Hemophilia B
Conditions
Keywords
Severe and moderately severe congenital hemophilia B, FIX functional activity
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, 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
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
Interventions
Sponsors
Regeneron Pharmaceuticals
Intellia Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Treatment-Emergent Adverse Events (TEAEs) | Up to 2 Years | Part 1, 2B, and 2C |
| Severity of TEAEs | Up to 2 Years | Part 1, 2B, and 2C |
| Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay | Up to 2 Years | Part 1 |
| Change in FIX functional activity in plasma, measured using the chromogenic substrate assay | Up to 2 Years | Part 2A, 2B, and 2C |
| Annualized Bleeding Rate (ABR) following sustained FIX functional activity among participants receiving the RDE | Up to 2 Years | Part 2A, 2B, and 2C |
| Occurrence of Serious Adverse Events (SAEs) | Through Long Term Follow Up (LTFU), Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Severity of SAEs | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Occurrence of Adverse Event of Special Interests (AESIs) | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Severity of AESIs | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Occurrence of clinically meaningful Adverse Events (AEs) | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Severity of clinically meaningful AEs | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in FIX functional activity in plasma measured using the chromogenic substrate assay | Up to 2 Years | Part 1 |
| ABR following sustained FIX functional activity among participants receiving the RDE | Through LTFU, Up to 15 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| FIX functional activity in plasma over time during the study period using the chromogenic substrate assay | Through LTFU, Up to 10 Years | LTFU Period for Part 1, 2A, 2B, and 2C |
| Annualized treated Bleeding Rate (tABR) following sustained FIX functional activity, among participants receiving the RDE | Through LTFU, Up to 15 years | Part 1, 2A, 2B, and 2C |
| Annualized utilization (IU/kg/year) of FIX replacement therapy following sustained FIX functional activity among participants receiving the RDE | Through LTFU, Up to 15 Years | Part 1, 2A, 2B, and 2C |
| Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Concentrations of REGV131 components | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Concentrations of LNP1265 components | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of antibodies to the Coagulation Factor IX gene (F9) transgene product FIX protein | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of Total binding Antibodies (TAbs) to the Adeno-Associated Virus 8 (AAV8) capsid proteins | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of Neutralizing Antibodies/Transduction Inhibitors (NAb/TI) to the AAV8 capsid proteins | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of antibodies to LNP1265 | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein | Up to 2 Years | Part 1, 2A, 2B, and 2C |
| Detection of vector DeoxyriboNucleic Acid (DNA) in blood | Up to 2 Years | Part 1 |
| Detection of vector DNA in saliva | Up to 2 Years | Part 1 |
| Detection of vector DNA in nasal secretions | Up to 2 Years | Part 1 |
| Detection of vector DNA in semen | Up to 2 Years | Part 1 |
| Detection of vector DNA in urine | Up to 2 Years | Part 1 |
| Detection of vector DNA in feces | Up to 2 Years | Part 1 |
| Occurrence of TEAEs | Up to 2 Years | Part 2A |
| Severity of TEAEs | Up to 2 Years | Part 2A |
| Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort | Up to 2 Years | Part 2A, 2B, and 2C |
| Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time | Up to 2 Years | Part 2B and 2C |
| Proportion of participants with zero spontaneous bleeding events following sustained FIX functional activity among those receiving RDE | Through LTFU, Up to 15 Years | Part 1, 2A, 2B, and 2C |
| Proportion of participants not requiring FIX replacement therapy following sustained FIX functional activity among those receiving RDE | Throught LTFU, Up to 15 Years | Part 1, 2A, 2B, and 2C |
Countries
Australia, Brazil, Canada, France, Germany, Italy, Spain, United Kingdom, United States
Contacts
CONTACTClinical Trials Administrator
STUDY_DIRECTORClinical Trial Management
Regeneron Pharmaceuticals
Outcome results
None listed