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ORLANDO—An investigational gene therapy can safely reduce bleeding in patients with severe hemophilia A, a phase 1/2 study suggests.

The therapy is BMN 270, a recombinant adeno-associated virus (AAV) vector coding for human coagulation factor VIII (FVIII).

Six of the 7 patients treated with the highest dose of BMN 270 had FVIII levels above 50%, and the number of bleeding events fell substantially from baseline.

None of the patients developed inhibitors to FVIII, there were no serious adverse events, and none of the patients discontinued the therapy due to safety reasons.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, presented the results of this study in a late-breaking oral presentation at the World Federation of Hemophilia 2016 World Congress.* The research was funded by BioMarin Pharmaceutical Inc.

This phase 1/2 dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

The primary endpoints are to assess the safety of a single dose of BMN 270 and the change from baseline of FVIII expression level at 16 weeks after infusion.

Secondary endpoints include assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses. Patients will be monitored for safety and durability of effect for 5 years.

Thus far, 9 patients with severe hemophilia A have received a single dose of BMN 270—1 at 6×1012 vg/kg, 1 at 2×1013 vg/kg, and 7 at 6 x 1013 vg/kg.

As of the July 6 data cutoff, post-treatment follow-up ranges from 12 weeks to 28 weeks.


The most common adverse events were arthralgia (9 events in 6 subjects), contusion (6 events in 3 subjects), back pain (4 events in 3 subjects), and ALT elevation (6 events in 6 subjects).

No clinically relevant sustained rises in ALT levels or other markers of liver toxicity have been observed.

The maximum ALT levels were between 23 U/L and 82 U/L (less than 2 times the upper limit of normal, which is 43 U/L for the central laboratory in this study) approximately 12 weeks after gene delivery and generally declined over the next few weeks. ALT rises have not been associated with any decrease in FVIII levels.

A steroid regimen administered to all high-dose patients has been well-tolerated. Patients are successfully tapering off of steroids. Two patients have been off steroid therapy for up to 2.5 weeks, with no adverse impact on FVIII expression or ALT levels.


The patient treated at the lowest dose (6×1012 vg/kg) had no change from baseline in FVIII levels. The patient treated at the mid-dose (2×1013 vg/kg) had a stable FVIII activity level greater than 2 IU/dL for more than 28 weeks.

All 7 patients treated at the highest dose (6×1013 vg/kg) had FVIII activity levels greater than 10 IU/dL after week 10.

As of each patient’s most recent reading, 6 of the 7 patients in the high-dose group had FVIII levels above 50%, as a percentage calculated based on the numbers of IU/dL. The seventh patient had levels above 10%.

Four patients who have been followed the longest had a mean FVIII level of 146% at their 20-week visit. Two patients with FVIII levels above 200% had no unexpected events or need for medical intervention.

For the 7 patients treated at the high dose, the median annualized bleeding rate measured from the day of gene transfer to the data cutoff fell from 20 to 5.

After week 7 post-infusion, there were no bleeds in 6 of the 7 patients. There were 10 bleeds from weeks 0 through 2 post-infusion, 7 bleeds from weeks 3 through 8, and 2 bleeds from weeks 9 through 28. From weeks 2 through 28, all but 1 bleed occurred in a single subject who is the lowest responder.

All of the patients in the high-dose cohort have switched to receiving FVIII therapy on-demand. Six of them were previously receiving FVIII therapy as prophylaxis.

“These data provide strong proof-of-concept evidence that restoration of clotting function may be achieved by gene therapy,” Dr Pasi said. “For the first time, patients have reason to hope to avoid bleeding and the opportunity to live a normal life.” end hematology article

*Pasi J et al, Interim results of an open-label, phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A, WFH 2016 World Congress, July 2016.

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