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FDA advisors conceded on Wednesday that the benefit-risk balance of patisiran (Onpattro) technically checks out in wild-type or hereditary transthyretin amyloid cardiomyopathy (ATTR-CM, also known as cardiac ATTR amyloidosis) -- though they were unconvinced that the benefits are actually meaningful.

At the end of the day, the Cardiovascular and Renal Drugs Advisory Committee ultimately voted 9-3 that patisiran's benefits outweigh its risks in ATTR-CM, with members expressing minimal concern about the safety of the RNA interference agent from Alnylam Pharmaceuticals. The panel's majority-yes votes were commonly attributed to the technicality of the question.

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," said Edward Kasper, MD, of Johns Hopkins School of Medicine in Baltimore.

Kasper suggested that patisiran would likely be a "niche" product at best, however, as its evidence is limited to monotherapy and not as a rescue for patients not responding to tafamidis (Vyndaqel or Vyndamax), the existing standard-of-care medication indicated to reduce cardiovascular mortality and cardiovascular-related hospitalization in ATTR-CM.

The crux of the issue is whether patisiran has enough benefit in cardiomyopathy to merit an expansion of its existing indication for polyneuropathy in ATTR amyloidosis.

Committee chairperson Javed Butler, MD, MPH, MBA, of the University of Mississippi Medical Center in Jackson, said he voted no because he was not sure if patisiran's benefits were clinically meaningful, a recurring remark among fellow panelists throughout the day.

Patisiran's application for an expanded indication rests on the phase III trial showing small gains in 6-minute walk test (6MWT) and health status and quality of life (as measured by the Kansas City Cardiomyopathy Questionnaire) -- none meeting subjective thresholds for clinical significance -- when comparing the gene silencer with placebo.

"What level of evidence would I give this? This wouldn't be a I or IIa. It would be IIb. The level of evidence is not high here," Kasper said.

Notably, APOLLO-B showed that these small benefits did not apply to people on background tafamidis. Like tafamidis, patisiran is intended to stop or slow the progression of cardiac amyloidosis.

The argument that nonresponders to tafamidis could be helped by having an alternate option in patisiran was shot down by Butler, who pointed out the negative interaction in the trial suggesting that patients in New York Heart Association class III -- likely those progressing nonresponders -- were a subgroup that did not see benefit in 6MWT.

"That makes the interpretation a little bit difficult, to say that the nonresponders are definitely going to respond to patisiran therapy," he said.

Moreover, some said it would be an indirect safety concern if patients mistook patisiran to be a viable alternative to tafamidis. "I would hate to see any unintended consequences if patients don't get put on tafamidis because of this drug, so I do think there could be harm," said David Moliterno, MD, of the University of Kentucky Medical Center in Lexington, adding that he did ultimately vote yes.

And while there may not be direct safety risks with the drug, there is nevertheless potential harm and the cost, time, and effort needed for an IV infusion every 3 weeks for patisiran therapy, suggested C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles, who voted no.

ATTR-CM is a rare, rapidly progressive disease caused by a gene mutation resulting in misfolded transthyretin protein and excess amyloid buildup in the heart and other organs.

Patisiran works by blocking the production of transthyretin protein and is already FDA approved for treating polyneuropathy associated with hereditary ATTR amyloidosis. It won this initial approval in 2018 based on its ability to slow the progression of peripheral neuropathy in patients with hereditary ATTR amyloidosis over 18 months in the APOLLO trial.

Some expect more from future therapies in this arena, as recently reported cases of spontaneous reversal suggest it is possible for amyloid to be cleared from the heart using antibody treatment, for a return to near-normal cardiac structure and function without scarring.

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