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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Genetic: ADVM-043


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Dose 1<br>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<br>* Gene transfer vector administration<br>* Other names: AAVrh.10hA1AT;|
| Experimental: Part A: Dose 2<br>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<br>* Gene transfer vector administration<br>* Other names: AAVrh.10hA1AT;|
| Experimental: Part A: Dose 3<br>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<br>* Gene transfer vector administration<br>* Other names: AAVrh.10hA1AT;|
| Experimental: Part A: Dose 4<br>ADVM-043 administered at a dose that will be determined | Genetic: ADVM-043<br>* Gene transfer vector administration<br>* Other names: AAVrh.10hA1AT;|
| Experimental: Part B (optional): Intrapleural administration<br>ADVM-043 administered intrapleurally at a dose that will be determined | Genetic: ADVM-043<br>* Gene transfer vector administration<br>* Other names: AAVrh.10hA1AT;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks | Change from baseline at Week 52 of plasma concentration of M-specific A1AT for subjects who did not receive PAT post-dose Note: 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. 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. | At Week 52 | 
| Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose | At Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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