Preliminary data from a phase 1/2 study suggest an investigational gene therapy can increase factor VIII (FVIII) levels in patients with severe hemophilia A.
The therapy, BMN 270, is a recombinant adeno-associated virus (AAV) vector coding for FVIII.
To date, 8 patients have received a single dose of BMN 270, and most have experienced an increase in FVIII levels and a decrease in the severity of their disease.
At last observation, patients receiving the highest dose of BMN 270 experienced increasing FVIII activity levels ranging between 4% and 60% (as a percentage calculated based on the numbers of International Units (IU) per milliliter of whole blood).
These results were recently announced by BioMarin Pharmaceutical Inc., the company developing BMN 270.
“If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of FVIII, it could have a real and meaningful clinical benefit by reducing the need for FVIII infusions and spontaneous bleeds,” said study investigator John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in the UK.
“I am looking forward to further assessing the data over the 16 weeks and beyond in this ongoing study.”
This dose-escalation study was designed to evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A.
The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for FVIII and determine 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. Researchers plan to monitor patients for safety and durability of effect for 5 years.
Results
A total of 8 patients with severe hemophilia A have received a single dose of BMN 270—one at 6 x 1012 vg/kg, one at 2 x 1013 vg/kg, and six at 6 x 1013 vg/kg.
At 20 weeks after administration, the patient who received the lowest dose of BMN 270 had a FVIII activity level of less than 1% and still had severe hemophilia.
At 16 weeks, the patient who received the middle dose of BMN 270 had a FVIII activity level of 2% and moderate hemophilia.
One patient in the highest dose group also had moderate hemophilia and a FVIII activity level of 4% at 7 weeks.
Three patients in the high-dose group had mild hemophilia and FVIII activity levels of 8%, 10%, and 21% at 7, 5, and 6 weeks, respectively.
And 2 patients in the high-dose group had normal levels of FVIII activity—57% at 16 weeks and 60% at 8 weeks.
Liver function
The researchers have monitored liver function tests closely during the trial. The first 3 patients did not receive prophylactic corticosteroids, and 2 of these patients experienced elevated alanine aminotransferase (ALT) levels.
Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14.
Two weeks later, Patient 3 began a new corticosteroid regimen when ALT levels became minimally abnormal for the first time. The expression of FVIII continued to increase during this ALT elevation and is currently at 57%.
In addition, Patient 1, who was treated at the lowest dose of BMN 270, experienced a rise in ALT level to 128 IU/L at 28 weeks after dosing.
After the third patient, all patients were started on prophylactic corticosteroid therapy. To date, no additional patients have experienced abnormal ALT levels.
BioMarin said it plans to discuss these findings with UK regulatory authorities prior to dosing the remaining patients.
“We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing FVIII levels over time,” said Hank Fuchs, MD, chief medical officer at BioMarin.
“BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of FVIII.”
BMN 270 has received orphan drug designation from the European Commission and US Food and Drug Administration. Phase 3 design preparation and high-volume manufacturing plans are underway.
