A Study of TSRA-196 in Adults With PiZZ Alpha-1 Antitrypsin Deficiency (AATD)

Официальное название

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

Обзор

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)

Вмешательства

• Препарат TSRA-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

Первичные конечные точки

• Part 1 (Dose Escalation): Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) [Срок оценки: 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 [Срок оценки: 1 Year]
• Part 2 (Dose Expansion): Change in functional AAT concentrations (determined using an elastase inhibition assay) from baseline to end of study [Срок оценки: 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 [Срок оценки: 1 Year]

Вторичные конечные точки (12)

• Part 1 (Dose Escalation): Proportion of participants who have serum levels of total AAT greater than or equal to LLN after TSRA-196 treatment [Срок оценки: 1 Year]
• Part 2 (Dose Expansion): Incidence of TEAEs and SAEs [Срок оценки: 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 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): Change in serum levels of total AAT from baseline over time [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Maximum observed blood concentration (Cmax) of TSRA-196 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Time to Cmax (tmax) of TSRA-196 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Half-life (t1/2) of TSRA-196 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: Clearance (CL) of TSRA-196 [Срок оценки: 1 Year]
• Part 1 (Dose Escalation) and Part 2 (Dose Expansion): PK parameter: The volume of distribution at terminal stage (Vz) of TSRA-196 [Срок оценки: 1 Year]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 3 центра

• Clinical Study Center — Boston
• Clinical Study Center — Charleston
• Clinical Study Center — Seattle

Австралия · 1 центр

• Clinical Study Center — Fitzroy

Идентификаторы

NCT: NCT07227207 · TSRA196-AAT-201

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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