The Clinical Trial Results Were ‘Beyond our Wildest Dreams’ as First Gene Therapy for Hemophilia in UK Works in Patients

Jan 6, 2020 | Blood Clotting, Gene Therapy, Hemophilia A, Protein, UK

The Clinical Trial Results were ‘Beyond our Wildest Dreams’ as First Gene Therapy for Hemophilia in UK Works in Patients

A breakthrough gene therapy has enabled British medics to sustainably treat the most serious form of hemophilia. Patients that used to need to visit the hospital at least three times per week and were in constant mortal risk from even small cuts are now able to live regular lives based on the results of this multi-site UK study for the investigational gene therapy known as BMN-270 (Biomarin). It is possible, experts convey, that this therapy could lead to a cure. The study results were recently published in the New England Journal of Medicine. Now the study sponsor, Biomarin, is filing a BLA with the FDA for approval. This could change how hemophilia is treated.

What is Hemophilia?

Hemophilia A is a genetic disease caused by the deficiency of clotting factor VIII. It is the most common type of hemophilia and occurs much more frequently in males; incidence is estimated at 1 in 4,000-5,000 male birth. In the UK, according to The Telegraph, about 2,000 patients suffer from the most serious inherited form known as hemophilia A. This form requires regular injections of the clotting protein factor VIII. Biomarin reports that there are approximately 90,000 Hemophilia A patients in territories where it conducts business.

The Studies

The study was sponsored by California biotech Biomarin. The study was conducted as an open label, dose escalation study in order to determine the safety and efficacy of valoctocogene roxaparvovec, an Adenovirus-Associated Virus based gene therapy vector  (BMN-270) in participants with severe Hemophilia A. The study commenced August 2015 and concludes February, 2022. 15 patients were planned in the protocol and, according to recent press, the study ultimately has enrolled 13 participants thus far.

Primary outcome measures include 1) number of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for 5 years following valoctocogene roxaparvovec infusion [Time Frame: 61 months)], and 2) Determine the dose of AAV5-hFVIII required to achieve expression of FVIII at or above 5% of normal activity ((>5 IU/dL) at 16 weeks after infusion. [ Time Frame: 61 Months ]

The study was conducted in the United Kingdom and included the following sites: Hampshire Hospitals NHS Foundation Trust; Queen Elizabeth Hospital Birmingham; University Hospitals Bristol NHS Foundation Trust; Cambridge University Hospital NHS Foundation Trust; Greater Glasgow Health Board;  Barts Health NHS Trust and Guy’s & St. Thomas’ NHS Foundation Trust; Imperial College Healthcare NHS Trust and University Hospital Southampton NHS Foundation Trust.

The broader Phase III program, as reported in a Biomarin annual report, notes that the complete Phase III study is targeting enrollment of 130 patients.

The Trial in the News

The Telegraph UK reported the exciting results. At Guy’s & St. Thomas’ hospital, it was reported that patients there achieved such changes to their protein levels that each patient could halt their regular injections of clotting products. The therapy, involving the generically engineered gene therapy known as BMN-270, was injected into the patient’s blood, then circulated to the patient’s liver and thereafter generated the clotting factor. The principal investigator at this British site, Dr. Bella Madan, noted the study “has been extremely successful and beyond our wildest dreams. These are the first patients with hemophilia to be treated with gene therapy.”

BLA Submitted to the FDA for Approval

As reported in Hematology Advisor, Biomarin submitted a Biologics License Application (BLA) to the FDA for BMN 270 for the treatment of hemophilia A in adults. This is the first marketing application submission for a gene therapy for any type of hemophilia.

About BMN 270 (Valoctocogene roxaparvovec)

BMN 270 is an investigational adeno-associated virus (AAV) gene therapy that is administered as a single infusion to produce clotting factor VIII. The BLA submission is supported by interim analysis of a Phase III and 3-year Phase I/II data. Recent results from the Phase I/II study revealed that for a third straight year, the bleed rate control and reduction in factor VIII usage was maintained following a single administration of the experimental gene therapy.

The FDA had already granted Breakthrough Therapy and Orphan Drug designations to the drug. Biomarin expects the FDA review to commence in 2020. Biomarin reports that there are approximately 90,000 Hemophilia A patients in territories where it conducts business.

Prospective Competition

Should this gene therapy (BMN 270) be approved and commercialized, it could run up against competition from marketed recombinant factor VIII replacement therapies, a novel bispecific antibody marketed by Roche, as well as clinical stage programs, including gene therapy product candidates under development by Bayer AG, Sangamo Therapeutics, Inc., Shire Plc, and Spark Therapeutics, Inc., and preclinical product candidates from other ventures, including Uniqure NV. Alnylam Pharmaceuticals, Inc. is developing a novel product candidate in the clinic for the treatment of hemophilia A.

Lead Research/Investigator

·         Savita Rangarajan, MB, BS

·         Liron Walsh, MD

·         Will Lester, MB, ChB, PhD

·         David Perry, MD, PhD

·         Bella Madan, MD, Consultant hematologist, Guys and St Thomas’ NHS Foundation Trust

·         Michael Laffan, DM

·         Hua Yu, PhD

·         Christian Vettermann, PhD

·         Glenn F. Pierce, MD, PhD

·         Wing Y. Wong, MD

·         John K. Pasi, MB, ChB, PhD

Call to Action: The sponsor, Biomarin, according to UK press, will seek regulatory approval with the European Medicines Agency; it has submitted a BLA to the FDA and expects review in 2020.


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