Pfizer and Sangamo today reported updated Phase I/II results showing that their severe hemophilia A gene therapy candidate giroctocogene fitelparvovec (SB-525 or PF-07055480) showed sustained factor VIII (FVIII) activity levels, no bleeding events, and no required FVIII infusions in all five patients within one of the study’s four dose cohorts.

The five all received the 3e13 vg/kg dose of giroctocogene fitelparvovec and underwent follow-up assessments over periods that varied per patient, stretching up to 61 weeks for the longest-treated participant. Their median activity level was 64.2% via chromogenic assay (patient-level geometric means after week 9 post-infusion)

The five were among 11 patients participating in the Alta study, an open-label, dose-ranging, multicenter clinical trial designed to assess the safety and tolerability of giroctocogene fitelparvovec in patients with severe hemophilia A. The mean age of the 11 patients assessed across the four dose cohorts was 30 years, with their ages ranging from 18–47 years.

Data from the trial is set to be presented today as a late-breaking oral abstract at the World Federation of Hemophilia 2020 World Congress, a virtual event being held through Friday.

“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,” Sangamo chief medical officer Bettina M. Cockroft, MD, said in a statement.

Giroctocogene fitelparvovec consists of a recombinant adeno-associated virus serotype 6 vector (AAV6) encoding the complementary deoxyribonucleic acid for B domain deleted human FVIII. Giroctocogene fitelparvovec has received the FDA’s Orphan Drug, Fast Track, and regenerative medicine advanced therapy (RMAT) designation, while the European Medicines Agency has granted its Orphan Medicinal Product designation to the gene therapy candidate.

The giroctocogene fitelparvovec expression cassette was designed for optimal liver-specific expression of FVIII protein and supports production of high yields of the vector. The giroctocogene fitelparvovec transcriptional cassette incorporates multi-factorial modifications to the liver-specific promoter module, FVIII transgene, synthetic polyadenylation signal, and vector backbone sequence.

“A new approach”

“The current standard of care for severe hemophilia A requires regular infusions to replace missing Factor VIII,” Cockcroft added. “Gene therapy, on the other hand, offers a new approach with the potential to provide a one-time treatment that would enable patients to produce the missing factor on their own.”

Pfizer and Sangamo began partnering on the gene therapy in 2017. In December 2019, Sangamo completed its transfer of the manufacturing technology and its IND application for giroctocogene fitelparvovec to Pfizer, earning a $25 million milestone payment. Sangamo is eligible to receive total potential milestone payments of up to $300 million for the development and commercialization of giroctocogene fitelparvovec, and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration.

Sangamo could also receive tiered royalties starting in the low teens and up to 20% of annual net sales of the gene therapy candidate.

“We look at hemophilia A and we see an area that’s large-scale, it’s commercially focused, it’s going to need reimbursement discussions, it’s competitive. And all of those things, we felt, would be better managed by a company like Pfizer,” Sangamo CEO Sandy Macrae, MBChB, PhD, told GEN Edge in January, explaining his company’s decision to partner out the gene therapy to Pfizer.

The data presentation comes six months after Pfizer and Sangamo presented data at the 61st Annual Meeting of the American Society of Hematology (ASH) in December 2019, showing that giroctocogene fitelparvovec was generally well tolerated and resulted in sustained FVIII levels up to 44 weeks, the extent of follow-up for the longest-treated patient in the 3e13 vg/kg dose cohort at that time.

Also reported at the time, one patient in the 3e13 vg/kg dose cohort had a treatment-related serious adverse event of hypotension (grade 3) and fever (grade 2), with symptoms of headache and tachycardia, which occurred six hours post-infusion with giroctocogene fitelparvovec, and which fully resolved within 24 hours. No other treatment-related serious adverse events were reported.

Data presented at ASH came from all 11 patients in the Alta study, who were treated across four ascending dose cohorts: 9e11 vg/kg (2 patients), 2e12 vg/kg (2 patients), 1e13 vg/kg (2 patients), and 3e13 vg/kg (5 patients).

“At the high dose, all five patients got into the normal reference range within 5–7 weeks of therapy. All five patients did not get any bleeds beyond the three weeks of the protocol where factor use is still allowed,” Adrian Woolfson, BM BCh PhD, Sangamo’s executive vice president of research and development, told GEN Edge in January. “The patients treated in the high-dose cohort were ethnically diverse, and all of them were quite heavily factor therapy replacement dependent when they came into the study. We also saw a really nice dose response in the study.”

Among those five patients in the 3e13 vg/kg high dose cohort, four received corticosteroids for liver enzyme (alanine aminotransferase, ALT) elevations. Three patients had subsequent ALT elevations that responded to corticosteroids. All episodes of ALT elevations fully resolved with oral corticosteroids, Pfizer and Sangamo said.

“We are encouraged”

“We are excited that these data affirm previous findings from this Phase I/II study, and that all five patients have sustained levels of factor VIII activity with no bleeding events or use of factor replacement therapy. We are encouraged by the potential of giroctocogene fitelparvovec to demonstrate longer-term durability, an important element for patients living with severe hemophilia A,” said Seng Cheng, senior vice president and CSO of Pfizer’s Rare Disease Research Unit.

Pfizer and Sangamo plan to present further follow-up data from the Alta study when all five patients in the 3e13 vg/kg dose cohort have been followed for at least one year.

The companies have also launched an ongoing Phase III “lead-in” study (NCT03587116), data from which is expected to provide a baseline for patients who are subsequently enrolled in the pivotal Phase III study (NCT04370054), which has yet to recruit patients.

The primary endpoint of the pivotal study is annualized bleeding rate (ABR) over 12 months, and secondary endpoints include steady state FVIII activity levels, annualized infusion rate of exogenous FVIII activity, annualized FVIII consumption, ABR and total ABR of specific type by cause and by location, and change in joint health using Hemophilia Joint Health Score, over 12 months.

“We look forward to dosing patients with this investigational gene therapy in the pivotal Phase III trial later this year,” Cheng added.

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