SB-525 Continues to Show Encouraging Results for Hemophilia A in Phase 1/2 Trial

Investigational gene therapy SB-525 is well-tolerated and leads to a dose-dependent increase in factor VIII (FVIII), according to interim results from eight patients with severe hemophilia A enrolled in the Phase 1/2 Alta clinical trial.

Data showed that patients who received the highest dose of SB-525 — 3e13 vg/kg dose — reached normal levels of FVIII.

Based on these initial findings, a safety monitoring committee has recommended that more patients be enrolled to the maximum dose group. Up to five more patients will be recruited to this group, according to Sangamo Therapeutics, which is developing the therapy along with Pfizer.

The open-label trial (NCT03061201) is now underway in 10 states in the U.S. More information on enrollment, including contacts and locations, is available here.

“The interim data from the first eight patients with hemophilia A treated with SB-525 gene therapy in the Alta study are encouraging and demonstrate a dose-dependent relationship, evidence of sustained factor levels, and low variability, both within each patient and within each cohort,” Edward Conner, MD, chief medical officer of Sangamo, said in a press release.

“These interim results suggest that SB-525 may be well-tolerated and may prove to have the predictability and sustained treatment effect that can bring clinical benefit in patients with hemophilia A. We need to continue observing how the data mature and how additional patients in the expansion cohort respond to SB-525. We look forward to working with Pfizer to potentially advance SB-525 into a registrational study,” he added.

Hemophilia A patients need to repeatedly receive FVIII blood infusions to replace defects in blood clotting FVIII and prevent bleeding. A one-time adminstration of SB-525 is aimed at reducing or even eliminating a patient’s need for FVIII replacement therapy by inducing cells to produce their own proteins.

SB-525 relies on a genetically engineered virus, a recombinant (lab-made) adeno-associated virus (rAAV), carrying a “healthy” FVIII gene construct. The rAAV is harmless for humans, and it delivers the corrected gene to cells in tissues. The rAAV for SB-525 is designed to restrict FVIII gene expression to the liver, a strategy intended to increase FVIII long-term hepatic production in hemophilia A patients.

The Phase 1/2 Alta study is investigating the safety, tolerability, and time-course profile of FVIII levels in severe hemophilia A patients infused with escalating doses of SB-525. Patients enrolled in the trial do not receive preventive (prophylactic) treatment with steroids.

The interim results include data from eight patients enrolled in four ascending dosage groups — 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg. Each group included two patients.

These results confirm early data and show a dose-dependent increase in FVIII levels along with increased FVIII activity.

In the highest dose group (3e13 vg/kg), patients achieved normal FVIII levels, ranging between 50% and 150%. This was accompanied by a decrease in the need for FVIII replacement therapy, also dose-dependent. Patients in the highest group no longer required replacement therapy after infusion and have experienced no bleeding events up to date.

SB-525 has been generally well-tolerated. One patient (in the highest dose group) developed low blood pressure and a fever, but the symptoms resolved within 24 hours.

In addition, one patient experienced an increase in alanine aminotransferase (ALT) four weeks after infusion — ALT is a marker of liver function whose levels increase upon liver damage — which required treatment with oral corticosteroids. This, however, had no negative impact on FVIII activity, and ALT levels were resolved five weeks after beginning treatment.

No treatment-related serious adverse events and no ALT elevations requiring more than seven days of corticosteroid treatment were seen in the first three study groups.

“The interim results with SB-525 gene therapy for patients with severe hemophilia A are early but very promising,” said Barbara Konkle, MD, associate chief scientific officer at Bloodworks Northwest, a professor of medicine at the University of Washington, and investigator on the Alta study. “It will be important to observe additional patients and for a longer follow-up duration to determine whether these positive interim findings are recapitulated and sustained.”

Results from longer-term follow-up data will be presented at an upcoming scientific meeting.

“We are encouraged by the early clinical data suggesting tolerability of the recombinant AAV6 vector and potential for normalization of Factor VIII levels. We look forward to the opportunity to expanding the cohort administered a 3e13 vg/kg dose and subsequent planning for the pivotal study,” said Seng Cheng, senior vice president and chief scientific officer of Pfizer’s Rare Diseases Research Unit.

“As the development and commercial partner for SB-525, we are encouraged by the possibility that SB-525 may one day transform the treatment landscape for patients with hemophilia A,” Cheng added.

The U.S. Food and Drug Administration has granted SB-525 fast track designation, and the European Medicines Agency has awarded it orphan medicinal product status for hemophilia A in Europe.