OC 02.4 - Long-Term Follow-Up of Participants in the Phase I/II Trial of Dirloctocogene Samoparvovec (SPK-8011): Durable FVIII Expression and Clinically Meaningful Reduction of Bleeding

Saturday, June 22, 2024

13:45 – 14:00 ICT

Room: Ballroom B2

Co-Author(s)

Lindsey A. George

Director of Clinical In Vivo Gene Therapy
Division of Hematology, Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States

Presenting Author(s)

Stacy E. Croteau, MD, MMS

Boston Children’s Hospital, Massachusetts, United States

Co-Author(s)

TC

Tiffany Chang

Senior Medical Director
Spark Therapeutics, Inc.
Philadelphia, Pennsylvania, United States
ME

M. Elaine Eyster

Director of the Hemophilia and Thrombosis Center and Professor of Medicine and Pathology
Department of Medicine, Division of Blood and Vascular Disorders, Penn State Health Milton S. Hershey Medical Center
Herhsey, Pennsylvania, United States
Huyen Tran, MBBS (Hons), MClinEpi, FRACP, FRCPA

Head of the Thrombosis & Hemostasis Unit and Director of the Hemophilia Treatment Centre
Ronald Sawyers Haemophilia Centre, The Alfred Hospital, Melbourne, Victoria, Australia
Melbourne, Victoria, Australia
Margaret V. Ragni

Professor of Medicine and Clinical and Translational Science
Department of Medicine, University of Pittsburgh
Pittsburgh, Pennsylvania, United States
SS

Spencer Sullivan

President, CEO and Hematologist
Mississippi Center for Advanced Medicine
Madison, Mississippi, United States
JR

John E. J. Rasko

Head of Department
Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
JM

Jill Moormeier

Professor and Chair
Department of Medicine, UMKC School of Medicine
Kansas City, Missouri, United States
Pantep Angchaisuksiri

Professor of Medicine and Chief of the Haemostasis and Thrombosis Unit
Department of Medicine, Ramathibodi Hospital, Mahidol University
Bangkok, Krung Thep, Thailand
Jerome Teitel

Medical Director of the Haemophilia Treatment Programme and Professor of Medicine
St Michael's Hospital Haemophilia Treatment Centre, University of Toronto
Tortonto, Ontario, Canada
GK

Gili Kenet

CONSULTANT PAEDIATRIC HAEMATOLOGIST
National Hemophilia Center Sheba Medical center, Tel Hashomer & Amalia Biron Research Institute of Thrombosis & Hemostasis, Tel Aviv University, Israel,
Tel Aviv, Tel Aviv, Israel
Tung Wynn, MD

Clinical Associate Professor
Division of Hematology and Oncology, Department of Pediatrics, University of Florida
Gainesville, Florida, United States
Benjamin Samelson-Jones

Assistant Professor of Pediatrics
Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
SJ

Savina Jaeger

Head of Biostatistics
Spark Therapeutics, Inc.
Philadelphia, Pennsylvania, United States
JR

Julia Ramos

Medical Director
Spark Therapeutics, Inc.
Philadelphia, Pennsylvania, United States
FM

Federico Mingozzi

Chief Science and Technology Officer
Spark Therapeutics, Inc.
Philadelphia, Pennsylvania, United States
GL

Gallia Levy

Chief Medical and Product Strategy Officer
Spark Therapeutics, Inc.
Philadelphia, Pennsylvania, United States

Background: Dirloctocogene samoparvovec (SPK-8011) is an investigational adeno-associated viral vector gene therapy for hemophilia A (HA). Previous Phase I/II trial (NCT03003533/NCT03432520) interim analysis indicated dirloctocogene samoparvovec was well tolerated; participants had sustained factor (F)VIII activity (cut-off: June 30, 2022; Croteau, ASH 2022).

Aims: Describe long-term safety and efficacy of dirloctocogene samoparvovec and novel non-steroid immune prophylaxis (tocilizumab, mycophenolate mofetil) use in the Phase I/II trial.

Methods: In this single-arm trial, adult males with moderate–severe HA received dirloctocogene samoparvovec (George, NEJM 2021).

Results: At cut-off (October 10, 2023), 25 participants were enrolled across dosing cohorts of 5×10^11 vg/kg (n=2), 1×10^12 vg/kg (n=3), 1.5×10^12 vg/kg (n=11), or 2×10^12 vg/kg (n=9). Median time since dosing was 220.6 weeks (range: 45.3–340.3). Sixty-six treatment-related adverse events occurred: 37 immunomodulation-related, 29 vector-related, including one serious Grade 2 alanine transaminase (ALT) elevation with elective hospitalization for intravenous corticosteroids. No FVIII inhibitors or thrombotic events occurred. In Year 1, 16 participants had transient ALT rise ≥1.5 fold over baseline; median time until rise was 40.5 days (Q1–Q3: 20.5–71.5).
FVIII expression was sustained in most participants (Figures). Three participants returned to prophylaxis. Median annualized bleed rate (ABR) post dirloctocogene samoparvovec administration was 0.2 (Q1–Q3: 0.0–3.2) vs historical ABR 5.0 (1.0–11.0) on prior prophylaxis (n=20), and 0.3 (0.2–0.5) vs historical ABR 30.0 (15.0–36.0) for on-demand treatment (n=5). Median annualized FVIII infusion rate (AIR) was 1.5 (Q1–Q3: 0.0–5.6) post vector administration vs historical AIR on prophylaxis 104.0 (57.5–156.0) and 0.6 (0.3–1.0) vs historical AIR 33.0 (30.0–36.0) for on-demand treatment.

Conclusion(s): Up to 7 years post dirloctocogene samoparvovec administration, data indicate that investigational gene therapy was well tolerated, with durable FVIII expression and clinically meaningful ABR and AIR reductions. Non-steroid immune prophylaxis did not abrogate use of steroids to treat presumed immune response.