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671 Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Editing, Therapy and Transfer II
Hematology Disease Topics & Pathways:
Hemophilia, Biological, Diseases, Bleeding and Clotting, Therapies, gene therapy
Monday, December 7, 2020: 11:30 AM

Andrew D. Leavitt, MD1, Barbara A. Konkle, MD2,3, Kimo Stine, MD4*, Nathan Visweshwar, MD5*, Thomas J. Harrington, MD6*, Adam Giermasz, MD, PhD7, Steven Arkin, MD8, Annie Fang, MD, PhD9*, Frank Plonski, RN, MA8*, Lynne Smith, MBA10*, Li-Jung Tseng, PhD, MBA9*, Gregory Di Russo, MD8*, Bettina M Cockroft, MD11*, Jeremy Rupon, MD10 and Didier Rouy, MD, PhD11*

1University of California, San Francisco, CA
2University of Washington, Seattle, WA
3University of Washington, Washington Center for Bleeding Disorders, Seattle, WA
4UAMS at Arkansas Children's Hospital, Little Rock, AR
5University of South Florida, Tampa, FL
6University of Miami Miller School of Medicine, Miami, FL
7University of California Davis, Sacramento, CA
8Pfizer Inc., Cambridge, MA
9Pfizer Inc., New York, NY
10Pfizer Inc., Collegeville, PA
11Sangamo Therapeutics, Brisbane, CA

Introduction: Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8 gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)–mediated gene transfer enables the delivery of a modified functional F8 gene to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. Updated results and follow-up from the Alta study, an ongoing gene therapy study in patients with severe hemophilia A, are presented.

Methods: The Alta study is a phase 1/2 dose-ranging, single-dose study of giroctocogene fitelparvovec (also known as SB-525 and PF-07055480), a recombinant AAV serotype 6 (rAAV6) vector encoding a modified F8 gene. Adults aged ≥18 years with severe hemophilia A were eligible for inclusion. Giroctocogene fitelparvovec was infused into patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13, and 3e13 vg/kg). The 3e13 vg/kg dose cohort was expanded with 3 additional patients. Key end points included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Presented data are from the ongoing Alta study (NCT#03061201; data cutoff date, 26 May 2020; database not locked; data reflect those at time of data cutoff, have not undergone standard quality checks, and may be subject to change).

Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; white, 81.8%). As of the cutoff date, patients have been followed for 35 to 144 weeks; one patient in the 1e13 vg/kg cohort discontinued from the study. Overall, the most commonly reported adverse events (AEs; n) included increased alanine aminotransferase (ALT; 8 [72.7%]), increased aspartate aminotransferase (AST; 5 [45.5%]), upper respiratory tract infection (4 [36.4%]), and pyrexia (4 [36.4%]). Treatment-related serious AEs were reported in 1 patient (in the 3e13 vg/kg cohort) who experienced hypotension and fever ≈6 hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge. In the 3 lower-dose cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients in the 3e13 vg/kg cohort, 4 had elevations in ALT that were managed with a tapering course of corticosteroids (ranging from 10–134 days) without loss of clinically relevant FVIII activity through 40 weeks, as evidenced by a lack of bleeding events before and after treatment with corticosteroids. Increases in FVIII activity from baseline were generally dose-dependent. Patients in the 3e13 vg/kg cohort achieved a mean normal-range of FVIII activity within 5 weeks post-infusion, with mean FVIII activity maintained through week 40, which is the last time point with data for all 5 patients in this cohort (Table). Following the initial prophylactic period of up to ≈3 weeks after giroctocogene fitelparvovec administration, no bleeding events occurred in any patient treated in the 3e13 vg/kg cohort. Use of FVIII replacement therapy ≥3 weeks after giroctocogene fitelparvovec administration was reported in 5/6 patients in the lower-dose cohorts (range: 9–115 infusions); none of the patients in the 3e13 vg/kg cohort required FVIII replacement beyond initial use of prophylactic factor for up to ≈3 weeks (prophylactic coverage stopped 3 weeks and 2 days after giroctocogene fitelparvovec administration in 1 patient in the 3e13 vg/kg cohort).

Conclusions: To date, a single infusion of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A 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 cohort (3e13 vg/kg). Additionally, patients treated in the highest-dose cohort achieved a mean FVIII activity in the normal range within 5 weeks, which was maintained through week 40. Data on all patients with more than 1 year of follow-up will also be presented. The study is ongoing, and these interim results support further development of giroctocogene fitelparvovec for the treatment of patients with severe hemophilia A.

Disclosures: Leavitt: BioMarin: Membership on an entity's Board of Directors or advisory committees. Konkle: Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sigilon: Consultancy, Research Funding; Roche: Consultancy. Stine: Biomarin: Consultancy; Applied Stem Cell Therapeutics: Consultancy. Visweshwar: Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Giermasz: uniQure: Consultancy, Research Funding; Sangamo Therapeutics: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau. Arkin: Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company. Fang: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Plonski: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Smith: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Tseng: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Di Russo: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Cockroft: Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics. Rupon: Pfizer Inc.: Current Employment, Other: own stock/options in the company. Rouy: Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics.

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