A Study to Investigate the Safety and Effectiveness of a Coagulation Factor IX Gene Insertion Therapy (REGV131-LNP1265) in Pediatric, Adolescent and Adult Participants With Hemophilia B (BEYOND-9)

A Two-Part Open-Label Study of REGV131-LNP1265, A CRISPR/Cas9 Based Coagulation Factor IX Gene Insertion Therapy in Participants With Hemophilia B

Participants in this study have a genetic mutation, specifically in the coagulation (blood clotting) Factor 9 gene that causes severe or moderately severe hemophilia B. This study is researching an experimental gene insertion therapy (the adding of a gene into your DNA) called REGV131-LNP1265, also called the "study drug". Gene insertion therapy aims to teach the body how to produce clotting factor long-term, without the need for factor replacement therapy.

The main aim of this study is to find a safe and well-tolerated dose of the study drug by checking the side effects that may happen from taking it, both in the near term and over time.

The study is looking at several other research questions including:

• How much study drug is in the blood at different times
• Whether the body makes antibodies against parts of the study drug, which could make the drug less effective or could lead to side effects. Antibodies are proteins produced by the body's immune system in response to a foreign substance
• Whether the body makes antibodies against the clotting factor replacement therapy
• How often factor replacement therapy is needed, both on a regular basis for prevention of bleeding, and as needed to treat bleeding events (and it if changes after taking study drug)
• Whether there is a difference in 2 different methods for measuring Factor 9 activity in the blood

Study Overview

• Status: Recruiting
• Conditions: Hemophilia B
• Intervention / Treatment: Drug: REGV131; Drug: LNP1265

Detailed Description

The study will be conducted with a 2-part adaptive design, with enrollment of patients into sequential parts of the study.

Part 1: Dose Escalation and Dose Confirmation in adult patients ≥18 years of age

• Dose Escalation Cohorts to determine the Recommended Dose for Expansion (RDE) of REGV131-LNP1265
• Dose Confirmation Cohort to gain further confidence in safety, tolerability, and Coagulation Factor IX (FIX) functional activity data at the RDE

Part 2: Dose Expansion at the RDE

• Part 2A: Adult patients ≥18 years of age: RDE of REGV131-LNP1265, as determined in Part 1
• Part 2B: Adolescent patients ≥12 to <18 years of age will be administered weight-adjusted RDE
• Part 2C: Adolescent and Pediatric patients ≥2 to <12 years may be enrolled in an age staggered sequential manner; first participants aged ≥6 to <12 years and then participants ≥2 to <6 years of age and will receive a weight-adjusted RDE

