Hemophilia A and B Gene Therapies Indicate Efficacy

Two early-stage studies of gene therapies from Pfizer, Spark Therapeutics, and BioMarin Pharmaceutical indicate efficacy for hemophilia A and B treatment.

At the 2018 World Federation of Hemophilia (WFH) conference in Glasgow, Scotland, results from 2 early-stage studies demonstrated that gene therapies from Pfizer, Spark Therapeutics, and BioMarin Pharmaceutical could potentially serve as eventual treatment options for both hemophilia A and B patients.

“Our commitment to gene therapy research across our hemophilia programs remains steadfast with the goal of developing a novel therapeutic approach with a positive benefit-risk profile that aims to free patients of the need for regular infusions while eliminating spontaneous bleeding,” stated Spark R&D chief, Katherine High, in a recent statement.

In Pfizer and Spark’s first phase 1/2 trial, all 15 participating patients were eligible based on the criteria that they had severe or moderately severe hemophilia B. Each was administered the gene therapy, SPK-9001 (an investigational adeno-associated virus vector) and discontinued routine factor IX concentrate infusions.

No serious adverse reactions were experienced by patients, and no thrombotic events or factor IX inhibitors occurred as of the May 7th data cut-off.

Pfizer and Spark reported that the study displayed a decline of 98% in the annualized bleeding rate in all 15 patients, reducing the annual rate to 0.2 bleeds per subject in comparison to the pre-treatment value of 8.9 bleeds in which only a single patient encountered a bleeding event 4 or more weeks following the SPK-9001 infusion. The annualized infusion rate was also reduced by 99% to an annual rate of 0.9 infusions in comparison to a baseline rate of 57.2 infusions prior infusion.

Additionally, all 13 subjects who had completed at least 12 weeks of follow-up following SPK-9001 infusions obtained stable factor IX levels, surpassing 12% (as of the May 7 data cut-off). Beginning at 12 weeks through 52 weeks of follow-up, the steady-state factor IX activity levels in the first 10 treated patients ranged from 14.3% to 76.8%. By using a formula of SPK-9001 that was manufactured using an enhanced process and reaching a minimum of 12 weeks of follow-up, 3 patients experienced steady-state factor IX levels that ranged from 38.1% to 54.5%.

To date, Spark has reached full enrollment with its study and plans to completely transition the program to Pfizer in accordance with their 2014 partnership terms. Spark also plans to give a batch of drug substance to Pfizer in order to allow the latter company to initiate a late-stage study.

As for BioMarin Pharmaceutical, it presented 2-year data from a phase 1/2 study at the World Federation of Hemophilia (WFH) conference. The data displayed an association between its valoctocogene roxaparvovec gene therapy (formerly known as BMN 270) and “continual and substantial reductions in bleeding requiring factor VIII infusions.” Reductions of 97% in the mean annualized bleeding rate were achieved by patients with severe hemophilia A in the 6e13 vg/kg cohort. No spontaneous bleeds and the elimination of all bleeds in target joints were experienced in the second year. Seventy-one percent and 86% of treated patients did not experience bleeding events that required factor VIII infusions in years 1 and 2 of treatment in comparison to 14% at baseline respectively.

Hank Fuchs, president of worldwide R&D at BioMarin, stated "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."

In addition, BioMarin provided updates for both the 4e13 vg/kg and 6e13 vg/kg doses in 2017, which displayed that median Factor VIII activity levels at week 52 were 89% in the higher dose group. At 104 weeks post-infusion, the median Factor VIII activity level of the 6e13 vg/kg cohort is near normal at 46%. Data from the Phase 1/2 study last year revealed that 11 of 13 patients who had been administered a single infusion of the gene therapy expressed normal or near-normal factor VIII levels.

The first patient in an early-stage study of valoctocogene roxaparvovec in the treatment of severe hemophilia A in patients with pre-existing AAV5 antibodies was dosed per announcement earlier this month.

The therapy was previously granted breakthrough therapy status by the US Food and Drug Administration (FDA) last year.

According to early stage data presented by Spark last December, SPK-9011 displayed less efficacy than valoctocogene roxaparvovec for the treatment of hemophilia A.

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