A Gene Therapy Study of BMN 331 in Subjects With Hereditary Angioedema (HAErmony-1)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hereditary Angioedema; HAE
• Intervention / Treatment: Genetic: Dose 1 of BMN 331; Genetic: Dose 2 of BMN 331; Genetic: Dose 3 of BMN 331; Genetic: Dose 4 of BMN 331; Genetic: Dose 5 of BMN 331; Genetic: Dose 6 of BMN 331; Genetic: Dose 7 of BMN 331

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.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia, 2050
    • Royal Prince Alfred Hospital,
• Spain
  • Barcelona, Spain
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain
    • Hospital Universitario La Paz
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Allervie Clinical Research
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of Arizona
  • California
    • San Diego, California, United States, 92122
      • University of California San Diego
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Asthma & Allergy Associates P.C.
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Dr. Henry J. Kanarek Allergy, Asthma & Immunology
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute For Asthma & Allergy
  • Mississippi
    • Madison, Mississippi, United States, 39110
      • Mississippi Center for Advanced Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Health
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati (UC) Physicians Company, LLC
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 16802
      • The Pennsylvania State University (Penn State) Milton S. Hershey Medical Center
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BMN 331; AAV Gene Therapy Infusion	Genetic: Dose 1 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 2 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 3 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 4 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 5 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 6 of BMN 331; BMN 331 AAV Gene Therapy; Genetic: Dose 7 of BMN 331; BMN 331 AAV Gene Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331	Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331	At 5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Time-normalized number of investigator-confirmed HAE attacks	At 5 years
Time-normalized number of investigator-confirmed HAE attacks by severity (mild, moderate, severe)	At 5 years
Time-normalized use of HAE-specific medication	At 5 years
Plasma levels of functional C1-INH following BMN-331 infusion and change from baseline	At 5 years
Plasma levels of C1-INH antigen following BMN 331 infusion and change from baseline	At 5 years
Detection of total antibodies against AAV5 capsid following BMN 331 infusion	At 5 years
Detection of total antibodies against C1-INH following BMN 331 infusion	At 5 years
Detection of neutralizing antibodies against C1-INH following BMN 331 infusion	At 5 years

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: MD Medical Director, BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2022
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: October 28, 2021
• First Submitted That Met QC Criteria: November 4, 2021
• First Posted (Actual): November 16, 2021

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 15, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; HAE; Hereditary Angioedema; 331-201; 331; Haermony
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary
• Other Study ID Numbers: 331-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No