A Two-Part Open-Label Study of REGV131-LNP1265, A CRISPR/Cas9 Based Coagulation Factor IX Gene Insertion Therapy in Participants With Hemophilia B
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 130
- 试验地点
- 75
- 主要终点
- Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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 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 or significant fatty liver, 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
研究组 & 干预措施
Part 2: Dose Expansion B
Participants ≥12 to <18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1
干预措施: LNP1265 (Drug)
Part 2: Dose Expansion C
Participants ≥2 to <12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1
干预措施: LNP1265 (Drug)
Part 1: Cohort 4 Dose Escalation for RDE
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
干预措施: LNP1265 (Drug)
Part 1: Cohort 4 Dose Escalation for RDE
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
干预措施: REGV131 (Drug)
Part 1: Cohort 2 Dose Escalation for RDE
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
干预措施: REGV131 (Drug)
Part 1: Cohort 1 Dose Escalation for RDE
Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE
干预措施: LNP1265 (Drug)
Part 2: Dose Expansion A
Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1
干预措施: REGV131 (Drug)
Part 2: Dose Expansion C
Participants ≥2 to <12 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1
干预措施: REGV131 (Drug)
Part 2: Dose Expansion A
Participants ≥18 Years of Age will receive the RDE of REGV131-LNP1265 determined by Part 1
干预措施: LNP1265 (Drug)
Part 2: Dose Expansion B
Participants ≥12 to <18 Years of Age will receive the administered weight-adjusted RDE of REGV131-LNP1265 determined by Part 1
干预措施: REGV131 (Drug)
Part 1: Cohort 1 Dose Escalation for RDE
Starting dose to determine the RDE of REGV131-LNP1265 and further assess the safety, tolerability, and FIX functional activity data at the RDE
干预措施: REGV131 (Drug)
Part 1: Cohort 3 Dose Escalation for RDE
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
干预措施: REGV131 (Drug)
Part 1: Cohort 3 Dose Escalation for RDE
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
干预措施: LNP1265 (Drug)
Part 1: Cohort 2 Dose Escalation for RDE
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
干预措施: LNP1265 (Drug)
结局指标
主要结局
Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay
时间窗: At day 29
Part 1
Change in FIX functional activity in plasma, measured using the chromogenic substrate assay
时间窗: 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
时间窗: Up to 104 Weeks
Part 1, Part 2B and Part 2C
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: 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
时间窗: Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing
Part 2A, Part 2B and Part 2C
Occurrence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: Up to 2 Years
Part 1, 2B, and 2C
Severity of TEAEs
时间窗: Up to 2 Years
Part 1, 2B, and 2C
Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay
时间窗: Up to 2 Years
Part 1
Change in FIX functional activity in plasma, measured using the chromogenic substrate assay
时间窗: Up to 2 Years
Part 2A, 2B, and 2C
Annualized Bleeding Rate (ABR) following sustained FIX functional activity among participants receiving the RDE
时间窗: Up to 2 Years
Part 2A, 2B, and 2C
Occurrence of Serious Adverse Events (SAEs)
时间窗: Through Long Term Follow Up (LTFU), Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
Severity of SAEs
时间窗: Through LTFU, Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
Occurrence of Adverse Event of Special Interests (AESIs)
时间窗: Through LTFU, Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
Severity of AESIs
时间窗: Through LTFU, Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
Occurrence of clinically meaningful Adverse Events (AEs)
时间窗: Through LTFU, Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
Severity of clinically meaningful AEs
时间窗: Through LTFU, Up to 15 Years
LTFU Period for Part 1, 2A, 2B, and 2C
次要结局
- ABR following sustained FIX functional activity among participants receiving the RDE(Over 52 Weeks; Weeks 26 to 78 post-REGV131-LNP1265 dosing)
- 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)
- Detection of vector DNA in semen(Up to 104 Weeks)
- Detection of vector DNA in feces(Up to 104 Weeks)
- Severity of TEAEs(Up to 104 Weeks)
- Concentrations of REGV131 components(Up to 29 Days)
- Detection of vector DNA in blood(Up to 104 Weeks)
- 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)
- 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)
- Concentrations of LNP1265 components(Up to 29 Days)
- 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)
- Incidence of TEAEs(Up to 104 Weeks)
- Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time(Up to 104 Weeks)
- 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)
- Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort(Up to 104 Weeks)
- Change in FIX functional activity in plasma measured using the chromogenic substrate assay(Up to 2 Years)
- ABR following sustained FIX functional activity among participants receiving the RDE(Through LTFU, Up to 15 Years)
- FIX functional activity in plasma over time during the study period using the chromogenic substrate assay(Through LTFU, Up to 10 Years)
- Annualized treated Bleeding Rate (tABR) following sustained FIX functional activity, among participants receiving the RDE(Through LTFU, Up to 15 years)
- 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)
- Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression(Up to 2 Years)
- Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period(Up to 2 Years)
- Concentrations of REGV131 components(Up to 2 Years)
- Concentrations of LNP1265 components(Up to 2 Years)
- Detection of antibodies to the Coagulation Factor IX gene (F9) transgene product FIX protein(Up to 2 Years)
- Detection of Total binding Antibodies (TAbs) to the Adeno-Associated Virus 8 (AAV8) capsid proteins(Up to 2 Years)
- Detection of Neutralizing Antibodies/Transduction Inhibitors (NAb/TI) to the AAV8 capsid proteins(Up to 2 Years)
- Detection of antibodies to LNP1265(Up to 2 Years)
- Detection of antibodies to CRISPR-associated protein 9 (Cas9) protein(Up to 2 Years)
- Detection of vector DeoxyriboNucleic Acid (DNA) in blood(Up to 2 Years)
- Detection of vector DNA in saliva(Up to 2 Years)
- Detection of vector DNA in nasal secretions(Up to 2 Years)
- Detection of vector DNA in semen(Up to 2 Years)
- Detection of vector DNA in urine(Up to 2 Years)
- Detection of vector DNA in feces(Up to 2 Years)
- Occurrence of TEAEs(Up to 2 Years)
- Severity of TEAEs(Up to 2 Years)
- Detection of vector DNA in relevant matrices based on data analysis of Part 1 Dose Confirmation Cohort(Up to 2 Years)
- Detection of vector DNA in relevant matrices over time based on data analysis from adult cohorts over time(Up to 2 Years)
- Proportion of participants with zero spontaneous bleeding events following sustained FIX functional activity among those receiving RDE(Through LTFU, Up to 15 Years)
- Proportion of participants not requiring FIX replacement therapy following sustained FIX functional activity among those receiving RDE(Throught LTFU, Up to 15 Years)