonstrated that vutrisiran achieved a 28% reduction in the composite endpoint of all-cause mortality and recurrent cardiovascular events in the overall population; notably, in the monotherapy group, a 33% reduction was observed. Additionally, vutrisiran treatment resulted in a 36% reduction in all-cause mortality in the overall population and a 35% reduction in the monotherapy group. The trial also reported significant improvements in functional capacity, quality of life measures and biomarkers indicative of disease progression.
Dr Yvonne Greenstreet, Chief Executive Officer of Alnylam, emphasized the significance of this development: “The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal advancement for patients, providing a new and clinically differentiated treatment option that has been shown to improve outcomes, including cardiovascular mortality and reduce progression for those living with this devastating disease.” She also acknowledged the collaborative efforts leading to this milestone and reiterated the company’s commitment to ongoing innovation for patients with ATTR amyloidosis.
Dr Ronald Witteles, a HELIOS-B investigator and Professor of Medicine at Stanford University School of Medicine, highlighted the therapeutic’s potential impact. “This FDA approval provides an opportunity to further transform ATTR-CM treatment with a new mechanism of action. The HELIOS-B clinical trial found that vutrisiran allowed patients to live longer, experience fewer hospitalizations, and improve how they function and feel.”
He noted that the trial’s enrollment reflected the real-world patient population, and expressed optimism regarding vutrisiran’s meaningful clinical benefits across cardiovascular outcomes and multiple measures of disease progression. “This is a very exciting day for patients with this challenging disease,” he added.
The landscape
The treatment landscape for transthyretin amyloid cardiomyopathy (ATTR-CM) has been led by Pfizer’s Vyndaqel (tafamidis), an oral therapy that stabilizes the transthyretin (TTR) protein to prevent amyloid deposition. Vyndaqel has seen significant commercial success, generating approximately $3.32 billion in global sales in 2023. In November 2024, BridgeBio Pharma received FDA approval for Attruby (acoramidis), another oral TTR stabilizer, based on positive results from the ATTRibute-CM Phase 3 trial, which demonstrated reductions in cardiovascular death and hospitalizations. Priced at $18,759.12 for a 28-day supply – equating to approximately $244,500 annually – Attruby entered the market as a slightly more affordable alternative to Vyndaqel, which costs around $268,000 per year.
In contrast, AMVUTTRA’s annual list price is approximately $477,000, which is significantly higher than its competitors. Despite the premium pricing, it is possible that AMVUTTRA’s efficacy, safety profile and convenient quarterly dosing regimen may drive strong market uptake; however, some caution that the higher cost could present challenges in market adoption.
Patient support
Alnylam has implemented multiple programs to facilitate broad and seamless patient access to AMVUTTRA, aiming to ensure that the majority of patients incur minimal or no out-of-pocket expenses. These initiatives are designed to address potential financial barriers and promote equitable access to this novel therapeutic option.
The clinical benefits demonstrated in the HELIOS-B trial, coupled with a quarterly dosing schedule, position AMVUTTRA as a significant addition to the treatment landscape for this life-threatening condition. As the therapeutic becomes integrated into clinical practice, its impact on patient outcomes and its role relative to existing treatments will be closely observed.
Photograph courtesy of Alnylam