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

Sponsor
Adverum Biotechnologies, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02168686
Collaborator
(none)
6
Enrollment
2
Locations
5
Arms
21
Actual Duration (Months)
3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Genetic: ADVM-043
 Phase 1/Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
6 participants
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.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
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
Actual Study Start Date :
Nov 28, 2017
Actual Primary Completion Date :
Aug 29, 2019
Actual Study Completion Date :
Aug 29, 2019

Arms and Interventions

Arm Intervention/Treatment
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

Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

    		•
    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

    Genetic: ADVM-043
    Gene transfer vector administration
    Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

    		•
    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

    Genetic: ADVM-043
    Gene transfer vector administration
    Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

    		•
    Experimental: Part A: Dose 4

    ADVM-043 administered at a dose that will be determined

    Genetic: ADVM-043
    Gene transfer vector administration
    Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

    		•
    Experimental: Part B (optional): Intrapleural administration

    ADVM-043 administered intrapleurally at a dose that will be determined

    Genetic: ADVM-043
    Gene transfer vector administration
    Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Treatment-emergent Adverse Events Related to ADVM-043 [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

    2. Abnormal Changes in Clinical Laboratory Parameters [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

    Secondary Outcome Measures

    1. Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks [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

    2. Changes in Total Plasma Concentrations of A1AT up to 52 Weeks [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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Florida Gainesville Florida United States 32610
    2 Medical University of South Carolina Charleston South Carolina United States 29425

    Sponsors and Collaborators

    • Adverum Biotechnologies, Inc.

    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

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Adverum Biotechnologies, Inc.
    ClinicalTrials.gov Identifier:
    NCT02168686
    Other Study ID Numbers:
    • ADVM-043-01
    First Posted:
    Jun 20, 2014
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Aug 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Adverum Biotechnologies, Inc.
    alpha-1 antitrypsin deficiency
    alpha1-antitrypsin deficiency
    alpha-1-antitrypsin deficiency
    alpha1AT
    A1AT
    ADVM-043
    AAVrh.10halpha1AT
    AAVrh.10hA1AT
    Gene transfer vector
    Gene therapy
    Lung disease
    Emphysema
    COPD
    ADVANCE study
    ADVM-043-01
    Additional relevant MeSH terms:
    Alpha 1-Antitrypsin Deficiency

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Arm/Group Description Single IV infusion of ADVM-043 at 8E13 total vg Single IV infusion of ADVM-043 at 4E14 total vg Single IV infusion of ADVM-043 at 1.2E15 total vg
    Period Title: Overall Study
    STARTED 2 2 2
    COMPLETED 2 2 2
    NOT COMPLETED 0 0 0

    Baseline Characteristics

    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3 Total
    Arm/Group Description Single IV infusion of ADVM-043 at 8E13 total vg Single IV infusion of ADVM-043 at 4E14 total vg Single IV infusion of ADVM-043 at 1.2E15 total vg Total of all reporting groups
    Overall Participants 2 2 2 6
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    2
    100%
    2
    100%
    1
    50%
    5
    83.3%
    >=65 years
    0
    0%
    0
    0%
    1
    50%
    1
    16.7%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    40.5
    53.5
    61.0
    51.7
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    1
    50%
    2
    100%
    3
    50%
    Male
    2
    100%
    1
    50%
    0
    0%
    3
    50%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    2
    100%
    2
    100%
    2
    100%
    6
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    2
    100%
    2
    100%
    2
    100%
    6
    100%

    Outcome Measures

    1. Primary Outcome
    Title Treatment-emergent Adverse Events Related to ADVM-043
    Description Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043
    Time Frame From ADVM-043 infusion through End-of-Study visit at 52 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Arm/Group Description Single IV infusion of ADVM-043 at 8E13 total vg Single IV infusion of ADVM-043 at 4E14 total vg Single IV infusion of ADVM-043 at 1.2E15 total vg
    Measure Participants 2 2 2
    Count of Participants [Participants]
    0
    0%
    1
    50%
    2
    100%
    2. Primary Outcome
    Title Abnormal Changes in Clinical Laboratory Parameters
    Description Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters
    Time Frame From ADVM-043 infusion through End-of-Study visit at 52 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3 Total
    Arm/Group Description Single IV infusion of ADVM-043 at 8E13 total vg Single IV infusion of ADVM-043 at 4E14 total vg Single IV infusion of ADVM-043 at 1.2E15 total vg All Participants
    Measure Participants 2 2 2 6
    Neutrophil Count Shifts to High
    2
    100%
    1
    50%
    2
    100%
    5
    83.3%
    Neutrophil Count Shifts to Low
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hemoglobin Shifts to High
    0
    0%
    1
    50%
    1
    50%
    2
    33.3%
    Hemoglobin Shifts to Low
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal)
    1
    50%
    1
    50%
    1
    50%
    3
    50%
    Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal
    0
    0%
    1
    50%
    1
    50%
    2
    33.3%
    Alanine Transaminase Shifts to High (max >3.0×upper limit of normal)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal)
    0
    0%
    1
    50%
    1
    50%
    2
    33.3%
    Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal)
    0
    0%
    0
    0%
    1
    50%
    1
    16.7%
    Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alkaline Phosphatase Shifts to High
    0
    0%
    0
    0%
    1
    50%
    1
    16.7%
    Creatinine Shifts to High
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Creatinine Shifts to Low
    0
    0%
    0
    0%
    1
    50%
    1
    16.7%
    Creatine Kinase Shifts to High
    1
    50%
    0
    0%
    1
    50%
    2
    33.3%
    Creatine Kinase Shifts to Low
    1
    50%
    0
    0%
    0
    0%
    1
    16.7%
    Albumin Shifts to High
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Albumin Shifts to Low
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Direct Bilirubin Shifts to High
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Direct Bilirubin Shifts to Low
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Serum Glucose Shifts to High
    2
    100%
    1
    50%
    1
    50%
    4
    66.7%
    Serum Glucose Shifts to Low
    1
    50%
    0
    0%
    2
    100%
    3
    50%
    3. Secondary Outcome
    Title Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks
    Description Change from baseline at Week 52 of plasma concentration of M-specific A1AT for subjects who did not receive PAT post -dose
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    Not analyzed per the statistical analysis plan because participants initiated PAT therapy
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3 Total: All Participants
    Arm/Group Description Single IV infusion at 8E13 total vg Single IV infusion at 4E14 total vg Single IV infusion at 1.2E15 total vg All subjects who received ADVM-043
    Measure Participants 2 0 0 2
    Mean (Standard Deviation) [uM]
    88.050
    (19.955)
    88.050
    (19.955)
    4. Secondary Outcome
    Title Changes in Total Plasma Concentrations of A1AT up to 52 Weeks
    Description Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose
    Time Frame At Week 52

