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

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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 Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Number and proportion of subjects experiencing adverse events

Secondary Outcome

 Changes in plasma concentrations of M-specific A1AT up to 52 weeks


Alpha 1-Antitrypsin Deficiency



Study Arms / Comparison Groups

 Part A: Dose 1
Description:  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


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

November 28, 2017

Completion Date

August 29, 2019

Primary Completion Date

August 29, 2019

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




18 Years - N/A

Accepts Healthy Volunteers



Charlton Strange, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

Adverum Biotechnologies, Inc.

Study Sponsor

Charlton Strange, MD, Principal Investigator, Medical University of South Carolina, Charleston, SC, USA

Verification Date

January 2020