While FDA panelists supported Alnylam Pharmaceuticals’ medicine in transthyretin amyloidosis cardiomyopathy, they recommended a limited FDA approval that would severely restrict the med’s addressable population. (FDA)
After Alnylam Pharmaceuticals faced FDA doubts about its bid to expand RNA-silencing drug Onpattro into a rare heart disease called transthyretin amyloidosis cardiomyopathy (ATTR-CM), the company has picked up key expert support.

Wednesday, an FDA advisory committee voted 9-3 in favor of the view that Onpattro has a favorable benefit-risk profile in ATTR-CM.

The positive vote contrasts with doubts about the magnitude of Onpattro’s efficacy the FDA’s staffers raised earlier this week. The experts’ backing bodes well for an approval, because the FDA typically follows its advisers’ opinions.

Still, comments during Wednesday’s panel suggest the Alnylam drug might win a limited approval that would put it at a severe disadvantage in a potential market clash with Pfizer.

The main issue the FDA staff flagged centers on the clinical meaningfulness of Onpattro’s performance among patients on a six-minute walk test and a patient-reported outcomes survey called KCCQ.

On the primary endpoint of the phase 3 APOLLO-B trial, Onpattro takers, at median, walked 14.7 meters further than those on placebo in six minutes at Week 12 of treatment. The Alnylam drug also outperformed placebo by 3.7 points on the KCCQ score, a key secondary endpoint.

Both improvements, while statistically significant, were small and not perceivable among patients, the FDA stressed. Besides, the agency noted that APOLLO-B lacked an “anchor,” or another variable to measure the results against, to help interpret the clinical meaningfulness of the data.

For its part, Alnylam argued that no established clinical meaningfulness threshold exists for the six-minute walk test in ATTR-CM. As for the anchor, the company argued that the KCCQ score could serve that purpose. Alnylam pointed to a 2005 paper that suggests a change of five points is a “small but clinically important change” in KCCQ.

In a counterargument, an FDA staffer raised the concern that the five-point bar referenced by the company came from one single study. Considerations for clinical research and regulatory decision-making often differ from the results of one study, the staffer said.

The external experts invited by the FDA all agreed that the magnitude of Onpattro’s benefit was indeed small. As Northwestern University’s David Cella, Ph.D., said, APOLLO-B showed “a light wind blowing in favor of” Onpattro. That sentiment was echoed by several other members of the panel.

Those who voted yes said the lack of safety problems means Onpattro’s benefit—however small—outweighs its risks.

“There is a light wind for benefit and no wind for risk,” Edward Kasper, M.D., a cardiologist from the Johns Hopkins School of Medicine, said.

Not all committee members saw it that way. Noel Bairey Merz, M.D., from Cedars-Sinai Medical Center, voted against Onpattro. She said the data did not meet existing clinically relevant thresholds typically used in cardiology.

The lack of benefit, Bairey Merz said, is outweighed not by toxicity but by the potential opportunity risk of a patient or doctor “opting out of one formulation for another one that may or may not be perceived as better.”

The other drug that Bairey Merz referred to is Pfizer’s tafamidis, which is sold under the brands Vyndaqel and Vyndamax. In APOLLO-B, Onpattro showed no benefit in patients who were also on background tafamidis, and the Alnylam therapy performed numerically worse than placebo in this group.

Bairey Merz’s concern was shared among several committee members, including those who voted in favor of Onpattro. They argued that Onpattro should not be given to patients who can take tafamidis.

“I would hate to see this drug get marketed or pushed forward as an alternative to tafamidis,” David Moliterno, M.D., from the University of Kentucky Medical Center, said of Onpattro. Despite a positive vote, Moliterno also voiced concerns of “unintended consequences” that may stem from patients not getting tafamidis because of Onpattro’s potential availability.

Csaba P. Kovesdy, M.D., from the Memphis Veterans Affairs Medical Center, and Lane Abernathy, a patient represenative, were among those who supported a limited nod for Onpattro that wouldn’t allow the Alnylam drug to replace the Pfizer stalwart.

An approval only in tafamidis nonresponders would significantly limit Onpattro’s addressable patient base. Tafamidis generated $2.4 billion in worldwide sales last year.

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