The FDA CRDAC convened on Septemeber 13 to discuss the sNDA for patisiran as a treatment for ATTR-CM, with the meeting concluding in a 9:3 vote in favor of the benefit-risk profile of patisiran.
The US Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9 to 3 in favor of the benefit-risk profile of patisiran for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM).1
Although the FDA is not required to follow the committee’s vote, with the September 13, 2023 meeting occurring less than a month before the agent’s Prescription Drug User Fee Act Target Action Date is October 8, 2023, the vote could set the stage for patisiran to receive an additional indication, with the investigational RNA interference therapeutic boasting a previous approval for hereditary TTR-mediated amyloidosis in 2018.1
“We are grateful for the CRDAC’s thoughtful review and discussion, and thank the patients, physicians and advocacy community who shared their valuable insights today,” said Pushkal Garg, MD, chief medical officer at Alnylam.1 “The positive outcome of today’s meeting is supported by the efficacy and safety data observed in the APOLLO-B Phase 3 study and is another step toward 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. We look forward to continuing to work with the FDA as they complete their review of our sNDA.”
A phase 3, randomized, double-blind, placebo-controlled trial, APOLLO-B was launched in 2019 and conducted at 69 sites in 21 countries with the intent of assessing the efficacy and safety of patisiran in patients with ATTR-CM. The trial enrolled 360 adult patients and randomized them in a 1:1 ratio to receive either 0.3 mg/kg patisiran or placebo intravenously every 3 weeks over a 12-month double-blind treatment period. At the conclusion of this 12-month period, study protocol requires patients to be switched to patisiran for an open-label extension period.2
The primary endpoint of the trial was change in from 6-minute walking test score from baseline to 12 months compared to placebo therapy. A key secondary endpoint for the trial was changes in health-related quality of life, which was measured through KCCQ-OS change.
Upon analysis, results suggested there was a median difference of 14.7 meters (P = .0162) for 6-minute walking test at 12 months favoring the patisiran group. The trial also indicated use of patisiran was associated with a statistically significant and clinically meaningful benefit on health status and quality of life (P = .0397).
“I voted yes because I believe we can develop the proper swim lane with the agency for the use of this, in particularly in the tafamidis naive patients. I want to compliment the sponsors for the conduct of the trial and impress how they were able to power through COVID and get a meaningful trial and they met their primary endpoint,” said CRDAC member Christopher O’Connor, president and executive director of the Inova Heart and Vascular Institute.
During the meeting, the FDA’s CRDAC expressed specific concerns over the design of the APOLLO-B trial. Among these concerns was a lack of qualitative data to aid in the evaluation of the clinical meaningfulness of treatment effects, which the committee suggested resulted in a lack of evidence to demonstrate treatment effects were clinically meaningful. The CRDAC also noted the applicant’s analyses did not align with FDA guidance, with a lack of an anchor-based method to ascertain the validity of the observed change in KCCQ-OS.
“I certainly struggled with this vote. My no vote does not reflect that the disease’s data is not important or that there is not an unmet need or that there is not a potential with the therapy, “ explained Javed Butler, MD, chair of the FDA’s CRDAC and president of the Baylor Scott and White Research Institute. “The reason I voted no was largely because I was not sure whether the benefits were clinically meaningful in the context of the study design and how the study was done. We do realize in certain circumstances once trial does lead to approval of the therapy.”