    Outcome Measure Data

    Analysis Population Description
    Not analyzed per the statistical analysis plan because participant initiated PAT therapy
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3 Total: All Participants
    Arm/Group Description Single IV infusion of ADVM-043 8E13 total vg Single IV infusion of ADVM-043 4E14 total vg Single IV infusion of ADVM-043 1.2E15 total vg All participant who received ADVM-043
    Measure Participants 2 2 2 6
    Mean change from Baseline at Week 24 serum Total Protein
    1.230
    1.870
    1.145
    1.415
    Mean change from Baseline at Week 52 serum Total Protein
    1.220
    0.640
    1.027

    Adverse Events

    Time Frame From ADVM-043 infusion through End-of-Study visit at 52 weeks
    Adverse Event Reporting Description Subject incidence of treatment-emergent serious adverse events
    Arm/Group Title Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Arm/Group Description Single IV infusion of ADVM-043 at 8E13 total vg Single IV infusion of ADVM-043 at 4E14 total vg Single IV infusion of ADVM-043 at 1.2E15 total vg
    All Cause Mortality
    Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 0/2 (0%) 0/2 (0%)
    Serious Adverse Events
    Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 2/2 (100%) 1/2 (50%)
    Infections and infestations
    Clostridium difficile colitis 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Influenza 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 2
    Pulmonary embolism 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Other (Not Including Serious) Adverse Events
    Part A: Dose 1 Part A: Dose 2 Part A: Dose 3
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/2 (100%) 2/2 (100%) 2/2 (100%)
    Gastrointestinal disorders
    Diarrhea 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Dysphagia 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Nausea 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Toothache 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    General disorders
    Face oedema 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Oedema peripheral 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Infections and infestations
    Bronchitis 0/2 (0%) 0 1/2 (50%) 1 1/2 (50%) 1
    Pneumonia 1/2 (50%) 1 1/2 (50%) 1 0/2 (0%) 0
    Chronic sinusitis 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Tooth abscess 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Upper respiratory tract infection 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Viral upper respiratory tract infection 1/2 (50%) 1 0/2 (0%) 0 1/2 (50%) 1
    Investigations
    Transaminases increased 0/2 (0%) 0 0/2 (0%) 0 2/2 (100%) 3
    Cortisol decreased 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Crystal urine present 0/2 (0%) 0 0/2 (0%) 0 1/2 (50%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Bursitis 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Psychiatric disorders
    Anxiety disorder 1/2 (50%) 1 0/2 (0%) 0 0/2 (0%) 0
    Insomnia 1/2 (50%) 1 0/2 (0%) 0 0/2 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/2 (0%) 0 1/2 (50%) 1 0/2 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/2 (0%) 0 1/2 (50%) 1 1/2 (50%) 1
    Vascular disorders
    Hypertension 1/2 (50%) 1 0/2 (0%) 0 0/2 (0%) 0

    Limitations/Caveats

    Enrollment was stopped after dosing was complete for participants in Cohorts 1, 2, and 3 of Part A. Cohort 4 of Part A and Part B were not enrolled. Only 6 of the up to 25 potentially anticipated participants were enrolled and received study treatment.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Disclosure restrictions on the PIs are that Sponsor can review communications by the PI prior to public release and can embargo communications regarding trial results for varying time periods from the time submitted to the sponsor for review. The Sponsor may require changes to the communication after review and may delay publication upon request by the Sponsor to allow the Sponsor to seek/obtain patent protection.

    Results Point of Contact

    Name/Title Chief Development Officer
    Organization Adverum Biotechnology, Inc.
    Phone 650-649-1413
    Email sseyedkazemi@adverum.com
    Responsible Party:
    Adverum Biotechnologies, Inc.
    ClinicalTrials.gov Identifier:
    NCT02168686
    Other Study ID Numbers:
    • ADVM-043-01
    First Posted:
    Jun 20, 2014
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Aug 1, 2022