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
- Registration Number
- NCT06379789
- Lead Sponsor
- Regeneron Pharmaceuticals
- Brief 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
- 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 \<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 & Eligibility
- Status
- RECRUITING
- Sex
- Male
- Target Recruitment
- 130
- 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
- Currently taking FIX prophylaxis and previous experience with FIX therapy, as defined in the protocol
- 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
- History of FIX inhibitor (clinical or laboratory-based assessment) on 2 or more occasions
- Bethesda inhibitor titer greater than the upper limit of normal (ULN) at screening
- 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).
- Any significant underlying liver disease such as: cholestatic liver disease, liver cirrhosis, portal hypertension, splenomegaly, hepatic encephalopathy
- Evidence of advanced liver fibrosis, as defined in the protocol
- Evidence of cirrhosis and/or portal hypertension as assessed by abdominal ultrasound at screening or measured within 6 months prior to the screening visit
- History of arterial or venous thrombo-embolic events, as defined in the protocol
- History of hypersensitivity to corticosteroids or known medical condition that requires chronic administration of corticosteroids
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 2: Dose Expansion A LNP1265 Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1 Part 1: Cohort 2 Dose Escalation for RDE LNP1265 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 Part 1: Cohort 4 Dose Escalation for RDE LNP1265 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 Part 2: Dose Expansion B LNP1265 Participants ≥12 to \<18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1 Part 1: Cohort 1 Dose Escalation for RDE LNP1265 Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE Part 2: Dose Expansion A REGV131 Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1 Part 1: Cohort 3 Dose Escalation for RDE REGV131 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 Part 1: Cohort 1 Dose Escalation for RDE REGV131 Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE Part 1: Cohort 2 Dose Escalation for RDE REGV131 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 Part 2: Dose Expansion C REGV131 Participants ≥2 to \<12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1 Part 1: Cohort 4 Dose Escalation for RDE REGV131 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 Part 2: Dose Expansion C LNP1265 Participants ≥2 to \<12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1 Part 2: Dose Expansion B REGV131 Participants ≥12 to \<18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1 Part 1: Cohort 3 Dose Escalation for RDE LNP1265 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
- Primary Outcome Measures
Name Time Method Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay At day 29 Part 1
Change in FIX functional activity in plasma, measured using the chromogenic substrate assay Baseline and at Week 26, after REGV131-LNP1265 dosing at the recommended dose for expansion (RDE) Part 2A, Part 2B and Part 2C
Severity of TEAEs Up to 104 Weeks Part 1, Part 2B and Part 2C
Incidence of treatment-emergent adverse events (TEAEs) Up to 104 Weeks Part 1, Part 2B and Part 2C
Annualized bleeding rate (ABR) following sustained FIX functional activity among participants receiving the RDE Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing Part 2A, Part 2B and Part 2C
- Secondary Outcome Measures
Name Time Method ABR following sustained FIX functional activity among participants receiving the RDE Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing Part 1
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 Detection of total binding antibodies (TAbs) to the adeno-associated virus 8 (AAV8) capsid proteins Up to 104 Weeks Detection of neutralizing antibodies/transduction inhibitors (NAb/TI) to the adeno-associated virus 8 (AAV8) capsid proteins Up to 104 Weeks Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein Up to 104 Weeks 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 Detection of vector DNA in saliva Up to 104 Weeks Part 1
Detection of vector DNA in semen Up to 104 Weeks Part 1
Detection of vector DNA in feces Up to 104 Weeks Part 1
Severity of TEAEs Up to 104 Weeks Part 2A
Detection of vector DNA in blood Up to 104 Weeks Part 1
Change in FIX functional activity in plasma measured using the chromogenic substrate assay Baseline and at Week 26, after REGV131-LNP1265 dosing at the RDE Part 1
FIX functional activity in plasma over time during the study period using the chromogenic substrate assay Up to 104 Weeks 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 Detection of antibodies to the F9 transgene product FIX protein Up to 104 Weeks Detection of vector DNA in nasal secretions Up to 104 Weeks Part 1
Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time Up to 104 Weeks Part 2B and Part 2C
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 Detection of antibodies to LNP1265 Up to 104 Weeks Detection of vector DNA in urine Up to 104 Weeks Part 1
Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort Up to 104 Weeks Part 2A
Concentrations of LNP1265 components Up to 29 Days Concentrations of REGV131 components Up to 29 Days Incidence of TEAEs Up to 104 Weeks Part 2A
Trial Locations
- Locations (9)
Yale HTC
🇺🇸New Haven, Connecticut, United States
Children's Hospital of Philadelphia (CHOP)
🇺🇸Philadelphia, Pennsylvania, United States
Addenbrooke's Hospital, Cambridge University Hospitals NHS FT
🇬🇧Cambridge, United Kingdom
Orthopaedic Hemophilia Treatment Center
🇺🇸Los Angeles, California, United States
University of California Davis
🇺🇸Sacramento, California, United States
University California San Francisco
🇺🇸San Francisco, California, United States
Tulane University School of Medicine, Louisiana Center for Bleeding and Clotting Disorders
🇺🇸New Orleans, Louisiana, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
McMaster University Medical Centre - Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada