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)

Regeneron Pharmaceuticals

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Hemophilia B

Treatments: Drug: LNP1265; Drug: REGV131

Study type: Interventional

Funder types: Industry

Identifiers

NCT06379789

R131L1265-HEMB-2318

2023-507260-40-00 (Registry Identifier)

Details and patient eligibility

About

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

Full 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

Enrollment: 130 estimated patients

Sex: Male

Ages: 2+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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130 participants in 7 patient groups

Part 1: Cohort 1 Dose Escalation for RDE

Experimental group

Description:

Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE

Treatment:

Drug: REGV131

Drug: LNP1265

Part 1: Cohort 2 Dose Escalation for RDE

Experimental group

Description:

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

Treatment:

Drug: REGV131

Drug: LNP1265

Part 1: Cohort 3 Dose Escalation for RDE

Experimental group

Description:

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

Treatment:

Drug: REGV131

Drug: LNP1265

Part 1: Cohort 4 Dose Escalation for RDE

Experimental group

Description:

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

Treatment:

Drug: REGV131

Drug: LNP1265

Part 2: Dose Expansion A

Experimental group

Description:

Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1

Treatment:

Drug: REGV131

Drug: LNP1265

Part 2: Dose Expansion B

Experimental group

Description:

Participants ≥12 to \<18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1

Treatment:

Drug: REGV131

Drug: LNP1265

Part 2: Dose Expansion C

Experimental group

Description:

Participants ≥2 to \<12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1

Treatment:

Drug: REGV131

Drug: LNP1265