-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3461 Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Bleeding and Clotting, Biological therapies, adult, hemophilia, Clinical Research, Diseases, Gene Therapy, Therapies, Study Population, Human
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Adam Giermasz, MD, PhD1, Nathan Visweshwar, MD2*, Thomas J. Harrington, MD3*, Andrew D Leavitt, MD4, Barbara Konkle5, Jeremy Rupon, MD, PhD6, Gregory Di Russo, MD7*, Li-Jung Tseng, PhD, MBA8*, Maria de los Angeles Resa, PhD8*, Florence Ganne9*, Delphine Agathon, PhD9*, Frank Plonski, RN, MA6*, Didier Rouy, MD, PhD10*, Bettina M. Cockroft, MD, MBA11*, Annie Fang, MD, PhD8* and Steven Arkin, MD7

1University of California Davis, Sacramento, CA
2University of South Florida, Tampa, FL
3University of Miami Miller School of Medicine, Miami, FL
4University of California San Fransico, San Francisco, CA
5Bloodworks Northwest and the University of Washington, Seattle, WA
6Pfizer Inc., Collegeville, PA
7Pfizer Inc., Cambridge, MA
8Pfizer Inc., New York, NY
9Pfizer Inc., Paris, France
10Sangamo Therapeutics, Brisbane, CA
11Sangamo Therapeutics, Inc., Brisbane, CA

Introduction: Hemophilia A, a sex-linked (F8 gene) disorder of hemostasis, results in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)–mediated gene transfer enables the delivery of a modified functional F8 coding sequence to hepatocytes. This subsequently synthesizes FVIII at levels preventing unprovoked bleeding events in the absence of exogenous FVIII. We present updated results with nearly 3-year follow-up on all participants from Alta, an ongoing gene therapy study in patients with severe hemophilia A (FVIII activity <1%).

Methods: The phase 1/2 Alta study (NCT03061201) is a dose-ranging study of giroctocogene fitelparvovec (PF-07055480, previously called SB-525), which is a recombinant AAV serotype 6 vector encoding a modified B-domain–deleted F8 coding sequence. Giroctocogene fitelparvovec was infused into adults aged ≥18 years with severe hemophilia A in 4 cohorts (n=2 each) across 4 ascending doses: 9e11, 2e12, 1e13, and 3e13 vg/kg. The 3e13-vg/kg dose cohort was expanded with 3 additional participants. Key endpoints included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. We present data with nearly 3 years of follow-up (data cutoff date: May 20, 2022).

Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; White, 81.8%). As of the cutoff date, participants had been followed for 147 to 247 weeks and 2 had not completed 3 years (156 weeks) . The most common treatment-related adverse events (AEs) reported in the highest dose cohort (3e13-vg/kg) included elevated liver enzymes and infusion-related reactions (n/N [%]): increased alanine aminotransferase (ALT; 3/5 [60.0%]), increased aspartate aminotransferase (AST; 2/5 [40.0%]), pyrexia (3/5 [60.0%]), and tachycardia (2/5 [40.0%]). Treatment-related serious AEs were reported in 1 participant (in the 3e13-vg/kg cohort) who experienced hypotension and fever with onset ≈6 h after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge the next day. AEs (all causality) of ALT increases requiring ≥7 days of corticosteroids were observed in 4 of the 5 participants in the 3e13-vg/kg cohort: elevations in ALT were managed with a tapering course of corticosteroids (median duration: 56 days; range: 7–135 days), with maintenance of efficacious levels of FVIII activity, as evidenced by a lack of bleeding events around the time of corticosteroid treatment and minimal bleeding events afterwards. No participant in the 3e13-vg/kg cohort developed a confirmed inhibitor to FVIII, and there have been no thrombotic events or hepatoma detected. The three of the 5 participants in the 3e13-vg/kg cohort with available data through Week 156 had mean FVIII activity maintained in the mild to normal range (Table). Of the data available for the remaining 2 participants, 1 maintained FVIII activity levels in the mild range through Week 130 and 1 participant had FVIII activity levels below lower level of quantification (<3%) as measured with a chromogenic assay and 5.4% measured with a 1-stage assay at Week 130. In this cohort, the mean annualized total bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion) / (observation period in years)] was 0 for the first year postinfusion and 0.9 throughout the total duration of follow-up. In the 3e13-vg/kg cohort, 2 participants experienced an overall total of 12 bleeding events necessitating treatment with exogenous FVIII (participant 1 (n=1 event): circumstances of bleed unknown, event occurred in a target joint; participant 2 (n=11): 6 traumatic; 4 spontaneous; 1 unknown, no events occurred in a target joint). No participants in the 3e13-vg/kg cohort have resumed prophylaxis.

Conclusions: A single infusion of giroctocogene fitelparvovec gene therapy in participants with severe hemophilia A remains generally well tolerated over a period of nearly 3 years postinfusion, with associated increases in FVIII levels in the moderate to normal range, without sustained AEs and with minimal overall bleeding in the highest-dose cohort (3e13 vg/kg). The ongoing phase 3 study (NCT04370054) in a larger cohort will provide more long-term data to further characterize the safety and durability of giroctocogene fitelparvovec in patients with moderately severe to severe hemophilia A.

Disclosures: Giermasz: uniQure: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; ATHN: Consultancy, Research Funding; LFB: Other: co-investigator in research funded by ; Hema Biologics: Consultancy; Genentech: Consultancy, Speakers Bureau; Sangamo: Research Funding; Sanofi Genzyme: Consultancy, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau; Adrenas: Consultancy. Leavitt: BioMarin Pharmaceutical: Consultancy, Research Funding; Pfizer: Consultancy, Current equity holder in publicly-traded company, Research Funding; Sangamo Therapeutics: Research Funding. Konkle: BioMarin: Honoraria; Uniqure: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Baxalta: Research Funding; Sigilon: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; CSL Behring: Honoraria; Spark: Honoraria. Rupon: Pfizer: Current Employment, Current equity holder in publicly-traded company. Di Russo: Pfizer: Current Employment, Current equity holder in publicly-traded company. Tseng: Pfizer: Current Employment, Current equity holder in publicly-traded company. de los Angeles Resa: Pfizer: Current Employment, Current equity holder in publicly-traded company. Ganne: Pfizer: Current Employment, Current equity holder in publicly-traded company. Agathon: Pfizer: Current Employment, Current equity holder in publicly-traded company. Plonski: Pfizer: Current Employment, Current equity holder in publicly-traded company. Rouy: Sanofi: Current Employment; Sangamo: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Cockroft: Annexon Biosciences: Current equity holder in publicly-traded company; Sangamo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fang: Pfizer: Current Employment, Current equity holder in publicly-traded company. Arkin: Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: S Arkin's spouse is an employee of Pfizer Inc and is a current equity holder in the company.

OffLabel Disclosure: Hemophilia A, a sex-linked (F8 gene) disorder of hemostasis, results in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV) mediated gene transfer enables the delivery of a modified functional F8 coding sequence to hepatocytes. This subsequently synthesizes FVIII at levels preventing unprovoked bleeding events in the absence of exogenous FVIII. Giroctocogene fitelparvovec (PF-07055480, previously called SB-525) is a recombinant AAV serotype 6 vector encoding a modified B-domain deleted F8 coding sequence. Giroctocogene fitelparvovec is currently under investigation in a phase 1/2 study for the treatment of severe (factor VIII activity <1%) hemophilia A and a phase 3 study for the treatment of moderately severe to severe (factor VIII activity <=1%) hemophilia A.

*signifies non-member of ASH