2020-10-08| Trials & Approvals

Pfizer, Sangamo Dose First Hemophilia A Patient in Phase 3 with Gene Therapy Candidate

by Rajaneesh K. Gopinath
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By Rajaneesh K. Gopinath, Ph.D.

Hemophilia A (HA) is predominantly an inherited bleeding disorder characterized by a genetic deficiency in an essential clotting factor VIII (fVIII). This rare hematological disorder is caused by a mutated F8 gene present in the X chromosome and is more commonly found in males than females. In healthy individuals, bleeding is controlled by activating a coagulation cascade, wherein fVIII brings together other factors, IXa, and X, to perform blood clotting. Due to low levels of these factors in HA patients, uncontrolled bleeding occurs either spontaneously or after injuries.

The standard treatment that exists for this condition is the replacement of fVIII with recombinant fVIII products. However, patients often develop inhibitory IgG antibodies called fVIII inhibitors that hamper therapy. Co-developed globally by Chugai, Roche, and Genentech, Hemlibra (Emicizumab) is an FDA-approved bispecific factor IXa- and X-directed antibody, designed to perform the function of fVIII and restore the blood clotting process.


Gene Therapy

As compared to standard therapies, gene therapies are promising as they could cure the disorder with a single drug administration. In principle, this strategy could deliver a functional copy of the defective gene into the cell effectively using adeno-associated viral (AAV) vectors. Currently, many biopharmaceutical companies are actively evaluating their gene therapy candidates in clinical trials. Among them, the most notable are candidates from BioMarin pharmaceuticals, Spark Therapeutics, and Sangamo Therapeutics.

In August this year, BioMarin’s Valoctocogene Roxaparvovec suffered a major blow when the FDA rejected the gene therapy candidate demanding more extensive data. On October 7th, Pfizer and Sangamo therapeutics announced that the first participant had been dosed in the Phase 3 AFFINE study, which evaluates their investigational gene therapy for hemophilia A patients. Giroctocogene fitelparvovec (SB-525) is a recombinant adeno-associated virus serotype 6 vector (AAV6) that encodes the cDNA for B domain deleted human FVIII. It has bagged the FDA’s Orphan Drug, Fast Track, and regenerative medicine advanced therapy (RMAT) designations.



Co-developed by Pfizer and Sangamo giroctocogene fitelparvovec is evaluated by a global Phase 3, open-label, multicenter, single-arm study in patients with moderately severe to severe hemophilia A. The primary endpoint of the AFFINE study is the improved effect of giroctocogene fitelparvovec on the annual bleed rate (ABR) through 12 months as compared to Factor VIII (FVIII) replacement therapy. Participants will be analyzed throughout the 5-year study period following the single infusion to further assess the durability and efficacy.

“The initiation of the pivotal Phase 3 dosing study of giroctocogene fitelparvovec is a significant achievement for Pfizer as we continue our longstanding commitment to improving care for the hemophilia community,” said Brenda Cooperstone, Chief Development Officer, Rare Disease, Pfizer Global Product Development. “Enrollment in the lead-in study is progressing well, and recruitment is on track for Phase 3. Given the Phase 1/2 study findings to date, we believe that giroctocogene fitelparvovec has the potential to sustain factor levels and reduce annual bleed rates, suggesting this one-time gene therapy could potentially transform the standard of care for eligible patients worldwide.”

Pfizer announced the updated Phase 1/2 data in the just-concluded investor event, demonstrating the high tolerability of giroctocogene fitelparvovec in patients. All five patients in the high dose cohort exhibited clinically meaningful FVIII activity levels with a geometric mean of ~71% when measured between the weeks of 9 and 52. There were no occurrences of bleeds or the need for prophylactic factor up to 85 weeks.

“We are encouraged that findings from the Phase 1/2 Alta study met two critically important measures for the hemophilia A patient community, showing clinically meaningful factor levels and reduced bleeds,” said Bettina M. Cockroft, M.D., M.B.A, Chief Medical Officer of Sangamo. “The progress of this program, the most advanced of our gene therapy product candidates, into Phase 3, is an important milestone for Sangamo, as it represents our first asset in a registrational trial.”


Collaboration Agreement

As per the agreement made in May 2017, the IND was transferred from Sangamo to Pfizer in December 2019, and the latter is now operationally and financially responsible for R&D, manufacturing, and commercialization of giroctocogene fitelparvovec. In addition to the $30 million milestone payment it has earned previously, Sangamo is eligible to receive total potential milestone payments of up to $300 million for the development and commercialization of giroctocogene fitelparvovec. It will also receive tiered royalties and up to 20% of annual net sales of giroctocogene fitelparvovec. It could also earn up to $175 million for additional gene therapy candidates developed under the collaboration.

Related Article: FDA Rejects BioMarin Pharmaceuticals’ Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A



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