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

• ClinicalTrials.gov Identifier: NCT05121376
• Recruitment Status: Recruiting
• First Posted: November 16, 2021
• Last Update Posted: December 11, 2023
• Sponsor: BioMarin Pharmaceutical
• Information provided by (Responsible Party): BioMarin Pharmaceutical

Tracking Information

• First Submitted Date: October 28, 2021
• First Posted Date: November 16, 2021
• Last Update Posted Date: December 11, 2023
• Actual Study Start Date: February 15, 2022
• Estimated Primary Completion Date: November 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 5, 2023)

Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331 [ Time Frame: At 5 years ]

Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331

• Original Primary Outcome Measures (submitted: November 4, 2021): Number of participants with treatment-emergent adverse events following a single IV administration of BMN 331 [ Time Frame: At 5 years ]

Current Secondary Outcome Measures (submitted: December 5, 2023)

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

Original Secondary Outcome Measures (submitted: November 4, 2021)

• Number and severity of investigator-confirmed HAE attacks [ Time Frame: At 5 years ]
• Annualized use of HAE medication [ Time Frame: At 5 years ]
• Plasma levels of functional C1-INH following BMN-331 infusion [ Time Frame: At 5 years ]
• Plasma levels of C1-INH antigen following BMN 331 infusion [ Time Frame: At 5 years ]
• Levels of total antibodies against AAV5 capsid following BMN 331 infusion [ Time Frame: At 5 years ]
• Levels of total antibodies against C1-INH following BMN 331 infusion [ Time Frame: At 5 years ]
• Levels of neutralizing antibodies against C1-INH following BMN 331 infusion [ Time Frame: At 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hereditary Angioedema
• HAE

Intervention

• 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

Study Arms

Experimental: BMN 331

AAV Gene Therapy Infusion

Interventions:

• 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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 5, 2023): 44
• Original Estimated Enrollment (submitted: November 4, 2021): 34
• Estimated Study Completion Date: November 2028
• Estimated Primary Completion Date: November 2028 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Trial Specialist; 1-800-983-4587; medinfo@bmrn.com

• Listed Location Countries: Australia, Spain, United States

Administrative Information

• NCT Number: NCT05121376
• Other Study ID Numbers: 331-201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: BioMarin Pharmaceutical
• Original Responsible Party: Same as current
• Current Study Sponsor: BioMarin Pharmaceutical
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD Medical Director; BioMarin Pharmaceutical

• PRS Account: BioMarin Pharmaceutical
• Verification Date: December 2023