Study of rnaivt9315 and rnacs24757 in Adults with Lung or Liver Disease due to Severe Alpha‑1 Antitrypsin Deficiency (PiZZ)

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What is this study about?

Adults who carry the PiZZ genotype of Alpha-1 Antitrypsin Deficiency often develop problems in the lungs, the liver, or both; the condition reduces a natural protein that protects lung tissue and can lead to breathing difficulties and liver damage. The study focuses on people with these lung and/or liver complications linked to this rare genetic disorder.

The investigational medicine, TSRA-196, is given as an intravenous (IV) infusion, meaning it is delivered directly into a vein through a small needle. It contains specially designed RNA molecules that aim to boost the body’s own production of the protective protein. The treatment is being tested to see if it can safely raise the level of this protein in the blood and improve its function.

The purpose of the study is to evaluate safety and the ability of the drug to increase protein levels after one dose and after a possible second dose. Participants receive a single infusion, then attend follow‑up visits over several months during which blood samples are taken to measure protein amounts and functional activity using an elastase inhibition assay, and health checks are performed to monitor any side effects. A second infusion may be given later, followed by the same monitoring schedule.

1 baseline evaluation

after enrollment, you will undergo a baseline evaluation that includes medical history, physical examination, laboratory blood tests, and lung function testing. the purpose is to document your condition before receiving any study medication.

the evaluation also confirms the presence of the pizz genotype associated with severe aatt deficiency and assesses any existing lung or liver disease.

2 first infusion of tsra-196 (single dose)

you will receive a single intravenous infusion of tsra-196. the medication is delivered through a vein as a solution for infusion. the exact amount of the dose is defined by the study protocol and is not disclosed here.

the infusion is administered in a clinical setting and typically lasts for a period determined by the study team.

3 post‑infusion safety monitoring

following the infusion, you will be observed for immediate side effects. monitoring continues for several days to record any treatment‑emergent adverse events (teae) or serious adverse events (sae).

you may be asked to keep a diary of symptoms and report any new health concerns to the study staff.

4 month 3 assessment

approximately three months after the first infusion, you will return for a follow‑up visit. blood samples will be taken to measure total aatt levels and functional aatt activity.

additional tests may include lung function measurement and safety laboratory assessments.

5 month 6 assessment

around six months after the first infusion, a second follow‑up visit is scheduled. the same laboratory and clinical evaluations performed at month 3 are repeated.

the results help determine whether total aatt levels remain at or above the lower limit of normal (lln).

6 month 12 assessment

twelve months after the first infusion, a final long‑term assessment is conducted. this includes measurement of total and functional aatt, lung function testing, and safety evaluations.

the data collected contribute to the overall evaluation of the treatment’s efficacy and safety.

7 second infusion of tsra-196 (if applicable)

depending on the study design, a second intravenous infusion of tsra-196 may be administered as a single dose. the timing of this dose is determined by the protocol after review of earlier results.

the second infusion follows the same procedure as the first dose.

8 follow‑up after second dose

after the second infusion, you will have follow‑up visits at approximately month 3 and month 6 to repeat blood tests for total and functional aatt, as well as safety assessments.

these visits are intended to evaluate whether the second dose maintains or improves aatt levels compared with baseline.

Who Can Join the Study?

Age: You must be 18 to 70 years old when you sign the consent form.
Gender: Both men and women can join.
Body weight: Your body‑mass index (BMI) must be between 18 and 37 kg/m² (a measure of weight relative to height).
Confirmed AATD diagnosis: You need a proven diagnosis of alpha‑1 antitrypsin deficiency (AATD) with the specific PiZZ genotype (a genetic test result).
Low AAT level: At least one blood test must show a total AAT level lower than 11 μmol/L (indicates deficiency).
No recent smoking: You must have not smoked for at least 6 months before screening and must stay non‑smoking for the whole study.
Alcohol restriction: You must avoid alcohol for 14 days before receiving the study drug, for 30 days after, and not drink large amounts at any other time during the study.
Lung disease group (Part 1A/2A): If you have lung disease related to AATD, it must be clinically significant but not more severe than the study’s exclusion limits, and you must have no or only minimal liver scarring (fibrosis) as shown by a liver biopsy or a non‑invasive test.
Liver disease group (Part 1B/2B): If you have liver disease related to AATD, you must have moderate‑to‑severe liver scarring (fibrosis) confirmed by a liver biopsy, with or without lung disease.
Liver fibrosis: This refers to scarring of the liver tissue, which can be mild (minimal) or more serious (moderate‑to‑severe).
Liver biopsy: A small sample of liver tissue taken with a needle to examine under a microscope for scarring.
Bilirubin level: Your blood test for bilirubin (a substance made when red blood cells break down) must meet the study’s required range, even if you have Gilbert’s syndrome (a common, mild condition that can raise bilirubin slightly).
Laboratory and blood counts: Your other lab results (such as blood cell counts) must fall within the ranges set by the study protocol.
Previous AAT treatment: You must either have never received treatment for AAT deficiency (treatment‑naïve) or have stopped any such treatments long enough to clear them from your body (washed out).