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Royal Prince Alfred Hospital, Haemophilia Treatment Centre
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Recruiting
      • University of Alberta Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Recruiting
      • McMaster University Medical Centre - Hamilton Health Sciences
  • Quebec
    • Montreal, Quebec, Canada, H4J 3A1
      • Recruiting
      • McGill University Health Center (MUHC)
• France
  • Lyon
    • Bron, Lyon, France, 69677
      • Recruiting
      • Hospices Civils de Lyon
  • Nord
    • Lille, Nord, France, 59037
      • Recruiting
      • Hemostase Clinique, Institut Coeur Poumon
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Recruiting
      • Hôpital Necker
• Germany
  • Hamburg, Germany, 20246
    • Recruiting
    • University Hospital Hamburg Eppendorf
  • Hesse
    • Frankfurt am Main, Hesse, Germany, 60590
      • Recruiting
      • University Hospital Frankfurt
• Italy
  • Vicenza, Italy, 36100
    • Recruiting
    • Ospedale San Bortolo
  • Firenze
    • Florence, Firenze, Italy, 50134
      • Recruiting
      • Careggi University Hospital
  • Lombardy
    • Milan, Lombardy, Italy, 20122
      • Recruiting
      • Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca Granda Ospedale Maggiore Policlinico
    • Rozzano, Lombardy, Italy, 20089
      • Recruiting
      • Irccs Humanitas Research Hospital
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28046
    • Recruiting
    • Hospital Universitario La Paz
  • Valencia, Spain, 46026
    • Recruiting
    • Haemostasis and Thrombosis Unit, Hospital La Fe
  • Zaragoza, Spain, 50009
    • Recruiting
    • Hospital Universitario Miguel Servet
  • Andalusia
    • Seville, Andalusia, Spain, 41013
      • Recruiting
      • Hospital Universitario Virgen del Rocio
  • Galicia
    • A Coruña, Galicia, Spain, 15006
      • Recruiting
      • Complejo Hospitalario Universitario de A Coruña (Edificio Teresa Herrera-Materno Infantil)
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Recruiting
      • Hospital Clinico Universitario Virgen de la Arrixaca
  • Principality of Asturias
    • Oviedo, Principality of Asturias, Spain, 33011
      • Recruiting
      • Hospital Universitario Central de Asturias
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrooke's Hospital, Cambridge University Hospitals NHS FT
  • London, United Kingdom, NW3 2QG
    • Recruiting
    • Royal Free London NHS Foundation Trust
  • London, United Kingdom, SE1 7EH
    • Recruiting
    • St. Thomas' Hospital
  • London, United Kingdom, W12 0HS
    • Recruiting
    • Hammersmith Hospital Comprehensive Care Centre
  • London, United Kingdom, E1 2ES
    • Recruiting
    • Pathology and Pharmacy Building, The Royal London Hospital
  • Scotland
    • Glasgow, Scotland, United Kingdom, G31 2ER
      • Recruiting
      • Glasgow Royal Infirmary - Clinical Research Facility
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Recruiting
      • Queen Elizabeth Hospital Birmingham
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90024
      • Recruiting
      • David Geffen School of Medicine at UCLA
    • Los Angeles, California, United States, 90007
      • Recruiting
      • Orthopaedic Hemophilia Treatment Center
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California Davis
    • San Francisco, California, United States, 94143
      • Recruiting
      • University California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Hemophilia and Thrombosis Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale HTC
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Recruiting
      • Indiana Hemophilia and Thrombosis Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Recruiting
      • Tulane University School of Medicine, Louisiana Center for Bleeding and Clotting Disorders
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia (CHOP)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Confirmed diagnosis of severe or moderately severe hemophilia B with medical history of FIX functional activity (≤2% or <0.02 IU/mL) or documented genotype known to produce severe hemophilia B
2. Currently taking FIX prophylaxis and previous experience with FIX therapy, as defined in the protocol
3. Participation in the lead-in period of this interventional study OR a separate lead-in study (R0000-HEMB-2187 [NCT05568459]) for at least 6 months for ABR data while taking FIX prophylaxis, as defined in the protocol

Key Exclusion Criteria:

1. History of FIX inhibitor (clinical or laboratory-based assessment) on 2 or more occasions
2. Bethesda inhibitor titer greater than the Upper Limit of Normal (ULN) at screening
3. Detectable pre-existing antibodies to the AAV8 capsid; as measured by Enzyme-Linked ImmunoSorbent Assay (ELISA) at prescreening (or final lead-in visit, if applicable)
4. Any significant underlying liver disease such as: cholestatic liver disease, liver cirrhosis, portal hypertension, splenomegaly, hepatic encephalopathy
5. Evidence of advanced liver fibrosis or significant fatty liver, as defined in the protocol
6. Evidence of cirrhosis and/or portal hypertension as assessed by abdominal ultrasound at screening or measured within 6 months prior to the screening visit
7. History of arterial or venous thrombo-embolic events, as defined in the protocol
8. History of hypersensitivity to corticosteroids or known medical condition that requires chronic administration of corticosteroids
9. Previously received any AAV gene-based therapy or intends to receive approved or investigational AAV-based gene therapy other than REGV131-LNP1265 during the study period

NOTE: Other Inclusion/Exclusion Protocol Defined Criteria Apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Cohort 1 Dose Escalation for RDE; Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 1: Cohort 2 Dose Escalation for RDE; Dose 2 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 1: Cohort 3 Dose Escalation for RDE; Dose 3 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 1: Cohort 4 Dose Escalation for RDE; Dose 4 of ascending dose level cohorts to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 2: Dose Expansion A; Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 2: Dose Expansion B; Participants ≥12 to <18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131
Experimental: Part 2: Dose Expansion C; Participants ≥2 to <12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1	Drug: REGV131; Administered per the protocol before LNP1265; Drug: LNP1265; Administered per the protocol following REGV131

