Despite panel support, FDA rejects patisiran for ATTR amyloidosis with cardiomyopathy
Key takeaways:
- The FDA declined to approve an expanded indication for patisiran for a form of amyloidosis with cardiomyopathy.
- The agency cited a lack of evidence of clinical meaningfulness.
The FDA rejected a supplemental new drug application for patisiran to treat cardiomyopathy of wild-type transthyretin-mediated or hereditary transthyretin-mediated amyloidosis, citing insufficient evidence of clinical meaningfulness.
In a complete response letter issued by FDA, the agency stated that it did not identify any clinical safety, study conduct, drug quality or manufacturing issues for patisiran (Onpattro, Alnylam). As a result of the FDA’s decision, Alnylam stated in a press release that it will no longer pursue an expanded indication for patisiran in the U.S.; however, it will maintain availability of patisiran for patients with transthyretin amyloidosis (ATTR) cardiomyopathy who are enrolled in the open label extension period of the APOLLO-B phase 3 study and patisiran U.S. expanded access protocol.
As Healio previously reported, the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9-3 in favor of expanding approval of patisiran to patients with ATTR cardiomyopathy, noting modest benefits but no significant safety concerns. At the time, panel members expressed concern that observed benefits with patisiran seen in the APOLLO-B study appeared modest at best, with small beneficial signals for improvements in 6-minute walk test and Kansas City Cardiomyopathy Questionnaire overall summary score, both markers of functional status. Additionally, researchers did not observe a benefit with patisiran in patients who were also prescribed tafamidis (Vyndamax, Pfizer), a subgroup who made up 25% of the study cohort.
Patisiran, a small interfering RNA agent, is approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis. In the release, Alnylam said the agency’s decision does not impact commercial availability of patisiran for its existing indication.
Alnylam said the company will now turn its full focus toward the HELIOS-B Phase 3 study of vutrisiran, an investigational RNA interfering therapy for the treatment of ATTR and ALN-TTRsc04, which the company stated has “the potential for greater than 90% TTR knockdown with once-annual dosing.”
“First and foremost, our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating and fatal disease and face significant unmet need,” Yvonne Greenstreet, MBChB, CEO of Alnylam Pharmaceuticals, said in the release. “We remain confident in the HELIOS-B Phase 3 study of vutrisiran and look forward to sharing topline results in early 2024. If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits. Beyond vutrisiran, we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen.”
Perspective
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APOLLO-B was a randomized controlled trial of patisiran vs. placebo in patients with ATTR-CM with a primary endpoint of change in 6-minute walk test at 12 months. The study met its primary endpoint, with a statistically significant difference — patients who received placebo experienced a 24% decline in 6-minute walk test and patients who received patisiran saw an 8% decline. It is not a surprise that both declined, as amyloidosis is a progressive condition. It is also not a surprise that there was not actual improvement for participants who received patisiran, as this therapy does not reverse disease. What patisiran does is slow progression. There was also less worsening in other endpoints like KCCQ as a measure of quality of life, and biomarkers like N-terminal pro-B type natriuretic peptide in the patisiran arm.
So, if the trial met the primary endpoint, why didn't the FDA approve it? My sense is that they felt that the magnitude of change, while statistically significant, was not clinically significant. While I want to provide my patients with amyloidosis with the best therapies to improve quality of life and survival, I can understand why the FDA felt that the magnitude of benefit, weighed against the need for an infusion every 3 weeks, was not meaningful enough to warrant approval.
However, I remain hopeful that there will be a role for TTR silencers in the future, as they are being tested in HELIOS-B and CARDIO-TTRansform, with 30-month endpoints of death and CV hospitalization. Those results should be available 2024 and 2025. At that point, we will have to determine the role of stabilizer and/or silencer therapy for patients. With monoclonal antibodies in clinical trials, hope for therapy that actually reverses disease is on the horizon.
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