Still reeling from rejection, BioMarin reports a glimpse of those 2-year valrox data FDA was looking for — but is it enough to change regulators' minds?
BioMarin now has the Phase III data it needs to refile valrox, its gene therapy for hemophilia A, at the EMA — and possibly convince the FDA to reconsider its requirement.
Pulling from a total of 134 patients who had been followed up for a mean of 71.6 weeks, the biotech zeroed in on a subgroup that was rolled over from a non-interventional study. Among those 112 patients, the annualized bleeding rate was reduced by 84% compared to prophylactic Factor VIII replacement. The one-time injection of valrox also cut mean annualized Factor VIII infusion by 99% (p <0.0001).
While an investigator hailed it as “the first statistical evidence demonstrating ABR superiority in a gene therapy trial,” analysts noted the results are roughly in line with investor expectations.
For them, a different number from another, smaller subgroup might matter more for the drug’s future: Factor VIII levels after two years.
Two-year safety and efficacy follow-up, after all, was the data that FDA regulators were looking for as they slapped a rejection on BioMarin’s first BLA. So far, 17 patients who had been directly enrolled into the Phase III GENEr8-1 trial without going through the observation period had reached that mark.
On average, Factor VIII activity was 42.2 IU/dL at one-year and declined to 24.4 IU/dL at 2 years. The median levels were lower (14.7 IUdL at Year 2), reflecting wide statistical distribution.
The company noted that the expression remained in the range that provides efficacy, with a mean annualized bleeding rate of 0.9 (and median 0.0) episodes per year. BioMarin said it will submit the data to the EMA, whose request for a full year’s worth of data spurred it to withdraw its initial application, in the second quarter of 2021 as planned while asking the FDA to “review two-year data request.”
But analysts are skeptical.
“(W)hile the pace of F8 decline here looks moderately better than the ph1/2, the dropoff in expression from year 1 to 2 is still meaningful, and we still believe that clinical durability (the question of how long will it last) will remain top of mind for clinicians, especially given that there are other good treatment options for Hemophilia A,” Stifel’s Paul Matteis wrote, adding that the FDA had given written feedback recommending two-year data from all patients. “Thus, while you never know, it’s hard for us to see why specifically these data would move the agency from their conservative stance.”
Besides, Joseph Schwartz of SVB Leerink noted, the product profile and responder rates remain unclear. More data might be needed, for instance, to clarify what role steroids might play in the regimen as the current results suggest their proactive administration does not seem to improve Factor VIII activity.
“Although the data are top-line, there are many standing questions such as how steroids will be implemented in the real world, assuming approval, and how much expression variability is there/are there enough adequate responders to Roctavian,” he wrote.