Efficacy of Gene Therapy SB-525 Now at 14 Months in Alta Hemophilia A Trial

Up to 14 months after a one-time infusion of SB-525, an investigational gene therapy, durable increases in the activity of clotting factor VIII (FVIII) are continuing in all five severe hemophilia A patients treated at the highest dose in the Alta Phase 1/2 trial.

None of these five people, given  SB-525 at 3×10¹³ vector genomes (vg)/kg in the dose-ranging study (NCT03061201), have experienced bleeding episodes or required replacement therapy with FVIII.

“We are excited that these data affirm previous findings from this Phase 1/2 study,” Seng Cheng, senior vice president and chief scientific officer of Pfizer’s Rare Disease Research Unit, said in a press release. “We are encouraged by the potential of giroctocogene fitelparvovec [SB-525] to demonstrate longer-term durability, an important element for patients living with severe hemophilia A.”

Updated trial findings were presented at the World Federation of Hemophilia (WFH) Virtual Summit 2020.

SB-525 is an experimental gene therapy for hemophilia A, originally developed by Sangamo Therapeutics and now being advanced by Pfizer. The one-time therapy uses an adeno-associated viral vector (AAV6), engineered to be harmless, to deliver genetic information required for the production of FVIII — the blood clotting protein missing in people with hemophilia A — to liver cells.

By doing so, SB-525 aims to restore the production of FVIII, reducing or eliminating the need for repeated infusions of FVIII throughout life.

The Alta trial is assessing the safety, tolerability, and effectiveness of a one-time infusion of four increasing doses of SB-525 — 9×10¹¹ vg/kg, 2×10¹² vg/kg, 1×10¹³ vg/kg, and 3×10¹³ vg/kg — in 11 men with severe hemophilia A. Patients’ average age is 30 (range 18-47).

Five adults were given the highest dose, while lower doses went to the other six, randomly assigned to two-person dosing groups.

Previous trial findings showed the therapy was well tolerated and led to a sustained increase in activity levels of FVIII. These levels were recorded in the longest treated high-dose patient out to 44 weeks, the point of cutoff data for these late 2019 results.

New data reaches up to 61 weeks post-dosing in this patient, and show that SB-525 at its highest dose (3×10¹³ vg/kg) continues to lead to durable increases in FVIII activity levels, with a median increase of 64.2%.

Treatment was again generally well tolerated, with no one in the high-dose group experiencing bleeding episodes, or requiring FVIII replacement therapy.

Treatment-related serious adverse events, including low blood pressure, fever, headache, and fast heart beat, were observed in one of the men in the high-dose group. All were fully resolved within 24 hours.

Four patients in this group were successfully treated with oral corticosteroids due to high levels of alanine aminotransferase (ALT), a liver enzyme that may indicate liver damage.

“These follow-up data indicate that treatment with giroctocogene fitelparvovec resulted in sustained factor levels up to 14 months following treatment and suggests the potential of this investigational gene therapy to alleviate the treatment burden of current hemophilia disease management,” Bettina M. Cockroft, MD, chief medical officer of Sangamo, said in the release.

Pfizer and Sangamo plan to present additional follow-up data from Alta’s high-dose group as soon as all five finish a full year of post-dosing examinations.

Based on Alta’s earlier findings, Pfizer launched a six-month lead-in study (NCT03587116) to support a pivotal Phase 3 clinical trial of SB-525 (NCT04370054), called AFFINE.

The lead-in trial, which is recruiting patients ages 18–64 worldwide, will assess the safety and efficacy of preventive replacement therapies in the usual care setting of hemophilia A and B. The hemophilia A group is reported to be fully enrolled.

The AFFINE trial, expected to open shortly, will enroll about 63 hemophilia A patients from among those taking part in the lead-in study, and follow these people for five years after treatment. As a pivotal study, its results may support a request for regulatory approval of SB-525.

“The Phase 3 lead in study is ongoing, and we look forward to dosing patients with this investigational gene therapy in the pivotal Phase 3 trial later this year,” Cheng said.