FDA adcomm votes in favor of Alnylam’s new indication for Onpattro

The FDA’s Cardiovascular and Renal Drugs Advisory Committee on Wednesday voted 9-3 in favor of Alnylam Pharmaceuticals’ Onpattro (patisiran) on whether its benefits outweigh its risks for the treatment of ATTR cardiomyopathy.

Panelists agreed that the magnitude of Onpattro’s benefit in this indication was small, but the risks were even smaller.

Adcomm member Edward Kasper of Johns Hopkins School of Medicine said he based his “yes” vote on the fact there’s a “light wind” for benefit and “no wind” for risk. David Cella, professor at Northwestern University Feinberg School of Medicine, also voted in favor and noted limited benefits but said that he hopes clinicians will counsel patients on this option.

Alnylam touted the results of the pivotal trial for Onpattro, which first won approval in 2018 as a treatment of peripheral nerve disease caused by hereditary transthyretin-mediated amyloidosis (hATTR), as the treatment showed statistical significance with the primary endpoint, which was the change from baseline at month 12 in a 6-minute walk test, and a secondary endpoint on the change in baseline on the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS).

But ahead of the meeting and throughout its presentations Wednesday, the FDA raised questions on the effect size of siRNA-based Onpattro, which is an injection given every three weeks, and whether the positive effects are actually clinically meaningful. If approved in this indication, Onpattro would have to compete with Pfizer’s Vyndamax (tafamidis) capsules, which FDA approved in 2019 as the first treatment for ATTR-CM.

“While the results from the APOLLO-B study statistically favor patisiran over placebo, the magnitude of the treatment effect on function and quality of life is small and may not be clinically meaningful,” the FDA said in briefing documents ahead of the meeting. The agency also made clear at the meeting that the trial did not show a benefit to mortality or irreversible morbidity.

On the question of the clinical meaningfulness of Onpattro, Cella said that the primary endpoint “was met with a very small number,” and “just comparing this number to the literature it’s quite small and that’s a big part about why we’re having this meeting.”

Panelist Christopher O’Connor, president and executive director of the Virginia-based Inova Heart and Vascular Institute, said he thought the magnitude of the treatment’s effect “feels small and low but the clinical meaningfulness is unclear,” as he noted “significant design flaws” in Alnylam’s pivotal trial.

Panelist David Moliterno, professor of internal medicine at University of Kentucky Medical Center, similarly called the treatment benefit “small,” and noted that in Black and other non-Caucasian subpopulations from the trial, the benefits looked even smaller. He said he’d be concerned if tafamidis gets “put on the side shelf” in favor of Onpattro.

The panelists all seemed to agree that the tafamidis interaction with Onpattro “was of concern,” according to the panel’s chair Javed Butler of the University of Mississippi, who voted against the benefit-risk profile of Onpattro, and he noted the panel was struggling to understand which patient populations might benefit of those who are progressing on tafamidis.

“I struggled with the vote,” Butler said. “I didn’t know if the benefits were clinically meaningful.”

But the panelists didn’t seem to go as far as the FDA did in questioning the use of the KCCQ-OSS, which noted on one of its slides:

There were neither appropriate anchor scales administered, nor qualitative data collected to aid in the evaluation of the clinical meaningfulness of the treatment effects of 6MWT or KCCQ-OSS, from the perspective of patients.

Panelist Noel Bairey Merz, a professor of cardiology at Cedars-Sinai Medical Center who voted against Onpattro in this indication, noted that after listening to the patients in the open public forum of the adcomm meeting, which she found “enlightening,” the 6MWT may not have been optimal in this case.

“I did not feel like there was benefit,” Bairey Merz said. “It was upset not by risks but by potential harm. Opting out of one formulation for another that may not be perceived as better is a potential harm.”

Ravi Thadhani, the EVP for health affairs at Emory University who voted in favor of Onpattro in ATTR-CM, said the benefit outweighed the risks and, regarding the clinical meaningfulness, “we know it’s minimal,” and “I would urge discussions between the agency and sponsor” on the subpopulations who did not benefit from Onpattro.

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