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Treatment-Emergent Adverse Events (TEAEs)	Part 1, 2B, and 2C	Up to 2 Years
Severity of TEAEs	Part 1, 2B, and 2C	Up to 2 Years
Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay	Part 1	Up to 2 Years
Change in FIX functional activity in plasma, measured using the chromogenic substrate assay	Part 2A, 2B, and 2C	Up to 2 Years
Annualized Bleeding Rate (ABR) following sustained FIX functional activity among participants receiving the RDE	Part 2A, 2B, and 2C	Up to 2 Years
Occurrence of Serious Adverse Events (SAEs)	LTFU Period for Part 1, 2A, 2B, and 2C	Through Long Term Follow Up (LTFU), Up to 15 Years
Severity of SAEs	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Occurrence of Adverse Event of Special Interests (AESIs)	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Severity of AESIs	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Occurrence of clinically meaningful Adverse Events (AEs)	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Severity of clinically meaningful AEs	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FIX functional activity in plasma measured using the chromogenic substrate assay	Part 1	Up to 2 Years
ABR following sustained FIX functional activity among participants receiving the RDE	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
FIX functional activity in plasma over time during the study period using the chromogenic substrate assay	LTFU Period for Part 1, 2A, 2B, and 2C	Through LTFU, Up to 10 Years
Annualized treated Bleeding Rate (tABR) following sustained FIX functional activity, among participants receiving the RDE	Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 years
Annualized utilization (IU/kg/year) of FIX replacement therapy following sustained FIX functional activity among participants receiving the RDE	Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression	Part 1, 2A, 2B, and 2C	Up to 2 Years
Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period	Part 1, 2A, 2B, and 2C	Up to 2 Years
Concentrations of REGV131 components	Part 1, 2A, 2B, and 2C	Up to 2 Years
Concentrations of LNP1265 components	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of antibodies to the Coagulation Factor IX gene (F9) transgene product FIX protein	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of Total binding Antibodies (TAbs) to the Adeno-Associated Virus 8 (AAV8) capsid proteins	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of Neutralizing Antibodies/Transduction Inhibitors (NAb/TI) to the AAV8 capsid proteins	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of antibodies to LNP1265	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein	Part 1, 2A, 2B, and 2C	Up to 2 Years
Detection of vector DeoxyriboNucleic Acid (DNA) in blood	Part 1	Up to 2 Years
Detection of vector DNA in saliva	Part 1	Up to 2 Years
Detection of vector DNA in nasal secretions	Part 1	Up to 2 Years
Detection of vector DNA in semen	Part 1	Up to 2 Years
Detection of vector DNA in urine	Part 1	Up to 2 Years
Detection of vector DNA in feces	Part 1	Up to 2 Years
Occurrence of TEAEs	Part 2A	Up to 2 Years
Severity of TEAEs	Part 2A	Up to 2 Years
Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort	Part 2A, 2B, and 2C	Up to 2 Years
Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time	Part 2B and 2C	Up to 2 Years
Proportion of participants with zero spontaneous bleeding events following sustained FIX functional activity among those receiving RDE	Part 1, 2A, 2B, and 2C	Through LTFU, Up to 15 Years
Proportion of participants not requiring FIX replacement therapy following sustained FIX functional activity among those receiving RDE	Part 1, 2A, 2B, and 2C	Throught LTFU, Up to 15 Years

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Collaborators: Intellia Therapeutics
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Information Website

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2024
• Primary Completion (Estimated): August 14, 2034
• Study Completion (Estimated): August 14, 2047

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 18, 2024
• First Posted (Actual): April 23, 2024

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Severe and moderately severe congenital hemophilia B; FIX functional activity
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Genetic Diseases, X-Linked; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Hemophilia B
• Other Study ID Numbers: R131L1265-HEMB-2318; 2023-507260-40-00 (Ctis: EU CTR Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing.

IPD Sharing Time Frame

When Regeneron has:

• received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• the legal authority to share the data, and
• ensured the ability to protect participant privacy

• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No