Buoyed by hemophilia A gene therapy update, BioMarin switches to head-to-head study — but shares slide on durability concerns

With its hemophilia A gene therapy poised to go through a pivotal program by the end of next year, BioMarin $BMRN set out to boost hopes for its success with a new batch of Phase I/II data for its valrox program (valoctocogene roxaparvovec/BMN 270). But the biotech’s shares turned wobbly and started to slide on concerns that the new numbers may have revealed some longterm weakness on efficacy.

Hank Fuchs

Researchers at a conference in Glasgow are pointing to one of the dosage arms where they tracked a 97% cut in annualized bleeding rate. And the biotech now plans to boost the number of patients in a registration study so they can provide clear evidence of the gene therapy’s ability to beat the current standard of care using factor replacement therapy.

The company will increase enrollment by 90, taking 130 patients into the pivotal program after seeing evidence of a durable ability over 2 years to slash bleed rates in patients..

“In order to make this option available with the urgency and data support that people with severe hemophilia A deserve, we plan to raise the sample size of our registrational study, Gener8-1 with the 6e13 dose to demonstrate benefits well beyond prophylactic factor use.” said Hank Fuchs, president, worldwide research and development at BioMarin.

The 6e13 vg/kg cohort saw no spontaneous bleeds and elimination of all bleeds in target joints in the second year. And 71% and 86% of participants had zero bleeds requiring Factor VIII infusions in years 1 and 2 respectively compared to 14% who had zero bleeds requiring Factor VIII infusions for a year at baseline. There was a 96% reduction in mean FVIII usage through week 104. Quality of life as measured by the six-domain Haemo-QoL-A instrument rapidly improved across all domains by up to 17.3 points in mean over baseline through the second year. 

Noted BioMarin: “This is well above the 5.2 point increase considered to be the minimal clinically important difference.”

Analysts, though, highlighted some concerns with the therapy’s ability to keep factor levels running at a consistent level, something no gene therapy developer wants to see. Leerink’s Joseph Schwartz picked out some sore points:

In the midst of today’s update, we believe investors will take issue with at least 2 points in the data – 1) the gradual decline in FVIII levels (breaching lower bound of normal on median FVIII), and 2) Haemo-QoL gap down – gap up both before and after week 52. To the first point, mgmt. referenced preclinical evidence as well as the biology of gene expression to suggest a stable plateau may have been achieved. Upon further observation, it appears the major gap down occurred between weeks 78 and 91 leading to the majority of pts. exhibiting normal levels of FVIII (50-150 IU/dL) by week 104. It is not exactly clear what triggered the drop, or whether this decrease was an anomaly (e.g., driven by 1-2 pts.); however, we would expect to see continued persistence of ~50 IU/dL level in subsequent updates potentially at the American Society of Hematology (ASH) by YE18. As for the sudden drop in Haemo-QoL, mgmt. clarified that the week 52-78 dynamic was driven by extraordinary circumstances in 1 pt. (including job loss and a pre-planned knee replacement). Overall, driven by a broad impact (i.e., across all six domains of the assessment), mgmt. is optimistic that the positive effects seen across clinical endpoints are also benefiting pt. QoL.

BioMarin’s shares slid 4% mid-day on the worries.

BioMarin has high hopes for this therapy, a bellwether treatment in a mix of drugs being positioned to take the hemophilia market by storm. Its progress on hemophilia A comes a year after Pfizer struck a pricey deal with Sangamo to use its zinc finger tech to make a rival — though BioMarin remains well in front. The Sangamo team dosed their first patient last fall, while BioMarin has two years of data on some patients.

In the meantime, BioMarin is waiting out the clock on its May 25 PDUFA deadline for pegvaliase, which it hopes will soon become its 7th marketed drug.


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Recursion Pharmaceuticals Salt Lake City, UT
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Atlas Venture Cambridge, MA

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