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

Overview

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

• Drug REGV131
  Administered per the protocol before LNP1265
• Drug LNP1265
  Administered per the protocol following REGV131

Primary outcome measures

• Occurrence of Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to 2 Years]
• Severity of TEAEs [Time frame: Up to 2 Years]
• Coagulation Factor IX (FIX) functional activity measured using the chromogenic substrate assay [Time frame: Up to 2 Years]
• Change in FIX functional activity in plasma, measured using the chromogenic substrate assay [Time frame: Up to 2 Years]
• Annualized Bleeding Rate (ABR) following sustained FIX functional activity among participants receiving the RDE [Time frame: Up to 2 Years]
• Occurrence of Serious Adverse Events (SAEs) [Time frame: Through Long Term Follow Up (LTFU), Up to 15 Years]
• Severity of SAEs [Time frame: Through LTFU, Up to 15 Years]
• Occurrence of Adverse Event of Special Interests (AESIs) [Time frame: Through LTFU, Up to 15 Years]
• Severity of AESIs [Time frame: Through LTFU, Up to 15 Years]
• Occurrence of clinically meaningful Adverse Events (AEs) [Time frame: Through LTFU, Up to 15 Years]

Secondary outcome measures (12)

• Change in FIX functional activity in plasma measured using the chromogenic substrate assay [Time frame: Up to 2 Years]
• ABR following sustained FIX functional activity among participants receiving the RDE [Time frame: Through LTFU, Up to 15 Years]
• FIX functional activity in plasma over time during the study period using the chromogenic substrate assay [Time frame: Through LTFU, Up to 10 Years]
• Annualized treated Bleeding Rate (tABR) following sustained FIX functional activity, among participants receiving the RDE [Time frame: 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 [Time frame: Through LTFU, Up to 15 Years]
• Remaining free of FIX replacement therapy among those receiving the RDE following sustained FIX expression [Time frame: Up to 2 Years]
• Remaining zero spontaneous bleeding events among those receiving the RDE over sustained FIX functional activity period [Time frame: Up to 2 Years]
• Concentrations of REGV131 components [Time frame: Up to 2 Years]
• Concentrations of LNP1265 components [Time frame: Up to 2 Years]
• Detection of antibodies to the Coagulation Factor IX gene (F9) transgene product FIX protein [Time frame: Up to 2 Years]
• Detection of Total binding Antibodies (TAbs) to the Adeno-Associated Virus 8 (AAV8) capsid proteins [Time frame: Up to 2 Years]
• Detection of Neutralizing Antibodies/Transduction Inhibitors (NAb/TI) to the AAV8 capsid proteins [Time frame: Up to 2 Years]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 15 centers

• Orthopaedic Hemophilia Treatment Center — Los Angeles
• David Geffen School of Medicine at UCLA — Los Angeles
• Children's Hospital Los Angeles — Los Angeles
• University of California Davis — Sacramento
• University California San Francisco — San Francisco
• University of Colorado Hemophilia and Thrombosis Center — Aurora
• Yale HTC — New Haven
• University of Florida — Gainesville
• … and 7 more centers

Spain · 8 centers

• Hospital Universitario Virgen del Rocio — Seville
• Complejo Hospitalario Universitario de A Coruña (Edificio Teresa Herrera-Materno Infantil) — A Coruña
• Hospital Clinico Universitario Virgen De La Arrixaca — El Palmar
• Hospital Universitario Central de Asturias — Oviedo
• Hospital Universitario Vall d'Hebron — Barcelona
• Hospital Universitario La Paz — Madrid
• Haemostasis and Thrombosis Unit, Hospital La Fe — Valencia
• Hospital Universitario Miguel Servet — Zaragoza

United Kingdom · 7 centers

• Glasgow Royal Infirmary - Clinical Research Facility — Glasgow
• Queen Elizabeth Hospital Birmingham — Birmingham
• Addenbrooke's Hospital, Cambridge University Hospitals NHS FT — Cambridge
• Pathology and Pharmacy Building, The Royal London Hospital — London
• Royal Free London NHS Foundation Trust — London
• St. Thomas' Hospital — London
• Hammersmith Hospital Comprehensive Care Centre — London

Australia · 4 centers

• Royal Prince Alfred Hospital, Haemophilia Treatment Centre — Camperdown
• Royal Brisbane and Women's Hospital — Herston
• Royal Adelaide Hospital — Adelaide
• Alfred Hospital — Melbourne

Italy · 4 centers

• Careggi University Hospital — Florence
• Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca Granda Ospedale — Milan
• Irccs Humanitas Research Hospital — Rozzano
• Ospedale san Bortolo — Vicenza

Canada · 3 centers

• University of Alberta Hospital — Edmonton
• McMaster University Medical Centre - Hamilton Health Sciences — Hamilton
• McGill University Health Center (MUHC) — Montreal

France · 3 centers

• Hospices Civils de Lyon — Bron
• Hemostase Clinique, Institut Coeur Poumon — Lille
• Hopital Necker — Paris

Germany · 2 centers

• University Hospital Frankfurt — Frankfurt am Main
• University Hospital Hamburg Eppendorf — Hamburg

Identifiers

NCT: NCT06379789 · R131L1265-HEMB-2318 · 2023-507260-40-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