FDA’s Acceptance of Vutrisiran’s sNDA for Cardiomyopathy Marks a Significant Milestone in Targeted Therapies for Transthyretin Amyloidosis

Alnylam Pharmaceuticals, Inc., a leader in RNA interference (RNAi) therapeutics, has announced that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for vutrisiran, a potential RNAi therapeutic for treating transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The FDA has set an action date of March 23, 2025, under the Prescription Drug User Fee Act (PDUFA), using a Priority Review Voucher. The FDA has also indicated that there will be no advisory committee meeting to review the application.

Vutrisiran, marketed as AMVUTTRA®, is already FDA-approved for treating the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. By reducing both the mutant and wild-type transthyretin (TTR), vutrisiran addresses the root cause of transthyretin amyloidosis (ATTR). If approved for ATTR-CM, it would become the first U.S. therapeutic to treat both the polyneuropathy and cardiomyopathy symptoms of ATTR.

“We are excited that the FDA has accepted our sNDA for vutrisiran in the treatment of ATTR-CM, a progressive, debilitating, and ultimately fatal disease,” stated Pushkal Garg, M.D., Chief Medical Officer at Alnylam. “In the HELIOS-B study, vutrisiran improved cardiovascular outcomes, survival, disease progression, and quality of life compared to placebo, in a patient population already receiving substantial background treatments. We look forward to working with the FDA to support their review and bring vutrisiran to patients with ATTR-CM in the U.S. next year.”

The sNDA submission is based on the positive results from the HELIOS-B trial, a Phase 3, randomized, double-blind, placebo-controlled study conducted globally. The trial demonstrated the positive effects of vutrisiran on cardiovascular outcomes, survival rates, functional capacity, and overall quality of life in ATTR-CM patients, even in the context of significant background treatments. Vutrisiran showed a safety and tolerability profile consistent with its established use. Detailed findings from the HELIOS-B study were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine on August 30, 2024.

Commentary by YourDailyFit columnist Alice Winters:

Alnylam Pharmaceuticals’ recent announcement regarding the FDA’s acceptance of their supplemental New Drug Application (sNDA) for vutrisiran marks an important milestone in the ongoing treatment landscape for transthyretin amyloidosis (ATTR). The company’s strategy of leveraging RNA interference (RNAi) technology to address both hereditary and wild-type forms of ATTR sets vutrisiran apart from traditional approaches.

The ability of vutrisiran to target and knock down transthyretin (TTR) offers a potential game-changer, particularly in ATTR-CM, where the disease can be both progressive and fatal. The expansion of vutrisiran’s indications to include cardiomyopathy is a critical development for patients suffering from this debilitating condition, and the potential to treat both polyneuropathy and cardiomyopathy under a single therapeutic could provide much-needed relief in a disease space with limited treatment options.

The HELIOS-B trial, which serves as the basis for the sNDA, provides robust evidence supporting the drug’s efficacy in improving cardiovascular outcomes, survival, and quality of life. This trial, as a randomized, double-blind, placebo-controlled study, adds weight to the claim of vutrisiran’s potential benefits. Moreover, the findings from the trial were not only presented at a prestigious medical congress but were also published in The New England Journal of Medicine, reinforcing the credibility of the data.

That being said, the introduction of vutrisiran into the U.S. market faces several key hurdles. First, while the study results are promising, the drug must maintain its safety and tolerability profile across broader patient populations. Ensuring that it does not interact negatively with other treatments commonly used for ATTR, such as tafamidis or diflunisal, will be essential. Furthermore, the long-term effects and sustainability of this treatment regimen, especially in patients already on substantial background therapies, need continued monitoring.

One notable aspect of Alnylam’s approach is their use of the Priority Review Voucher (PRV), which has expedited the review timeline, providing patients with a glimmer of hope for a potentially life-altering treatment in the near future. However, as the FDA has decided against holding an advisory committee meeting, which is often a critical part of the drug approval process, the final approval process may not be as rigorous in public scrutiny, a factor worth considering as the application moves forward.

From a broader perspective, the potential approval of vutrisiran underscores an increasing shift toward precision medicine, where the underlying causes of diseases like ATTR are directly targeted. This is a positive development for the field of RNAi therapeutics, especially as more diseases are identified as having potential for such targeted treatments.

In conclusion, while the path to approval for vutrisiran is promising, its ultimate success will depend on continued clinical validation and real-world outcomes. The treatment’s ability to improve both quality of life and survival for patients with ATTR-CM could make it a vital addition to the therapeutic arsenal, but the industry will be watching closely to see how it performs beyond controlled study conditions. Alnylam’s continued commitment to advancing RNAi-based therapies holds great promise for those suffering from rare, genetic diseases, but only time will reveal how widely applicable and accessible these innovations will truly be.