NEJM Study Shows Safety of Gene Transfer in Hemophilia A

Results from a phase 1-2, dose escalation study conducted by BioMarin Pharmaceutical were recently published in the New England Journal of Medicine and assessed the safety and efficacy of a single peripheral infusion of AAV5-hFVIII-SQ in 9 men with severe hemophilia A, and displayed that the changes in the vector and gene resulted in successful gene transfer, despite the large size of the coding region.

From September 2015 through April 2016, participants were enrolled sequentially into 3 different dose cohorts at 5 sites in the United Kingdom. Each received a single dose of AAV5-hFVIII-SQ infused into a peripheral vein, over a period of approximately 60 minutes. The lowest-dose cohort included 1 participant who received a dose of 6x10¹² vector genomes (vg) per kilogram (kg) of body weight. The intermediate-dose cohort also only had 1 participant, and he received a dose of 2x10¹² vg/kg. The remaining 7 participants were placed into the high-dose cohort, and each received 6x10¹³ vg/kg.

Escalation to the next dose cohort occurred after a single patient had received a dose safely and if the factor VIII activity level was less than 5 international unit (IU) per deciliter at week 3 following gene transfer. Each of the participants was hospitalized for the study-drug infusion and was observed for 24 hours.

Hemophilia A is an X-linked bleeding disorder that results from mutations in the gene-encoding coagulation factor VIII. Patients with severe hemophilia A are vulnerable to impulsive or triggered bleeding in joints and soft tissue, which can lead to excruciating and incapacitating arthropathy, poor quality of life (QOL), and escalated risks of intracranial hemorrhage and early death.

Safety, the primary endpoint of the study, was met, as there was only one serious adverse event (AE) observed; Participant 6 experienced the progression of chronic arthropathy, which occurred at an anatomical site that had often been a bleeding site prior to treatment and for which the participant had surgical knee replacement afterward. All other AEs were mild and included alanine aminotransferase level (7), arthralgia (6), back pain (4), an increased aspartate aminotransferase level (3), fatigue (3), and productive cough (3). Long-term safety is continuing to be monitored.

No participant had abnormal elevations in the bilirubin or alkaline phosphatase level.

The prospectively specified primary efficacy goal was a factor VIII activity level of a minimum of 5 IU per deciliter at week 16 after gene transfer, and secondary efficacy measures were the frequency of factor VIII use and the number of bleeding episodes. In the low-dose cohort, the factor VIII activity level remained under 1 IU per deciliter through week 54 in Participant 1. In the intermediate-dose cohort, Participant 2 had a low, but stable, factor VIII activity level (1-3 IU per deciliter). In the high-dose cohort, the factor VIII activity level gradually increased and then plateaued at or above physiologic levels in weeks 20 through 24.

In the 6 participants who had received factor VIII prophylaxis prior to the study, the median annualized bleeding rate dropped from 16 events per year before the study to 1 event per year after gene transfer.

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