PB0235 - Trial-in-progress: A two-part open-label study of an in vivo CRISPR/Cas9-based coagulation factor IX targeted gene insertion therapy (REGV131-LNP1265), in participants with hemophilia B (BEYOND-9)

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

MO

Meagan P. O'Brien

Senior Medical Director
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States

Co-Author(s)

Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan
Ann Arbor, Michigan, United States
Wolfgang Miesbach, MD

Professor and Head of Coagulation Disorders and Comprehensive Care Centre
University Hospital Frankfurt, Frankfurt, Germany
Frankfurt, Hessen, Germany
Lindsey A. George

Director of Clinical In Vivo Gene Therapy
Division of Hematology, Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Glenn F. Pierce, MD PhD

World Federation of Hemophilia/Consultant
World Federation of Hemophilia/Consultant
La Jolla, California, United States
LS

Leah Sabin

Executive Director, Regeneron Genetic Medicines
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States
DC

Dan Chalothorn

Director in Cardiovascular and Renal Research
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States
KC

Kuo-Chen Chan

Associate Director, Biostatistics, Global Development
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States
NS

Neena Sarkar

Senior Director
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States
RR

Rickey Reinhardt

Consultant
Intellia Therapeutics, Inc.
Cambridge, Massachusetts, United States
AH

Alexandra Haagensen

Senior Medical Director
Intellia Therapeutics, Inc.
Cambridge, Massachusetts, United States
LW

Liron Walsh

Vice President and Head of Development - In Vivo Programs
Intellia Therapeutics, Inc.
Cambridge, Massachusetts, United States
PR

Petra Rietschel

Executive Medical Director Translational & Clinical Sciences Hematology
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States
DG

David E. Gutstein

Vice President, Strategic Program Direction – Hematology Translational & Clinical Sciences
Regeneron Pharmaceuticals, Inc.
Tarrytown, New York, United States

Background: While recombinant adeno-associated viral vector episomal gene therapy to treat hemophilia B may eliminate the need for regular exogenous coagulation factor IX (FIX) concentrate administration, the long-term efficacy and safety remains undemonstrated. Furthermore, this strategy may be unsuitable to address the significant unmet need in pediatric patients.

Alternatives are being explored, including targeted insertion of a functional F9 gene into the albumin locus in hepatocytes to restore FIX activity. REGV131-LNP1265 is an in vivo CRISPR/Cas9-based targeted gene insertion therapy being investigated for hemophilia B in adults, and in the future also in children. Gene insertion is intended to mediate durable expression in liver growth states.

Aims: Identify the recommended dose for expansion (RDE) of a single intravenous administration of REGV131-LNP1265, based on its safety and effects on plasma FIX activity among individuals with hemophilia B. Confirm safety and efficacy in dose confirmation and expansion cohorts.

Methods: This phase 1/2 open-label study (BEYOND-9; R131L1265-HEMB-2318) has a 2-part adaptive design, with sequential progression from Part 1 to Part 2 based on cumulative data review. Part 1 (dose escalation/confirmation) will evaluate safety and plasma FIX activity to establish the RDE, and Part 2A (dose expansion) will assess outcomes following RDE administration. Parts 1 and 2A will enroll ≤70 participants aged ≥18 years with severe or moderately severe hemophilia B, who are currently receiving FIX prophylaxis. Participants will receive single-dose REGV131-LNP1265 after a 6-month to 2-year lead-in period, with a 2-year post-treatment follow-up (Figure 1). All participants will be enrolled in a long-term follow-up study.

Results: Study endpoints are outlined in Table 1.

Conclusion(s): Enrollment will commence in July 2024 with consent obtained from all participants. Following adult data review, pediatric expansion cohorts may open. The study will undergo ethics review per International Council for Harmonisation guidelines. This study is funded by Regeneron Pharmaceuticals Inc. and Intellia Therapeutics.