A Gene Therapy Study of BMN 331 in Subjects With Hereditary Angioedema

Hereditary Angioedema Clinical Trial

— HAErmony-1  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05121376
• Other study ID #: 331-201
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 15, 2022
• Est. completion date: November 2028

Study information

• Verified date: December 2023
• Source: BioMarin Pharmaceutical
• Contact: Trial Specialist
• Phone: 1-800-983-4587
• Email: medinfo[@]bmrn.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 44
• Est. completion date: November 2028
• Est. primary completion date: November 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Angioedema
• HAE
• Hereditary Angioedema

Intervention

Genetic:
• Dose 1 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 2 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 3 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 4 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 5 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 6 of BMN 331
BMN 331 AAV Gene Therapy
• Dose 7 of BMN 331
BMN 331 AAV Gene Therapy

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
BioMarin Pharmaceutical

Countries where clinical trial is conducted

United States,  Australia,  Spain, 

Outcome

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