May 28, 2019
BIOINVEST NEWS: BioMarin (BMRN)
Hem A Gene Therapy Update Is Good Enough; Will Likely File For FDA/EMA Approval By Year End, Durability Question Still Lingers
The widely anticipated BioMarin hemophilia A gene therapy delivered good news this morning, albeit with some caveats. BMRN announced both positive Phase I/II and Phase III data for ValRox (valoctocogene roxaparvovec) for adults with severe hemophilia A. While the data achieved pre-specified and regulatory-agreed upon clinical criteria to qualify for review in the U.S. and Europe, there are some questions. In the Phase I/II update, the FVIII levels and Annual Bleed Rates (ABRs) after 3 years remain impressive despite a very slight diminution from Year 2 and in our view should qualify for accelerated FDA approval. The interim data from the Phase III trial, however, showed the overall response curve is less than Phase I/II results with 8/20 patients responding to the pre-specified level of at least 40 IU/dL. This data could also improve as three patients are not yet evaluable. Valrox Phase I/II data at three years resulted in FVIII levels that continued to decline (median chromogenic: 19.9%) but still remains well above the 12% threshold we discussed in our last Issue. In our view, the slower rate of decline in FVIII exceeded most expectations and hints at the potential for multiple years of durability. On the conference call, management showed models implying at least eight years of potential treatment for Hem A with a single gene therapy injection.
o As of May 28, 8 patients in the 20-patient cohort of the Phase III GENEr8-1 study achieved Factor VIII levels of at least 40IU/dL or more at 23-26 weeks, meeting the pre-specified criteria for Factor VIII activity levels. The company will meet with the FDA and EMA to review the Phase III data and the other elements of a submission and intends to announce the timing for filing applications in Q3:19.
Details: An update to its previously reported results of an open-label Phase I/II study of ValRox for adults with severe hemophilia A are as follows:
o The three-year update demonstrated that bleed rate control with the 6e13 vg/kg dose was maintained for a third year with a median Annualized Bleed Rate (ABR) of 0 and mean ABR of 0.7 in that year.
o Factor VIII levels in the 6e13 vg/kg dose appeared to be approaching a plateau in Year 3. Factor VIII levels measured with the chromogenic substrate (CS) assay at the end of Year 3 were mean and median of 32.7 IU/dL and 19.9 IU/dl, respectively, compared with mean and median of 36.4 IU/dL and 26.2 IU/dL, respectively, at the end of Year 2.
Full updated results will be submitted for presentation at the International Society on Thrombosis and Haemostasis 2019 (ISTH, Melbourne) and the next key update from BMRN will be in Q3 when they provide the timing and decisions for filing in both the U.S. and Europe. After the regulatory update, the ASH conference in December will likely be the next important clinical catalyst for BMRN’s Hem A program, where we will also get updates from competitors ONCE and SGMO.
On the conference call BMRN indicated FVIII levels seemed to be approaching a plateau and, based on conservative modeling, expect durability of at least eight years. While we are encouraged by the data and expect multiple years of durability, the durability debate will linger as only additional years of data can resolve the issue for good. Interestingly, management noted they have identified an AAV capsid that could enable re-dosing of the gene therapy, and help differentiate it from the competition. In our view, the data appear good enough to file and likely gain accelerated approval. The regulatory agencies, we also believe, will likely monitor the durability over the long-term term (e.g., at least 5 years) in order to gain full FDA approval. For the stock, we believe traders are walking away from the trade today and that has created an opportunity. In our view, based on the data that BMRN shares will rebound shortly and steadily move upwards as we move closer to ISTH in early July, the filing announcement (Q3) and ASH (December).