First Successful Gene Therapy Performed for Hemophilia A

In an ongoing phase I/II study of patients with hemophilia A, those who received a single infusion of BMN 270 (an adeno-associated virus serotype 5 [AAV5] vector containing the B-domain-deleted F8 gene) had improved levels of factor VIII (FVIII), with 11 of 13 treated patients achieving normal or near-normal FVIII levels.

“Because hemophilia A is an X-linked single gene disorder of FVIII, it is an ideal candidate for gene therapy,” said lead author K. John Pasi, MD, from Barts and The London School of Medicine and Dentistry in the United Kingdom, during his presentation of the results at the 2017 ASH Annual Meeting. “The clinical data to date for this investigational gene therapy exceeded our expectations, in increasing FVIII levels and reducing the annualized bleed rate.”

The phase I/II, first-in-human, dose-escalation BMN 270-201 trial enrolled men with severe hemophilia A (FVIII <1 IU/dL) who had at least 150 days of previous exposure to FVIII concentrate or cryoprecipitate. Patients were infused with a single intravenous dose of BMN 270 at four doses: 6×1012 vg/kg, 2×1013 vg/kg, 6×1013 vg/kg, or 4×1013 vg/kg. “Prophylactic corticosteroids were initiated in the first three cohorts out of an abundance of caution, after one patient had alanine aminotransferase (ALT) elevation.”

Dr. Pasi reported results from patients in the two highest dose cohorts: 6×1013 vg/kg (n=7) and 4×1013 vg/kg (n=6).

As of July 28, 2017 (data cutoff), patients had been followed for up to 19 months, and all patients began producing FVIII.

In the cohort receiving 6×1013 vg/kg, FVIII activity plateaued by 20 weeks following infusion with BMN 270. FVIII levels remained in the normal range (86-122 IU/dL) through follow-up, with a median FVIII level of 90 IU/dL (range = 65-107 IU/dL) at 78 weeks.

Patients receiving the lower dose (4×1013 vg/kg) experienced steady increases in FVIII levels at up to one year of follow-up, “with levels approaching or within the lower end of the normal range of FVIII activity,” Dr. Pasi said. Median FVIII level was 34 IU/dL (range = 28-40 IU/dL) at 20 weeks, and in the three patients who were followed for at least 48 weeks, median FVIII level was 49 IU/dL (range not provided).

This gene therapy appears to have long-lasting effects following a single infusion, compared with FVIII infusions, a standard of care for patients with severe hemophilia A. Before enrollment in this study, participants required a median of 155.5 infusions per year (range = 112-183 infusions) in the high-dose cohort and 138.5 infusions per year (range = 122-157 infusions) in the low-dose cohort. After infusion, patients in both dose cohorts discontinued prophylactic FVIII infusions. From four weeks after infusion through the final follow-up visit, 10 of the 13 patients had no episodes of bleeding that required FVIII treatment.

“This clinical result has the potential to improve the lives of patients who now must infuse themselves with factor VIII as often as every other day, Dr. Pasi said. “With this experimental treatment, we are researching whether it may be possible for hemophilia A patients to reduce or eliminate FVIII treatment over an extended timeline.”

No patients showed evidence of an adverse immune system response. Patients experienced only mild, grade 1, asymptomatic ALT increases, reported in all seven people in the 6×1013 vg/kg cohort and four of six in the 4×1013 vg/kg cohort. All but one patient in the low-dose cohort have a normal ALT level as of last follow-up, and all but one person in this groups is off of corticosteroid therapy.

As a limitation of the study, the authors noted that they did not assess the possibility of vector integration, and they were not able to explain the variability of FVIII activity levels among participants.

The authors report financial relationships with BioMarin Pharmaceutical, the manufacturers of BMN 270.


Pasi JK, Rangarajan S, Kim B, et al. Achievement of normal circulating factor VIII activity following BMN 270 AAV5-FVIII gene transfer: Interim, long-term efficacy and safety results from a phase 1/2 study in patients with severe hemophilia A. Abstract #603. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.