Gene therapies for haemophilia A and B show promise in early-stage studies

Results from two early-stage studies presented Tuesday at the World Federation of Hemophilia (WFH) conference showed that experimental gene therapies from Pfizer and Spark Therapeutics, as well as from BioMarin Pharmaceutical, have the potential to offer new treatments for both haemophilia B and haemophilia A, respectively. 

In the first Phase I/II trial, Pfizer and Spark said that all 15 patients with severe or moderately severe haemophilia B who received the investigational adeno-associated virus vector SPK-9001 had discontinued routine factor IX concentrate infusions. The companies also noted that none of the patients experienced serious adverse reactions, nor were there any thrombotic events or factor IX inhibitors as of the May 7 data cut-off. Spark R&D chief Katherine High remarked "our commitment to gene therapy research across our haemophilia programmes 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." 

Pfizer and Spark said results from the study, whose preliminary findings were unveiled in December 2017, showed that the annualised bleeding rate for all 15 participants was slashed by 98 percent to an annual rate of 0.2 bleeds per participant, versus the pre-treatment value of 8.9 bleeds, with only a single patient experiencing a bleeding event four or more weeks after SPK-9001 infusion. Further, the annualised infusion rate was reduced by 99 percent to an annual rate of 0.9 infusions, versus a baseline rate of 57.2 infusions before infusion.

In addition, as of the May 7 data cut-off, all 13 patients who had completed at least 12 weeks of follow-up after SPK-9001 infusion had achieved stable factor IX levels exceeding 12 percent. Moreover, the steady-state factor IX activity levels in the first 10 treated patients, beginning at 12 weeks through 52 weeks of follow-up, ranged from 14.3 percent to 76.8 percent. The companies noted that in the three patients infused with SPK-9001 manufactured using an enhanced process and who reached at least 12 weeks of follow-up, the steady-state factor IX levels ranged from 38.1 percent to 54.5 percent. 

According to the drugmakers, Spark has completed enrolment in this study and plans to fully transition the programme to Pfizer under the terms of their 2014 partnership. Spark also expects to deliver a batch of drug substance to Pfizer, allowing the latter company to initiate a late-stage study. 

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Meanwhile, BioMarin Pharmaceutical presented two-year data at the WFH conference from a Phase I/II study showing that its valoctocogene roxaparvovec gene therapy, formerly known as BMN 270, was associated with "continued and substantial reductions in bleeding requiring factor VIII infusions." Specifically, patients with severe haemophilia A in the 6e13 vg/kg cohort achieved reductions of 97 percent in the mean annualised bleeding rate, with no spontaneous bleeds and elimination of all bleeds in target joints in the second year. 

The drugmaker also stated that 71 percent and 86 percent of treated patients experienced no bleeding events requiring factor VIII infusions in years 1 and 2 of treatment, respectively, compared to 14 percent at baseline. Hank Fuchs, president of worldwide R&D at BioMarin, commented "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." 

BioMarin also reported that in the 4e13 vg/kg cohort of the Phase I/II trial, valoctocogene roxaparvovec was associated with a 92-percent decrease in the annualised bleeding rate for bleeds requiring factor VIII infusions. Additionally, 83 percent of patients experienced no bleeding events necessitating factor VIII infusions after one year of treatment, compared to 17 percent before treatment. 

BioMarin previously issued updates for both the 4e13 vg/kg and 6e13 vg/kg doses in 2017, which showed that in the higher dose group, median Factor VIII activity levels at week 52 were 89 percent. The company indicated Tuesday that at 104 weeks post-infusion, the median Factor VIII activity level of the 6e13 vg/kg cohort is near normal at 46 percent (for related analysis, read ViewPoints: BioMarin skates by durability concerns in haemophilia A). BioMarin also presented data from the Phase I/II study last year showing that 11 of 13 patients who had received a single infusion of the gene therapy exhibited normal or near-normal factor VIII levels. 

Earlier this month, BioMarin announced that it had dosed the first patient in an early-stage study of valoctocogene roxaparvovec in the treatment of severe haemophilia A in patients with pre-existing AAV5 antibodies (for related analysis, see ViewPoints: BioMarin tries its hand against the toughest patients in haemophilia.) The therapy was previously granted breakthrough therapy status by the FDA for the treatment of haemophilia A. 

Last December, Spark presented early-stage data showing that their experimental gene therapy SPK-8011 for the treatment of haemophilia A appeared to be less effective than valoctocogene roxaparvovec.

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