A Trial to Learn if REGV131-LNP1265 is Safe and Works to Help the Body Make Clotting Factor in Pediatric, Adolescent and Adult Patients With Hemophilia B

Hemophilia B Clinical Trial

— BEYOND-9  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06379789
• Other study ID #: R131L1265-HEMB-2318
• Secondary ID: 2023-507260-40-0
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: July 25, 2024
• Est. completion date: July 3, 2032

Study information

• Verified date: April 2024
• Source: Regeneron Pharmaceuticals
• Contact: Clinical Trials Administrator
• Phone: 844-734-6643
• Email: clinicaltrials[@]regeneron.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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. 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 quality of life is affected by hemophilia B and if it changes after taking study drug - How joint health is affected by hemophilia B and if it changes after taking study drug - How often visits are required for the emergency room, urgent care center, physician's office, hospital, telephone or online are required as a result of bleeding events, and if the frequency changes after taking study drug - 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

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 <18 and ≥12 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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 130
• Est. completion date: July 3, 2032
• Est. primary completion date: July 3, 2032
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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 adeno-associated virus serotype 8 (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, 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

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia B

Intervention

Drug:
• REGV131
Single dose administered via intravenous (IV) infusion before LNP1265
• LNP1265
Single dose administered via IV infusion following REGV131

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Regeneron Pharmaceuticals	Intellia Therapeutics

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of treatment-emergent adverse events (TEAEs)	Part 1, Part 2B and Part 2C	Up to 104 Weeks
Primary	Severity of TEAEs	Part 1, Part 2B and Part 2C	Up to 104 Weeks
Primary	Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay	Part 1	At day 29
Primary	Change in FIX functional activity in plasma, measured using the chromogenic substrate assay	Part 2A, Part 2B and Part 2C	Baseline and at Week 26, after REGV131-LNP1265 dosing at the recommended dose for expansion (RDE)
Primary	Annualized bleeding rate (ABR) following sustained FIX functional activity among participants receiving the RDE	Part 2A, Part 2B and Part 2C	Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	Change in FIX functional activity in plasma measured using the chromogenic substrate assay	Part 1	Baseline and at Week 26, after REGV131-LNP1265 dosing at the RDE
Secondary	ABR following sustained FIX functional activity among participants receiving the RDE	Part 1	Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	FIX functional activity in plasma over time during the study period using the chromogenic substrate assay		Up to 104 Weeks
Secondary	Annualized treated bleeding rate (tABR) following sustained FIX functional activity, among participants receiving the RDE		Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	Annualized utilization (IU/kg/year) of FIX replacement therapy following sustained FIX functional activity among participants receiving the RDE		Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression		Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period		Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary	Concentrations of REGV131 components		Up to 29 Days
Secondary	Concentrations of LNP1265 components		Up to 29 Days
Secondary	Detection of antibodies to the F9 transgene product FIX protein		Up to 104 Weeks
Secondary	Detection of total binding antibodies (TAbs) to the adeno-associated virus 8 (AAV8) capsid proteins		Up to 104 Weeks
Secondary	Detection of neutralizing antibodies/transduction inhibitors (NAb/TI) to the adeno-associated virus 8 (AAV8) capsid proteins		Up to 104 Weeks
Secondary	Detection of antibodies to LNP1265		Up to 104 Weeks
Secondary	Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein		Up to 104 Weeks
Secondary	Detection of vector DNA in blood	Part 1	Up to 104 Weeks
Secondary	Detection of vector DNA in saliva	Part 1	Up to 104 Weeks
Secondary	Detection of vector DNA in nasal secretions	Part 1	Up to 104 Weeks
Secondary	Detection of vector DNA in semen	Part 1	Up to 104 Weeks
Secondary	Detection of vector DNA in urine	Part 1	Up to 104 Weeks
Secondary	Detection of vector DNA in feces	Part 1	Up to 104 Weeks
Secondary	Incidence of TEAEs	Part 2A	Up to 104 Weeks
Secondary	Severity of TEAEs	Part 2A	Up to 104 Weeks
Secondary	Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort	Part 2A	Up to 104 Weeks
Secondary	Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time	Part 2B and Part 2C	Up to 104 Weeks