Who Cannot Join the Study?

Having a genetic change near the PiZ variant that might affect how the study drug works, found by a DNA test (called genotyping).
Having serious lung disease that is not caused by Alpha‑1 Antitrypsin Deficiency (AATD), as judged by the doctor.
Being hospitalized one or more times for a severe flare‑up of lung disease in the year before screening, or having received intravenous (IV) antibiotics for a lung infection within the past 6 months.
Having unstable AATD‑related chronic obstructive pulmonary disease (COPD) or severe widening of the airways called bronchiectasis, as judged by the doctor.
Having had lung‑volume‑reduction surgery in the past year, or planning to have this surgery during the study period.
Needing continuous positive airway pressure therapy (a machine that helps keep the airway open) for more than just nighttime use.
Having received an organ transplant or being on a waiting list for an organ transplant.
Being dependent on continuous supplemental oxygen.
Having received a live, weakened (attenuated) vaccine within 30 days before the study dose, or any other vaccine within 14 days before the dose.
Having previously received gene therapy that uses viruses to change DNA, or planning to permanently alter DNA (RNA‑based treatments are allowed).
Testing positive for HIV, active hepatitis B (positive blood tests for hepatitis B surface antigen or core antibody with detectable virus DNA), or hepatitis C (positive RNA test or antibody, depending on the study part).
Having a history of blood clot problems, heart attack (myocardial infarction), or stroke within the past 6 months.
Having high blood pressure that is not under control, as defined in the study rules.
Having had a serious reaction to the lipid nanoparticle (LNP) component of the drug that is rated Grade 3 or higher on the standard toxicity scale (CTCAE).
Having an active cancer diagnosed within the past 5 years, except for certain skin cancers (basal cell carcinoma, squamous cell carcinoma that was completely removed), treated cervical precancer, or low‑grade prostate cancer that is only being watched.
Having a “null” or loss‑of‑function change in the SERPINA1 gene, identified by DNA testing.
Having liver disease that is not caused by AATD.
Having signs of liver scarring (cirrhosis), such as enlarged veins in the esophagus (varices) or fluid buildup in the abdomen (ascites).

Where you can join this trial?

Verified and Recommended Sites

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Verified Sites

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Other Sites

Site Name	City	Country
Beaumont Hospital	Dublin	Ireland
Karolinska University Hospital	Solna	Sweden
Queen Silvia Childrens Hospital – Sahlgrenska University Hospital – Vaestra Goetalandsregionen	Gothenburg	Sweden
Lmyue Uzmxqcytyzpx Momqqva Ciegtww (jdtxb	Leiden	The Netherlands

Trial status

Country	Status	Recruitment Start
Ireland	Not yet recruiting	30.04.2026
Sweden	Not yet recruiting	30.04.2026
The Netherlands	Not yet recruiting	30.04.2026

Trial locations

TSRA-196 is an experimental medicine being tested for the first time in people who have severe alpha‑1 antitrypsin deficiency (AATD). It is given as a liquid that is infused into a vein. The product contains specially designed RNA molecules that are meant to help the body make more of the missing protein, alpha‑1 antitrypsin, which protects the lungs and liver. In this study, participants receive a single infusion of TSRA‑196 to see if it is safe and well‑tolerated, and then researchers look at how well it works to raise the protein levels and improve lung or liver health. A second dose may be given later to further test its effectiveness.

Investigated diseases:

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency-associated lung and/or liver disease – This condition occurs when a genetic lack of alpha‑1 antitrypsin reduces protection of lung tissue, allowing enzymes to damage the airways over time. In the lungs, the damage can lead to a gradual loss of breathing capacity and increased airway obstruction. In the liver, the abnormal protein can accumulate, causing slowly progressive liver changes. Both organ systems may show worsening function as the deficiency persists.

Trial ID:

2025-523497-16-00

Protocol code:

TSRA196-AAT-201

NCT ID:

NCT07227207

Trial Phase:

Phase I and Phase II (Integrated) – First administration to humans

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Study of rnaivt9315 and rnacs24757 in Adults with Lung or Liver Disease due to Severe Alpha‑1 Antitrypsin Deficiency (PiZZ)

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?