Clinical trial NCT06379789: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hemophilia B
Keywords: Severe and moderately severe congenital hemophilia B
FIX functional activity
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Intellia Therapeutics
First posted: 2024-04-23
Enrollment: 130
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

Eligibility 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 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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 104 Weeks
measure: Severity of TEAEs
timeFrame: Up to 104 Weeks
measure: Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay
timeFrame: At day 29
measure: Change in FIX functional activity in plasma, measured using the chromogenic substrate assay
timeFrame: Baseline and at Week 26, after REGV131-LNP1265 dosing at the recommended dose for expansion (RDE)
measure: Annualized bleeding rate (ABR) following sustained FIX functional activity among participants receiving the RDE
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Secondary outcomes:
measure: Change in FIX functional activity in plasma measured using the chromogenic substrate assay
timeFrame: Baseline and at Week 26, after REGV131-LNP1265 dosing at the RDE
measure: ABR following sustained FIX functional activity among participants receiving the RDE
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
measure: FIX functional activity in plasma over time during the study period using the chromogenic substrate assay
timeFrame: Up to 104 Weeks
measure: Annualized treated bleeding rate (tABR) following sustained FIX functional activity, among participants receiving the RDE
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
measure: Annualized utilization (IU/kg/year) of FIX replacement therapy following sustained FIX functional activity among participants receiving the RDE
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
measure: Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
measure: Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period
timeFrame: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
measure: Concentrations of REGV131 components
timeFrame: Up to 29 Days
measure: Concentrations of LNP1265 components
timeFrame: Up to 29 Days
measure: Detection of antibodies to the F9 transgene product FIX protein
timeFrame: Up to 104 Weeks
measure: Detection of total binding antibodies (TAbs) to the adeno-associated virus 8 (AAV8) capsid proteins
timeFrame: Up to 104 Weeks
measure: Detection of neutralizing antibodies/transduction inhibitors (NAb/TI) to the adeno-associated virus 8 (AAV8) capsid proteins
timeFrame: Up to 104 Weeks
measure: Detection of antibodies to LNP1265
timeFrame: Up to 104 Weeks
measure: Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in blood
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in saliva
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in nasal secretions
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in semen
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in urine
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in feces
timeFrame: Up to 104 Weeks
measure: Incidence of TEAEs
timeFrame: Up to 104 Weeks
measure: Severity of TEAEs
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort
timeFrame: Up to 104 Weeks
measure: Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time
timeFrame: Up to 104 Weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Orthopaedic Hemophilia Treatment Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: San Francisco
country: United States
facility: University California San Francisco
state: California
city: New Haven
country: United States
facility: Yale HTC
state: Connecticut
city: New Orleans
country: United States
facility: Tulane University School of Medicine, Louisiana Center for Bleeding and Clotting Disorders
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Hamilton
country: Canada
facility: McMaster University Medical Centre - Hamilton Health Sciences
state: Ontario
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary - Clinical Research Facility
state: Scotland
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital, Cambridge University Hospitals NHS FT
city: London
country: United Kingdom
facility: Hammersmith Hospital Comprehensive Care Centre
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: