Patisiran (Onpattro) for ATTR Cardiomyopathy Gets FDA Panel Thumbs Up

Megan Brooks

September 14, 2023

The RNA interference (RNAi) therapeutic patisiran (Onpattro), is one step closer to being approved in the United States for treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy.

Yesterday, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 9 to 3 that the benefits of patisiran outweigh the risks for the treatment of ATTR amyloidosis cardiomyopathy — although many panel members questioned whether the benefits are clinically meaningful.

ATTR amyloidosis is an underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by misfolded TTR proteins, which accumulate as amyloid deposits in various parts of the body, including the heart.

Intravenously administered patisiran is already approved in the US and Canada for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults.

As reported previously by | Medscape Cardiology, in the APOLLO-B trial, patisiran showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT) compared with placebo, in patients with ATTR amyloidosis with cardiomyopathy.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

But in explaining her "no" vote, committee member C. Noel Bairey Merz, MD, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, said she "did not feel like there was benefit" using existing clinically relevant thresholds typically used in cardiology.

Committee chair Javed Butler, MD, MPH, Baylor Scott & White Research Institute, Dallas, Texas, who also voted no, said he "struggled" with this vote and emphasized that it "absolutely does not reflect that there is not a potential with the therapy."

Butler said he voted no largely because he wasn't sure whether the benefits are clinically meaningful in the context of the study design and how it was conducted. He did not have any safety concerns, which was the general feeling of the committee.

Edward Kasper, MD, Johns Hopkins School of Medicine, Baltimore, Maryland, who voted in favor of patisiran for ATTR amyloidosis with cardiomyopathy, said there is a "light wind for benefit and no wind for risk. So, if you're asking do benefits outweigh the risks, the answer is yes."

But Kasper also noted, "It would have been a more difficult question to answer: Is there clinically meaningful benefit vs risk? But that's not what the question asked."

In explaining his "yes" vote, Ravi Thadhani, MD, MPH, Emory University, Atlanta, Georgia, said, "We're dealing with a rare disease with few options and devastating consequences. We heard from clinicians loud and clear, and from patients for that matter, that options and alternatives are critical, and that there is a continuous decline of cardiac function and worsening of disease in a number of patients that have received the current standard of care. For me, the benefits outweigh the risks."

Thadhani also noted that from the data provided, no benefit was shown —"disappointingly" he lamented — for women, for Black persons, and among individuals who were receiving tafamidis, and he urged the FDA and sponsor to consider this.

The FDA has set a target action date for patisiran for ATTR amyloidosis cardiomyopathy of October 8.

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