Even though committee members supported use of Onpattro for patients with cardiomyopathy related to transthyretin-mediated amyloidosis, they had questions about whether it provided a clinically meaningful benefit. The FDA set an action date of Oct. 8, 2023.
The FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9 to 3 in support of Alnylam Pharmaceutical’s Onpattro (patisiran), which is being reviewed by the agency to treat patients with cardiomyopathy of transthyretin-mediated (ATTR) amyloidosis. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of Oct. 8, 2023.
ATTR amyloidosis is a rare, progressive, debilitating disease caused by misfolded transthyretin proteins that accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract. In cardiomyopathy, the heart loses its ability to pump blood. In ATTR amyloidosis, the ATTR protein can build up in the heart muscle, leading to shortness of breath and swelling in the legs. Patients with ATTR cardiomyopathy can also have arrhythmias that can lead to stroke or death.
Onpattro, already approved by the FDA to treat the polyneuropathy of hereditary ATTR amyloidosis in adults – which affects the peripheral nerves — netted $558 million in revenue in 2022. Its wholesale acquisition cost is $9,785 per vial.
The submission is based on positive results from APOLLO-B, a phase 3 global study that demonstrated the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The safety profile in APOLLO-B was consistent with what was observed in APOLLO and in postmarketing use of Onpattro. In APOLLO-B, the majority of adverse events were mild or moderate in severity.
The study met its primary endpoint of a change from baseline at month 12 in a six-minute walk test and also met a secondary endpoint in a change from baseline at month 12 in KCCQ-OSS, a cardiomyopathy questionnaire that also captures physical limitations, symptom score, social limitations and health-related quality of life.
At issue for FDA reviewers was the small magnitude of benefit seen in the pivotal trial. The agency in a briefing document indicated that there was no evidence of treatment effect in patients who were also taking Vyndamax (tafamidis), the only other drug available to treat cardiomyopathy in ATTR and is considered standard of care. FDA officials noted that 25% of the 360 patients in the study were taking Vyndamax and the analysis of these patients did not provide evidence for or against treatment effect. Regulators pointed out the study was not powered to provide conclusions about these patients.
Committee members who voted no said that there was no evidence of clinically meaningful benefit. Chairperson Javed Butler, M.D., distinguished professor of Medicine at the University of Mississippi, said his vote does not reflect that the disease state is not important or that there is not an unmet need.
“I struggled with this vote,” he said after the voting. “The reason I voted no was largely because I wasn’t sure whether the benefits were clinically meaningful in the context of the study design and how the study was done… This was a marginally positive study. This may not have been a concern if the benefits were more robust. But in absence of more robust benefit, analytic become more important.”
Even those who votes yes noted that there was uncertainty about whether Onpattro has a clinically meaningful benefit for patients with cardiomyopathy in ATTR.
Lane Abernathy, a patient representative in Washington, D.C., voted yes, but said she agreed with other committee members who were looking for more clarity around the complex nature of what is being measured and how. “I struggled with this too,” she said. “But it was enough to sway me. There is something there and there were no apparent risk and that swayed me toward the more positive side.”
Ravi I. Thadhani, M.D., executive vice president for health affairs at Emory University, voted yes as well and said that with a rare disease such ATTR that options and alternatives are critical. “There is a continuous decline in cardiac function and worsening of disease in patients who have received the current standard of care,” he said. “The benefits outweighed the risks for me. Clinical meaningfulness is subjective, as we’ve heard.”