Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency (ADVANCE)

• ClinicalTrials.gov Identifier: NCT02168686
• Recruitment Status: Completed
• First Posted: June 20, 2014
• Results First Posted: August 8, 2022
• Last Update Posted: October 5, 2023
• Sponsor: Adverum Biotechnologies, Inc.
• Information provided by (Responsible Party): Adverum Biotechnologies, Inc.

Tracking Information

• First Submitted Date: June 10, 2014
• First Posted Date: June 20, 2014
• Results First Submitted Date: June 30, 2022
• Results First Posted Date: August 8, 2022
• Last Update Posted Date: October 5, 2023
• Actual Study Start Date: November 28, 2017
• Actual Primary Completion Date: August 29, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 30, 2022)

• Treatment-emergent Adverse Events Related to ADVM-043 [ Time Frame: From ADVM-043 infusion through End-of-Study visit at 52 weeks ]
  Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043
• Abnormal Changes in Clinical Laboratory Parameters [ Time Frame: From ADVM-043 infusion through End-of-Study visit at 52 weeks ]
  Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters

Original Primary Outcome Measures (submitted: June 17, 2014)

Change in adverse events as a measure of safety and tolerability [ Time Frame: screening, pre-therapy, 3, 6, and 12 months post-vector administration ]

The following study parameters will assess safety: clinical assessment, routine bloodwork, routine urinalysis, EKG, chest x-ray and lung function test

Current Secondary Outcome Measures (submitted: September 18, 2023)

• Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks [ Time Frame: At Week 52 ]
  Change from baseline at Week 52 of plasma concentration of M-specific A1AT for subjects who did not receive PAT post-dose Note:

  1. Two subjects in Dose 1 Arm/Group, had results available at Week 52; the remaining 4 subjects in Dose 2 Arm/Group and Dose 3 Arm/Group had resumed PAT therapy after Week 24, and their results were censored from the Week 52 timepoint.
  2. While data on the Total Plasma Concentrations of A1AT up to 52 Weeks were collected for 1 study participant in Part A: Dose 3, no data were collected on the Change in Plasma Concentrations of M-specific A1AT due to the initiation of PAT after 24 weeks in Part A: Dose 3 subjects.
• Changes in Total Plasma Concentrations of A1AT up to 52 Weeks [ Time Frame: At Week 52 ]
  Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose

Original Secondary Outcome Measures (submitted: June 17, 2014)

Change in therapeutic serum and alveolar epithelial lining fluid levels of a1AT as a preliminary measure of efficacy [ Time Frame: screening, pre-therapy, 3, 6, and 12 months post-vector administration ]

The following study parameter will measure preliminary efficacy: bloodwork and bronchoscopy

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

Descriptive Information

• Brief Title: Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency
• Official Title: Phase 1/2 Study of Intravenous or Intrapleural Administration of a Serotype rh.10 Replication Deficient Adeno-associated Virus Gene Transfer Vector Expressing the Human Alpha-1 Antitrypsin cDNA to Individuals With Alpha-1 Antitrypsin Deficiency
• Brief Summary: The ADVANCE study is being conducted by Adverum Biotechnologies, Inc. as an open-label, multicenter, dose-escalation study in order to assess the safety and protein expression of ADVM-043 following a single intravenous or intrapleural administration.

Detailed Description

Alpha-1 Antitrypsin (A1AT) is a major inhibitor of serine proteases and plays an important role in the lung as an inhibitor of neutrophil elastase. A1AT deficiency is associated with decreases in plasma A1AT levels and is associated with an increased risk for developing asthma, emphysema/COPD, and bronchiectasis. Much of the lung damage is thought to be caused by proteolytic damage from neutrophil elastase and other proteases.

ADVM-043 is an investigational gene therapy product (serotype AAVrh.10 vector) expressing human A1AT that is intended to deliver a functional gene to the liver of patients with A1AT deficiency. Study ADVM-043-01 will study up to 4 dose levels in up to 20 patients and assess the hypothesis that a single administration of an AAV vector expressing the human M-type A1AT (i.e., ADVM-043) to patients with A1AT deficiency is safe and results in persistent therapeutic levels of A1AT in blood and alveolar epithelial lining fluid (epithelial lining fluid is only to be collected in subjects who are dosed intrapleurally). The primary endpoint is safety, and changes in plasma A1AT levels at multiple time points up to 52 weeks after dosing. A prophylactic tapering corticosteroid regimen will be used to protect against potential vector induced transaminitis. Subjects will be followed for up to 52 weeks after dosing. Safety and efficacy data from the IV cohorts will be considered when determining whether to proceed to intrapleural administration. After completion of this study, subjects will be asked to enroll in a Long Term Follow Up study.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Open-label, multicenter, dose-escalation clinical study to assess the safety and treatment effect of ADVM-043 in subjects with Alpha-1 Antitrypsin Deficiency.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Alpha 1-Antitrypsin Deficiency

