Alpha-1 Antitrypsin Deficiency (AATD)
Conditions
Brief summary
This is a Phase 1/2, open-label, multi-center, dose escalation (Part 1), dose expansion (Part 2), and single repeat dose (Part 3) study to evaluate the safety, tolerability, efficacy, and PK/PD parameters of TSRA-196 in adults with the PiZZ genotype who have lung and/or liver disease associated with severe alpha-1 antitrypsin deficiency (AATD)
Interventions
DRUGTSRA-196
TSRA-196 is an in-vivo genome editing product formulated in lipid nanoparticles (LNPs) for the treatment of patients with alpha-1 antitrypsin deficiency (AATD), via intravenous (IV) infusion
Sponsors
Tessera Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent * Body mass index of 18 to 37 kg/m2, inclusive * Confirmed diagnosis of AATD and PiZZ genotype * At least one previous measure of blood total AAT level \<11 µmol/L * Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration * Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels for 5 half-lives or at least 4 weeks, whichever is longer, before TSRA-196 administration Parts 1A and 2A (AATD lung disease with no or minimal liver fibrosis) * Clinically significant lung disease, defined as 1) evidence of emphysema or bronchiectasis by computed tomography or 2) DLCO \<70% of the predicted value or 3) ppFEV1 \<80% * ppFEV1 ≥35% * METAVIR fibrosis score F0 or F1 confirmed by liver biopsy at screening, or a liver stiffness measure by FibroScan ≤7 kPa at screening * FIB-4 index score ≤3.25 at screening * ALT and/or AST \<ULN at screening Parts 1B and 2B (AATD liver disease with significant or severe liver fibrosis, with or without AATD lung disease) * METAVIR fibrosis score F2 or F3 confirmed by liver biopsy at screening. A liver biopsy conducted within 12 months before screening is acceptable as a substitute. * Liver stiffness measure by FibroScan \>7 and ≤15 kPa at screening * ALT and/or AST \<2 x ULN at screening
Exclusion criteria
* Presence of genetic variation in SERPINA1 gene that may disrupt the function of TSRA-196, determined by screening genotyping * History of liver disease unrelated to AATD, or history of or clinical signs of cirrhosis * Significant lung disease not attributable to manifestations of AATD, as determined by the investigator * History of one or more hospitalizations due to severe exacerbation of underlying lung disease during the year before screening or received IV antibiotics for treatment of a pulmonary infection within 6 months before screening * Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis * Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period * Documented chronic need for positive airway pressure therapy beyond nocturnal use * Seropositive for human immunodeficiency virus (HIV) (HIV-1 or HIV-2) * Seropositive for hepatitis B (hepatitis B surface antigen \[HBsAg\] or hepatitis B core antibody \[HBcAb\] positive) with detectable HBV DNA * Hepatitis C virus (HCV) RNA positive at screening (Parts 1A and 2A), or HCV RNA positive and/or HCV antibody positive at screening (Parts 1B and 2B) * Has received an organ transplant or is on a waiting list for an organ transplant * Prior treatment with gene therapy using viral vectors or intended to permanently change the patient's DNA * Any investigational products within 30 days before dosing or plan to take an investigational product before the end of study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 (Dose Escalation): Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | 1 Year |
| Part 2 (Dose Expansion): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after TSRA-196 treatment | 1 Year |
| Part 2 (Dose Expansion): Change in functional AAT concentrations (determined using an elastase inhibition assay) from baseline to end of study | 1 Year |
| Part 3 (Single Repeated Dose): Proportion of participants who have serum levels of total alpha-1 antitrypsin (AAT) greater than or equal to Lower Limit of Normal (LLN) after a second dose of TSRA-196 | 1 Year |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 (Dose Escalation): Proportion of participants who have serum levels of total AAT greater than or equal to LLN after TSRA-196 treatment | 1 Year |
| Part 2 (Dose Expansion): Incidence of TEAEs and SAEs | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Proportion of participants who have serum levels of total AAT greater than or equal to 11 μM after TSRA-196 treatment | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change in serum levels of total AAT from baseline over time | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Incidence of Adverse Event of Special Interest (AESI) from day of dosing through end of study | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change over time in safety measures, including clinical laboratory parameters, vital signs, and ECG parameters | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Pharmacokinetic (PK) parameter: Area under the blood concentration time curves (AUC) of TSRA-196 | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Maximum observed blood concentration (Cmax) of TSRA-196 | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Time to Cmax (tmax) of TSRA-196 | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Half-life (t1/2) of TSRA-196 | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Clearance (CL) of TSRA-196 | 1 Year |
| Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: The volume of distribution at terminal stage (Vz) of TSRA-196 | 1 Year |
| Part 2 (Dose Expansion): Change in post-bronchodilator percent predicted forced expiratory volume (ppFEV1) from baseline through end of study | 1 Year |
| Part 2 (Dose Expansion): Incidence of COPD exacerbations from baseline over time | 1 Year |
Countries
Australia, United Kingdom, United States
Contacts
CONTACTTessera Clinical Trials Information
Outcome results
None listed