Blog June 25, 2018

First Up For The New FDA RMAT Designation: Gene Therapeutics for Hemophilia

Red blood cellsWe recently wrote about the U.S. Food and Drug Administration’s (FDA) creation of a Regenerative Medicine Advanced Therapy (RMAT) designation in an effort to speed up the approval process for certain types of treatments, including gene therapies. The agency has specifically chosen gene therapy for hemophilia as its first focus, due to the considerable effort currently underway to develop treatments for two different forms of this disease.


Hemophilia is an inherited condition where a patient’s blood does not clot properly, causing the affected person to bleed profusely from even a minor injury. The condition is caused by insufficiency of a particular coagulation protein. Type A hemophiliacs – the largest sub-group — have a deficiency in clotting Factor VIII, while type B are deficient in Factor IX; in addition, there are other rarer forms of hemophilia caused by lack of other clotting factors. When the bleeding is internal, damage can occur to joints, muscles, and organs, and may be life-threatening. Current treatment for hemophilia consists primarily of replacement infusions of the missing protein, administered to stop a bleed or, in severely affected patients, administered prophylactically.


The latest gene therapy approaches, instead, involve a single infusion of a drug engineered to replace the missing gene responsible for production of the blood-clotting protein.


Several of the companies currently developing these gene therapy products for type A or type B hemophilia have reported very promising results and are now preparing to enter pivotal studies with their treatment candidates.


BioMarin, who is developing Valrox as a gene therapy for hemophilia A, reported the elimination of spontaneous bleeds and bleeds into joints in the high-dose cohort of the company’s Phase 1/2 trial; 71% and 86% of the high-dose cohort had zero bleeds requiring Factor VIII infusions in years 1 and 2 respectively, compared to 14% who had zero bleeds requiring Factor VIII for a year at baseline. Of the low-dose cohort patients, 83% experienced no bleeds requiring Factor VIII infusions following one year of treatment, compared to 17% for the same timeframe at baseline. Overall, there was a 96-98% reduction in mean Factor VIII usage throughout the trial, with enrolled patients also reporting an improved quality of life above baseline. While BioMarin reported that Factor VIII measurements appeared to slowly decline over time, it is not yet known whether the decline is a leveling off of Factor VIII production or a sign that treatment effectiveness only has a limited duration. BioMarin plans to initiate pivotal testing of its treatment by the end of 2019, with the aim of providing evidence that its gene therapy can best the current standard of care.


uniQure’s AMT-060, under development for hemophilia B, has received both Breakthrough designation from FDA and PRIME designation from the European Medicines Agency, and the company is preparing to initiate a pivotal study during 2018. Spark Therapeutics and its partner Pfizer are also developing a treatment for hemophilia B and are planning to initiate a Phase 3 pivotal study. Spark recently presented data at the World Federation of Hemophilia World Congress, showing a 98% reduction in the rate of annualized bleeding, as well as a 99% decrease in Factor IX infusions, for the 15 patients who participated in a Phase 1/2 trial of its therapeutic candidate, SPK-9001.


The FDA has stated that it could evaluate and approve such gene therapies based on whether a treatment increases the targeted proteins in blood, regardless of actual clinical benefit (i.e., less bleeding in patients). Thus, these approvals may be accompanied by the requirement that the drug sponsor perform post-approval studies to demonstrate that the treatment actually does reduce bleeding. The agency’s main goal is to speed its review — and hopefully, approval — of these types of therapies; the FDA currently has more than 500 active Investigational New Drug applications for gene therapies under review, with more than 100 of them received in the last year alone.


One big challenge is looming for both developers as well as for the agency, as traditional clinical trials may not be able to determine the duration of response for gene therapies. Further down the line, we expect that not knowing how long a treatment lasts will also challenge payers and raise questions around the appropriate pricing and reimbursement of such treatments, especially if repeat treatments are required.