Clinical trial NCT05121376: A Gene Therapy Study of BMN 331 in Subjects With Hereditary Angioedema
Official title: A Phase 1/2 Open-Label, Dose-Escalation Study to Determine the Safety Tolerability & Efficacy of BMN 331 an AAV Vector-Mediated Gene Transfer of Human SERPING1 Gene in Subjects With HAE Due to Human C1-INH Deficiency
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hereditary Angioedema
HAE
Keywords: HAE
Hereditary Angioedema
Gene Therapy
331-201
331
Haermony
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2021-11-16
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2, single-arm, open-label, dose-escalation and dose-expansion study of BMN 331 for the treatment of hereditary angioedema (HAE) due to C1 Esterase Inhibitor (C1-INH) protein deficiency. The study drug BMN 331is identified as AAV5 hSERPING1, an adeno-associated virus (AAV5)-based gene therapy vector that expresses wild-type human C1 Esterase Inhibitor (hC1-INH), under the control of a liver-selective promoter, and is being developed for the treatment of HAE with C1-INH deficiency. The pharmaceutical form of BMN 331 is a solution for intravenous infusion.

Detailed description: BMN 331 is an investigational, single administration gene therapy intended to modify the disease course of HAE. Preclinical studies have shown that BMN 331 can transduce hepatocytes resulting in restoration of the deficient circulating levels of hC1-INH that cause HAE.

Study 331-201 is a two-part (part A and part B), first-in-human, Phase 1/2 study designed to assess the safety and efficacy of BMN 331 in patients with HAE. Subjects will be followed for 5 years following BMN 331 infusion. Part A of the study is a dose escalation phase designed to assess the preliminary safety of a single IV administration of BMN 331 and to determine whether there is a dose-dependent increase in C1-INH protein expression following administration of BMN 331. Part B is a dose expansion phase designed to demonstrate that up to three safe doses of BMN 331 (as determined in Part A) sustains a clinically meaningful increase in C1-INH levels.

Eligibility criteria: Inclusion Criteria:

1. Female or male adults ( ≥ 18 years old)
2. Part A only: Confirmed diagnosis of Type I HAE due to C1-INH deficiency confirmed by genotyping of the SERPING1 gene Part B only: Confirmed diagnosis of Type I or II HAE due to C1-INH deficiency confirmed by genotyping of the SERPING1 gene
3. Currently using an HAE medication regimen that consists of a routine long-term prophylactic treatment for at least 6 months prior to enrollment or an on-demand therapy regimen for a documented attack frequency of at least 4 attacks within the last 12 months prior to enrollment or at least 2 attacks within the last 6 months prior to enrollment
4. Trained in self-administering acute attack treatment and is able to adequately manage acute attacks in a home setting
5. Willingness to abstain from consumption of alcohol for at least 52 weeks post BMN 331 infusion and to use highly effective contraception

Exclusion Criteria:

1. Evidence of active or chronic infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or any immunosuppressive disorder
2. Contraindication to using glucocorticosteroids GCS, including a diagnosis of glaucoma or untreated osteoporosis
3. Active malignancy (except non-melanoma skin cancer) autoimmune, metabolic (i.e., diabetes), hematologic, cardiac, or renal disease that is of clinical significance defined as requiring regular medical attention and treatment
4. Prior gene therapy treatment
5. Prior use of high-dose attenuated androgens in the last 1 year prior to the study
6. History or current clinically relevant liver disease (eg, nonalcoholic steatohepatitis \[NASH\], or chronic viral hepatitis B or C \[HBV or HCV\] or autoimmune hepatitis)
7. Have a history or are at risk for clinically significant thromboembolic events (TEE) , or known underlying risk factor for thrombosis including thrombotic microangiopathy (TMA)

Primary outcomes:
measure: Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331
timeFrame: At 5 years
Secondary outcomes:
measure: Time-normalized number of investigator-confirmed HAE attacks
timeFrame: At 5 years
measure: Time-normalized number of investigator-confirmed HAE attacks by severity (mild, moderate, severe)
timeFrame: At 5 years
measure: Time-normalized use of HAE-specific medication
timeFrame: At 5 years
measure: Plasma levels of functional C1-INH following BMN-331 infusion and change from baseline
timeFrame: At 5 years
measure: Plasma levels of C1-INH antigen following BMN 331 infusion and change from baseline
timeFrame: At 5 years
measure: Detection of total antibodies against AAV5 capsid following BMN 331 infusion
timeFrame: At 5 years
measure: Detection of total antibodies against C1-INH following BMN 331 infusion
timeFrame: At 5 years
measure: Detection of neutralizing antibodies against C1-INH following BMN 331 infusion
timeFrame: At 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: AllerVie Clinical Research
state: Alabama
city: Scottsdale
country: United States
facility: Medical Research of Arizona
state: Arizona
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Colorado Springs
country: United States
facility: Asthma & Allergy Associates P.C.
state: Colorado
city: Overland Park
country: United States
facility: Dr. Henry J. Kanarek Allergy, Asthma & Immunology
state: Kansas
city: Chevy Chase
country: United States
facility: Institute For Asthma & Allergy
state: Maryland
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati (UC) Physicians Company, LLC
state: Ohio
city: Columbus
country: United States
facility: Optimed Research, LTD
state: Ohio
city: Hershey
country: United States
facility: The Pennsylvania State University (Penn State) Milton S. Hershey Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: AARA Research Center
state: Texas
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital,
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
Study officials:
affiliation: BioMarin Pharmaceutical
name: MD Medical Director
role: STUDY_DIRECTOR
References: