A Phase 1/2, Open‑Label, Multi‑Center, Dose Escalation, Dose Expansion, and Single Repeat Dose Study of TSRA‑196 in Adults With the PiZZ Genotype Who Have Lung and/or Liver Disease Associated With Severe Alpha‑1 Antitrypsin Deficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Tessera Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18]

Decision date (initial)

2026-06-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Tessera Therapeutics, Inc.

External identifiers

EU CT number

2025-523497-16-00

ClinicalTrials.gov

NCT07227207

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety, Therapy, Dose response

Part 1: To evaluate the safety and tolerability of a single dose of TSRA-196 in adults with AATD
Part 2: To evaluate the efficacy of a single dose of TSRA-196 in adults with AATD
Part 3: To evaluate the efficacy of a second dose of TSRA-196 in adult participants with AATD

Secondary objectives 12

1. Part 1: To evaluate the efficacy of a single dose of TSRA-196
2. Part 1 and 2: To evaluate the incidence of AESIs after a single dose of TSRA-196
3. Part 1 and 2: To evaluate changes in safety laboratory values, vital signs and ECG parameters after a single dose of TSRA-196
4. Part 1 and 2: To evaluate the PK of TSRA-196
5. Part 2: To evaluate the safety and tolerability of a single dose of TSRA-196
6. Part 2: To evaluate additional efficacy endpoints for a single dose of TSRA-196
7. Part 3: To evaluate the safety and tolerability of a second dose of TSRA-196
8. Part 3: To evaluate additional efficacy endpoints for a second dose of TSRA-196 in adult participants with AATD
9. Part 3: To evaluate the incidence of AESIs following a second dose of TSRA-196
10. Part 3: To evaluate the PK of a second dose of TSRA-196
11. Part 2 and 3: To evaluate the effect of TSRA-196 on lung function
12. Part 2 and 3: To evaluate the effect of TSRA-196 on COPD exacerbations

Conditions and MedDRA coding

Lung and/or Liver Disease Associated with Alpha-1 Antitrypsin Deficiency (AATD)

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, National Agency For The Safety Of Medicine And Health Products, Food And Drug Administration, Medicines And Healthcare Products Regulatory Agency, Norwegian Medical Products Agency, Health Canada, Medicines Evaluation Board, Swedish Medical Products Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Males or females who are 18 to 70 years of age, inclusive, at the time of signing the informed consent
2. Body mass index of 18 to 37 kg/m2, inclusive
3. Confirmed diagnosis of AATD and PiZZ genotype
4. At least one previous measure of blood total AAT level <11 μmol/L
5. Nonsmoker for at least 6 months before screening and must remain nonsmoking for the entire study duration
6. Agrees to not consume alcohol for 14 days before TSRA-196 administration and for 30 days after TSRA-196 administration and understands that they should not consume significant amounts of alcohol consumption for the entire study duration.
7. Total bilirubin value at screening with or without Gilbert’s syndrome as defined in the protocol.
8. Laboratory, hematology values as defined in the protocol
9. Either AAT treatment-naïve or washed out of all investigational or approved treatments that modify AAT levels
10. Part 1A and 2A (AATD lung disease with no or minimal liver fibrosis) • Clinically significant lung disease at baseline that is not more severe than specified in the exclusion criteria • No or minimal liver fibrosis determined by liver biopsy or non-invasive assessment at baseline
11. Part 1B and 2B (AATD liver disease with significant or severe liver fibrosis, with or without AATD lung disease) • Moderate-to-severe liver fibrosis determined by liver biopsy at baseline

Exclusion criteria 18

1. Presence of genetic variation in the region around the PiZ variant that may disrupt the function of TSRA-196, determined by screening genotyping.
2. Seropositive for HIV (HIV-1 or HIV-2), active hepatitis B (HBsAg or HBcAb positive with detectable HBV DNA), or hepatitis C infection (Parts 1A/2A: HCV RNA positive; Parts 1B/2B: HCV RNA and/or antibody positive)
3. History of thromboembolic disease, myocardial infarction, or stroke within 6 months of screening
4. Uncontrolled hypertension as defined in the protocol
5. History of LNP-related reaction classified as CTCAE Grade 3 or higher
6. History of active malignancy within 5 years before screening, except basal cell carcinoma of the skin, curatively resected squamous cell carcinoma of the skin, cervical carcinoma in situ curatively treated or low-grade prostate adenocarcinoma for which appropriate management is observation alone.
7. Presence of a null or projected loss-of-function variant in the SERPINA1 gene determined by screening genotyping.
8. History of liver disease unrelated to AATD
9. History of or clinical signs of cirrhosis, e.g., varices or ascites.
10. Significant lung disease not attributable to manifestations of AATD, as determined by the investigator.
11. 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.
12. Unstable AATD-related COPD, as determined by the investigator, or severe bronchiectasis
13. Lung volume reduction surgery within 1 year before screening or plan to receive lung volume reduction surgery during the study period (between Screening and the Month 12 EOS visit).
14. Documented chronic need for positive airway pressure therapy beyond nocturnal use
15. Has received an organ transplant or is on a waiting list for an organ transplant.
16. Dependent on continuous supplementary oxygen
17. Immunization within 30 days before dosing for attenuated live vaccines and 14 days before dosing for all other vaccines.
18. Prior treatment with gene therapy using viral vectors or intended to permanently change the patient’s DNA. Prior treatment with RNA therapeutics is acceptable.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part 1: Incidence of TEAEs and SAEs Part 2: Proportion of participants who have serum levels of total AAT ≥LLN at Month 3 and Month 6 after TSRA-196 treatment Part 3: Proportion of participants who have serum levels of total AAT ≥LLN at Month 3 and Month 6 after a second dose of TSRA-196 Part 2 and 3: Change from baseline in functional AAT concentrations (determined using an elastase inhibition assay) to Month 12

Secondary endpoints 14

1. Part 1: Proportion of participants who have serum levels of total AAT ≥LLN: • at Month 3 and Month 6 after TSRA-196 treatment • from Month 6 through Month 12 after TSRA-196 treatment • from Month 3 through Month 12 after TSRA-196 treatment
2. Part 1: Proportion of participants who have serum levels of total AAT ≥11 μM: • at Month 3 and Month 6 after TSRA-196 treatment • from Month 6 through Month 12 after TSRA-196 treatment • from Month 3 through Month 12 after TSRA-196 treatment
3. Part 1 and 2 and 3: Change in serum levels of total AAT from baseline over time
4. Part 1 and 2 and 3: Incidence of AESI from day of dosing through EOS/ET
5. Part 1 and 2 and 3: Change in clinical laboratory parameters, vital signs, and ECG parameters over time
6. Part 1 and 2 and 3: PK parameters for • ionizable lipid in blood • DMG-PEG2000 in blood • mRNA in blood • tgRNA in blood
7. Part 2 and 3: Incidence of TEAEs and SAEs
8. Part2: Proportion of participants who have serum levels of total AAT ≥LLN • from Month 6 through Month 12 after TSRA-196 treatment • from Month 3 through Month 12 after TSRA-196 treatment
9. Part 2: Proportion of participants who have serum levels of total AAT ≥11 μM: • at Month 3 and Month 6 after TSRA-196 treatment • from Month 6 through Month 12 after TSRA-196 treatment • from Month 3 through Month 12 after TSRA-196 treatment
10. Part 3: Proportion of participants who have serum levels of total AAT ≥LLN: • from Month 6 through Month 12 after a second dose of TSRA-196 • from Month 3 through Month 12 after a second dose of TSRA-196
11. Part 3: Proportion of participants who have serum levels of total AAT ≥11 μM: • at Month 3 and Month 6 after a second dose of TSRA-196 • from Month 6 through Month 12 after a second dose of TSRA-196 • from Month 3 through Month 12 after a second dose of TSRA-196
12. Part 2 and 3: Change from baseline in functional AAT concentrations (determined using an elastase inhibition assay) to Month 3 and to Month 6
13. Part 2 and 3: Change from baseline in post-bronchodilator ppFEV1 through Month 12
14. Part 2 and 3: Incidence of COPD exacerbations from baseline over time

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Tessera Therapeutics Inc.

Sponsor organisation

Tessera Therapeutics Inc.

Address

101 South Street Suite 500

City

Somerville

Postcode

02143-4278

Country

United States

Scientific contact point

Organisation

Tessera Therapeutics Inc.

Contact name

Susan Sparks

Public contact point

Organisation

Tessera Therapeutics Inc.

Contact name

Christina Zhang

Third parties 5

Locations

3 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications