Alpha 1-Antitrypsin Deficiency
Conditions
Keywords
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
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.
Interventions
GENETICADVM-043
Gene transfer vector administration
Sponsors
Adverum Biotechnologies, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Dose 1 Single IV infusion of ADVM-043 at 8E13 total vg | 2 |
| Part A: Dose 2 Single IV infusion of ADVM-043 at 4E14 total vg | 2 |
| Part A: Dose 3 Single IV infusion of ADVM-043 at 1.2E15 total vg | 2 |
| Total | 6 |
Baseline characteristics
| Characteristic | Total | Part A: Dose 2 | Part A: Dose 3 | Part A: Dose 1 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 51.7 years | 53.5 years | 61.0 years | 40.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 6 participants | 2 participants | 2 participants | 2 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 2 / 2 | 1 / 2 |
Outcome results
Primary
Abnormal Changes in Clinical Laboratory Parameters
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to High | 1 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to High | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to Low | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to Low | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to Low | 1 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to Low | 1 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to High | 2 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to High | 2 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to High | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to High | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal) | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 1 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to Low | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to Low | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to High | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to Low | 0 participants |
| Part A: Dose 1 | Abnormal Changes in Clinical Laboratory Parameters | Alkaline Phosphatase Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to High | 1 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 1 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to Low | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal | 1 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to High | 1 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 1 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal) | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Alkaline Phosphatase Shifts to High | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 2 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to High | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to High | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to High | 2 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to Low | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to High | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to Low | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal) | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Alkaline Phosphatase Shifts to High | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to High | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to Low | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to High | 1 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to Low | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to Low | 2 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to Low | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to High | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to Low | 0 participants |
| Part A: Dose 3 | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to High | 1 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to Low | 3 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to High | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal) | 1 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Serum Glucose Shifts to High | 4 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Albumin Shifts to Low | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 2 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >3.0×upper limit of normal) | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to Low | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to High | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal | 2 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal) | 3 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Neutrophil Count Shifts to High | 5 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Direct Bilirubin Shifts to Low | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to Low | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to High | 2 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to Low | 1 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Hemoglobin Shifts to High | 2 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Creatine Kinase Shifts to Low | 1 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Creatinine Shifts to High | 0 participants |
| Total | Abnormal Changes in Clinical Laboratory Parameters | Alkaline Phosphatase Shifts to High | 1 participants |
Primary
Treatment-emergent Adverse Events Related to ADVM-043
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Dose 1 | Treatment-emergent Adverse Events Related to ADVM-043 | 0 Participants |
| Part A: Dose 2 | Treatment-emergent Adverse Events Related to ADVM-043 | 1 Participants |
| Part A: Dose 3 | Treatment-emergent Adverse Events Related to ADVM-043 | 2 Participants |
Secondary
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: 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.
Time frame: At Week 52
Population: Not analyzed per the statistical analysis plan because participants initiated PAT therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Dose 1 | Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks | 88.050 uM | Standard Deviation 19.955 |
| Total | Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks | 88.050 uM | Standard Deviation 19.955 |
Secondary
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
Time frame: At Week 52
Population: Not analyzed per the statistical analysis plan because participant initiated PAT therapy
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A: Dose 1 | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 24 serum Total Protein | 1.230 uM |
| Part A: Dose 1 | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 52 serum Total Protein | 1.220 uM |
| Part A: Dose 2 | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 24 serum Total Protein | 1.870 uM |
| Part A: Dose 3 | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 52 serum Total Protein | 0.640 uM |
| Part A: Dose 3 | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 24 serum Total Protein | 1.145 uM |
| Total | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 24 serum Total Protein | 1.415 uM |
| Total | Changes in Total Plasma Concentrations of A1AT up to 52 Weeks | Mean change from Baseline at Week 52 serum Total Protein | 1.027 uM |