Alnylam Pharmaceuticals' RNA interference (RNAi) therapy Onpattro (patisiran) has secured a positive recommendation from an FDA advisory committee for the treatment of transthyretin amyloidosis cardiomyopathy (ATTR-CM), despite earlier concerns raised by FDA reviewers about the drug's efficacy.
The expert panel voted 9-3 that the benefits of Onpattro outweigh its risks in treating ATTR-CM, a progressive condition characterized by amyloid fibril deposits in heart tissue. The FDA is expected to make its final decision by October 8th.
Clinical Trial Results Under Scrutiny
The recommendation follows the FDA's release of a briefing document that questioned aspects of Onpattro's data from the phase 3 APOLLO-B study. In this pivotal trial, Onpattro demonstrated a statistically significant improvement in functional capacity as measured by the 6-minute walk test (6-MWT), with treated patients able to walk approximately 15 meters further than those receiving placebo at the 12-month mark.
While the drug also met secondary objectives showing improvements in health status and quality of life, FDA reviewers characterized these differences as "small" and raised "questions about its clinical meaningfulness." Particularly concerning to regulators was the apparent lack of benefit when Onpattro was used in combination with Pfizer's Vyndamax (tafamidis), which is currently widely used for ATTR-CM. Approximately 25% of patients in the APOLLO-B study were taking both medications.
Weighing Benefits Against Limitations
Despite these concerns, the advisory committee ultimately favored approval, with panel members acknowledging Onpattro's modest efficacy but emphasizing its well-documented and manageable safety profile. This positive assessment potentially opens the door for a new treatment option that addresses the underlying cause of ATTR-CM.
"The advisory committee vote is another step towards bringing patients with the cardiomyopathy of ATTR amyloidosis a novel treatment option that addresses the underlying cause of disease and has the potential to meaningfully benefit patients' functional capacity and quality of life," said Pushkal Garg, Alnylam's chief medical officer.
Market Implications
If approved for ATTR-CM, Onpattro will compete directly with Pfizer's Vyndamax and Vyndaqel (tafamidis meglumine), which generated worldwide sales of $2.5 billion last year. The competitive landscape is also expected to include BridgeBio's acoramidis, which is advancing through clinical development despite mixed results in the phase 3 ATTRibute-CM trial.
RNAi Pioneer
Onpattro made history in 2018 as the first FDA-approved RNA interference therapy when it received clearance for treating polyneuropathy associated with hereditary ATTR. The drug works by selectively blocking the RNA strand that transcribes a defective gene into misfolded proteins that cause disease.
As Alnylam's top-selling product, Onpattro contributed $588 million to the company's revenue in 2022. The potential expansion into ATTR-CM represents a significant opportunity to address a broader patient population affected by this rare but serious disease.
ATTR Disease Background
Transthyretin amyloidosis is a rare, inherited, rapidly progressive and life-threatening condition affecting approximately 50,000 people worldwide. The disease can manifest as polyneuropathy (nerve damage) and/or cardiomyopathy (heart muscle disease), significantly impacting patients' quality of life and survival.
The approval of Onpattro for polyneuropathy in 2018 marked a breakthrough for patients with the neurological manifestations of the disease. If approved for the cardiac manifestation, it would provide another treatment option for patients with ATTR-CM, who currently have limited therapeutic choices.
Future Outlook for RNAi Therapeutics
The potential expansion of Onpattro's indication underscores the growing importance of RNAi therapeutics in addressing previously untreatable conditions. Alnylam continues to advance several other RNAi therapies through clinical development, including givosiran for acute hepatic porphyrias and fitusiran for hemophilia.
This advisory committee recommendation represents another potential milestone for RNAi technology, which has overcome significant development challenges to emerge as an important therapeutic modality for genetic diseases.
