High Dose of Gene Therapy SB-525 Raises FVIII Levels, Prevents Bleeds, Alta Trial Data Show

When administered at the highest dose, the investigational gene therapy SB-525 (giroctocogene fitelparvovec) prevented bleeds and the use of clotting factor VIII (FVIII) in men with severe hemophilia A, according to follow-up data from the Alta Phase 1/2 clinical trial.

All five men given the highest dose — 3×10¹³ vector genomes (vg)/kg — also showed a fast and sustained increase in FVIII activity.

The findings, “Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia,” were presented at the 62nd Annual Meeting & Exposition of the American Society of Hematology, held virtually Dec. 5–8.

“We continue to be encouraged by the findings from this Phase 1/2 study, which now include durable factor VIII expression through one year of follow-up, and we look forward to continuing to follow these patients,” Seng Cheng, PhD, senior vice president and chief scientific officer of Pfizer’s rare disease research unit, said in a press release.

Pfizer is advancing SB-525 in collaboration with Sangamo Therapeutics.

“With the first patient dosed in the Phase 3 AFFINE study in October 2020, we are on track for a readout from this pivotal Phase 3 trial in 2022, which will allow us to better assess the potential of our gene therapy across a larger sample size,” Cheng added. AFFINE is still recruiting patients in the U.S.; more information is available here.

Andrew D. Leavitt, MD, an investigator of the Alta and AFFINE studies, said “it is promising to see how quickly all five patients in the 3 x 10¹³ vg/kg [group] achieved steady-state FVIII activity levels, with no bleeding events and no factor usage within the first year and only one target joint bleed after 52 weeks.”

“Our focus now is to confirm these exciting findings in the Phase 3 study, and to gather long-term data,” from all SB-525-treated patients, added Leavitt, who also is a professor of medicine at the University of California San Francisco.

SB-525 uses a modified and harmless version of an adeno-associated virus 6 (AAV6) to deliver a functional copy of the F8 gene — which is mutated in people with hemophilia A, impairing FVIII production — to liver cells, where clotting factors are produced.

Given through a single infusion directly into the bloodstream, the therapy is expected to restore FVIII production, reducing or eliminating the need for a lifetime of FVIII replacement therapies.

SB-525 received fast track, orphan drug, and regenerative medicine advanced therapy designations from the U.S. Food and Drug Administration, as well as orphan medicinal product designation from the European Medicines Agency.

These designations are meant to speed the therapy’s clinical development and review by providing regulatory support and financial benefits, as well as a marketing exclusivity period of seven years in the U.S. and 10 years in Europe upon approval.

The ongoing Alta trial (NCT03061201) is evaluating the five-year safety, tolerability, and effectiveness of four different doses of SB-525 — 9×10¹¹ vg/kg, 2×10¹² vg/kg, 1×10¹³ vg/kg, and 3×10¹³ vg/kg — in 11 adult men with severe hemophilia A.

Patients’ mean age at study start was 30.3 years (range, 19–47). Two men have been dosed per group, except for the highest dose group, which was expanded to five patients.

Previous six-month data showed the therapy was generally well-tolerated and resulted in dose-dependent, sustained raises in FVIII activity levels. Earlier this year, updated results from the highest dose group demonstrated durable FVIII increases in all five men, with no bleeding episodes or the need for replacement therapy.

Newly presented data, at a data cut-off date of Aug. 31, cover one to three years of follow-up after the single SB-525 dosing (except for one participant in the 1×10¹³ vg/kg group who discontinued the study).

Results showed that all men receiving the highest dose achieved steady-state FVIII activity by week nine, which was maintained through at least one year (median activity of 56.9%). The therapy prevented bleeds and the need for FVIII usage in all men during the first year. One joint bleed requiring FVIII therapy occurred in the second year.

In addition, SB-525 continued to be generally safe. A total of 26 treatment-related adverse events (side effects) occurred in six men, with the most common being elevated liver enzymes — a known side effect of gene therapy that can indicate liver damage. All episodes of liver enzyme raises were fully resolved with oral corticosteroids (an immunosuppressive treatment).

SB-525-related serious adverse events, including low blood pressure and fever, were reported in one man in the highest dose group immediately after dosing and fully resolved within nearly 12 hours.

At the last assessment, no participant was on corticosteroids, no corticosteroid use had been initiated after one year, and no man had experienced a COVID-19-related adverse event or developed FVIII inhibitors (neutralizing antibodies).

These findings highlighted that a single infusion of SB-525 “resulted in dose-dependent and sustained increases in FVIII levels without administration of exogenous FVIII, bleeding episodes or sustained adverse events in the highest-dose [group],” the researchers wrote in the abstract.

Bettina Cockroft, MD, Sangamo’s chief medical officer, said “these latest results demonstrate that this gene therapy may bring clinical benefit to patients and has the potential to serve as an alternative to the burdensome standard of care for patients with hemophilia A.

“We look forward to continuing to support our collaboration partners at Pfizer as they conduct the Phase 3 AFFINE study and assess the full potential of this promising therapy,” Cockroft added.

Pfizer and Sangamo plan to present more results from the Alta study when all men in the highest dose group have at least two years of follow-up data.