After facing doubts from the FDA regarding the expansion of its RNA-silencing drug Onpattro into the treatment of transthyretin amyloidosis cardiomyopathy (ATTR-CM), Alnylam Pharmaceuticals has gained crucial expert support. An FDA advisory committee voted 9-3 in favor of the opinion that Onpattro has a favorable benefit-risk profile for ATTR-CM.
This positive vote contrasts with earlier concerns raised by FDA staff regarding the magnitude of Onpattro’s efficacy. The FDA experts’ endorsement bodes well for approval, as the FDA typically follows its advisers’ opinions.
However, there are indications that Onpattro might receive a limited approval, putting it at a disadvantage in a potential market competition with Pfizer.
The FDA staff’s main concern revolves around the clinical significance of Onpattro’s performance in 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 recipients walked 14.7 meters further than those on placebo at Week 12 of treatment, a statistically significant but clinically small improvement. Similarly, Onpattro outperformed placebo by 3.7 points on the KCCQ score, another statistically significant but small improvement that was not perceptible to patients. Moreover, the trial lacked an “anchor” variable to help interpret the clinical meaningfulness of the data.
Alnylam argued that no established clinical meaningfulness threshold exists for the six-minute walk test in ATTR-CM. Regarding the anchor, the company pointed to a 2005 paper suggesting that a change of five points in the KCCQ score is “small but clinically important.” However, an FDA staffer raised concerns about relying on this single study for clinical research and regulatory decision-making.
External experts invited by the FDA agreed that Onpattro’s benefit was indeed small, with one expert characterizing it as “a light wind blowing in favor of” Onpattro.
While those who voted in favor cited the lack of safety problems as a reason to support Onpattro, not all committee members shared this view. Some argued that the data did not meet clinically relevant thresholds typically used in cardiology.
A significant concern raised during the discussion was the potential risk of patients or doctors choosing Onpattro over Pfizer’s tafamidis, which is already established in the market for ATTR-CM treatment. In APOLLO-B, Onpattro showed no benefit in patients also on tafamidis and even performed numerically worse than placebo in this group.
Despite a positive vote, concerns were voiced about “unintended consequences” stemming from patients not receiving tafamidis due to the potential availability of Onpattro.
The approval of Onpattro may be limited to tafamidis nonresponders, significantly restricting its potential patient base. Tafamidis generated $2.4 billion in worldwide sales last year.