Intervention

Genetic: ADVM-043

Gene transfer vector administration

Other Names:

• AAVrh.10halpha1AT
• AAVrh.10hA1AT

Study Arms

• Experimental: Part A: Dose 1
  ADVM-043, at the lowest dose of three planned dose levels, of 8E13 total vg (equivalent to 1E12 vg/kg based on an 80-kg patient) administered IV
  Intervention: Genetic: ADVM-043
• Experimental: Part A: Dose 2
  ADVM-043 at the intermediate dose of three planned dose levels, of 4E14 total vg (equivalent to 5E12 vg/kg based on an 80-kg patient) administered IV
  Intervention: Genetic: ADVM-043
• Experimental: Part A: Dose 3
  ADVM-043 at the highest dose of three planned dose levels, of 1.2E15 total vg (equivalent to 1.5E13 vg/kg based on an 80-kg patient) administered IV
  Intervention: Genetic: ADVM-043
• Experimental: Part A: Dose 4
  ADVM-043 administered at a dose that will be determined
  Intervention: Genetic: ADVM-043
• Experimental: Part B (optional): Intrapleural administration
  ADVM-043 administered intrapleurally at a dose that will be determined
  Intervention: Genetic: ADVM-043

• Publications *: Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol. 2021 Aug;59:149-156. doi: 10.1016/j.coph.2021.06.001. Epub 2021 Jul 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 31, 2020): 6
• Original Estimated Enrollment (submitted: June 17, 2014): 20
• Actual Study Completion Date: August 29, 2019
• Actual Primary Completion Date: August 29, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Capable of providing informed consent
• Alpha1AT genotype of ZZ or Z Null
• Males and females 18 years and older
• Ongoing treatment with A1AT augmentation is not required, however any subject receiving A1AT augmentation therapy must be willing to washout. Washout is defined as at least 8 weeks between last augmentation therapy and pre-treatment plasma A1AT level
• Willing to remain off PAT for at least 3 months following treatment
• Body mass index 18 to 35 kg/m2
• Fertile men and women of childbearing potential must agree to use barrier contraception for 3 months after treatment

Key Exclusion Criteria:

• FEV1 <35 percent of predicted value at the Screening visit
• Receiving systemic corticosteroids or other immunosuppressive medications
• Immunodeficiency disease or evidence of active infection of any type, including human immunodeficiency virus
• Abnormal liver function tests
• Organ transplant recipient or awaiting transplantation
• Participation in another current or previous gene transfer study
• AAVrh.10 neutralizing antibody titer ≥ 1:5
• Female who is pregnant or lactating
• History of alcohol or drug abuse within the past 5 years
• Any history of allergies that may prohibit study-specific investigations
• Receiving an investigational medicinal product or participating in another investigational study within 3 months prior to consent
• Cigarette smoking, or any other tobacco use, e-cigarettes or other recreational inhalant within 1 year of the Screening Visit

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02168686
• Other Study ID Numbers: ADVM-043-01
• 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: Adverum Biotechnologies, Inc.
• Original Responsible Party: Weill Medical College of Cornell University
• Current Study Sponsor: Adverum Biotechnologies, Inc.
• Original Study Sponsor: Weill Medical College of Cornell University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Charlton Strange, MD; Medical University of South Carolina, Charleston, SC, USA
• Principal Investigator: Friedrich Kueppers, MD; Temple University Hospital, Philadelphia, PA, USA
• Principal Investigator: Mark Brantly, MD; University of Florida, Gainesville, FL, USA
• Principal Investigator: Kyle Hogarth, MD; University of Chicago Medical Center, Chicago, IL, USA
• Principal Investigator: Igor Barjakatarevic, MD; Ronald Reagan UCLA Medical Center, Santa Monica, CA, USA

• PRS Account: Adverum Biotechnologies, Inc.
• Verification Date: September 2023