FDA rejection of BioMarin gene therapy raises durability questions

BioMarin, the frontrunner in the hemophilia A gene therapy race, went to the FDA armed with several years of data from a phase 1/2 study and interim results from an ongoing phase 3. The evidence was widely expected to be strong enough to secure approval.

However, the FDA issued a complete response letter (CRL), denting BioMarin’s hopes of winning approval for valoctocogene roxaparvovec in the near term.

In a statement to disclose the setback, BioMarin said the FDA had asked for two years of data from the phase 3 trial to show “substantial evidence of a durable effect​” on the annualized bleeding rate of participants.

The statement features pointed comments about the request. BioMarin said it had previously agreed “on the extent of data necessary to support the [Biologics License Application]​” with the FDA, adding that the agency did not request longer-term phase 3 results “at any time during development or review​.”  In BioMarin’s telling, the CRL was the first time the FDA raised the need for more data.

The FDA rejection comes shortly after the release of four-year data from a phase 1/2 clinical trial of valoctocogene roxaparvovec, also known as Roctavian. The update revealed Factor VIII expression had fallen 63% over the years, although bleeding and prophylactic Factor VIII use remained down.

Analysts expressed surprise at the rejection. The team at Bank of America said “it is difficult to have conviction​” that Roctavian will come to market in the US before the middle of 2022. If that is correct, the headstart BioMarin looked set to enjoy over hemophilia A gene therapy rivals Roche and Pfizer-Sangamo Therapeutics could evaporate.

Another detail from the CRL shared by BioMarin suggests the transition from phase 1/2 to phase 3 is a cause of concern for the FDA. The agency concluded differences between the two studies “limited its ability to rely on the Phase 1/2 study to support durability of effect​,” according to BioMarin.

BioMarin fielded questions about differences between the two trials after releasing phase 3 data last year. The Factor VIII expressions levels seen in the phase 3 were lower than those triggered in phase 1/2 subjects at the same time point.

After looking into the difference, BioMarin identified the timing of steroid administration as a potential factor. The phase 1/2 and phase 3 studies used clinical trial materials produced at different sites, with BioMarin switching from a contract manufacturer to its in-house cGMP facility between the trials, but the company has downplayed the significance of that change.

At its R&D day last year, BioMarin said its data show “patient factor expression levels vary even when treated with the same lot of product​,” leading it to conclude “it is not the material that results in variable levels of factor expression​.” BioMarin also said its analytical characterization and clinical data show the comparability of the clinical and commercial batches.