BioMarin to Begin Phase 3 Gene Therapy Trials for Hemophilia A

BioMarin announced the results from their ongoing Phase 1/2 gene therapy studies evaluating  BMN 270 for patients with hemophilia A. Based on encouraging data, Phase 3 studies are being planned to start later this year.

Hemophilia A is a chronic, genetic disorder that results in impaired clotting mechanisms due to missing or reduced levels of Factor VIII. People with this rare disorder experience recurrent painful bleeding episodes, some of which can be life-threatening. Numerous orphan drugs have been approved and are available to treat the bleeding episodes and 2 orphan drugs – Advate and Kogenate – are approved for prophylactic use in patients with hemophilia A.

BMN 270 is an AAV 5 factor VIII vector designed to restore factor VIII plasma concentrations to levels that would essentially cure the person of the disorder.

In the Phase 1/2 study, patients with severe hemophilia A were given doses of BMN 270, 4e13 vg/kg or 6e13 vg/kg.

In the 6 patients given the 4e13 vg/kg dose, each has shown increased plasma levels of Factor VII and has experienced a dramatic reduction in bleeding episodes.  Three of the patients have been monitored for 32 weeks and 3 others monitored for 20 weeks. Results from those patients are shown in the table below.

Table 1:  Factor VIII Levels (%) of 4e13 vg/kg Dose Patients 

Week Mean Factor VII Levels (%) (mean) Range (low, high)
          4 (n=6)
2, 10
3, 21
6, 32
5, 38
7, 45
          24 (n=3)
24, 42
32, 44
48, 54

Table 2:  Mean Annualized Bleeding Rate (ABR) and FVIII Infusions of 4e13 vg/kg Dose Patients Previously on Prophylaxis (N=6) up to 32 Weeks

Before BMN 270 Infusion** After BMN 270 
Annualized Bleeding Rate* (mean) 12.2 1.0
Annualized FVIII Infusions* (mean) 144.2 4.8

* Post infusion data were based on data after Factor VIII levels were above 5%
**Obtained from medical records.
***5 of 6 patients had 0 bleeds requiring Factor VIII infusions after Factor VIII levels were above 5%.

Similar trends were observed in the 7 patients receiving the higher dose (6e13 vg/kg). Those patients have been monitored for 52 weeks, the mean Factor VIII levels continue to be above 50%.

Based on the results, BioMarin plans to initiate 2 separate Phase 3 studies; a study with the 4e13 vg/kg dose and another with the 6e13 vg/kg dose. They are expected to start in the 4th quarter of 2017 and will enroll about 100 patients.

Hank Fuchs, M.D., President, Worldwide Research and Development at BioMarin said. “Given the low level of pre-existing immunity to AAV5, we expect that approximately 90 percent of patients would be treatment candidates for BMN 270 based on this criteria.”

BMN 270 was well-tolerated and no patients withdrew from the study. The most common adverse events across all dose cohorts were alanine aminotransferase (ALT) elevation in 11 patients; arthralgia, aspartate aminotransferase elevation, and headache in 7 patients each, and; back pain and fatigue in 5 patients each. One patient developed Grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270. The event resolved within 48 hours but was determined to be related to BMN 270.


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