Study to Check the Safety of Fazirsiran and Learn if Fazirsiran Can Help People With Liver Disease and Scarring (Fibrosis) Due to an Abnormal Version of Alpha-1 Antitrypsin Protein

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify, Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

27 Jun 2023 → ongoing

Decision date (initial)

2023-05-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center America Inc, United State

External identifiers

EU CT number

2022-501943-34-00

ClinicalTrials.gov

NCT05677971

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis, Safety, Efficacy, Pharmacodynamic, Pharmacokinetic

The primary objective of this study is to evaluate the efficacy of fazirsiran compared with placebo at improving measures of histologic fibrosis in alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD).

Secondary objectives 1

1. 1. To evaluate the pharmacodynamic (PD) effect of fazirsiran via measurement of intrahepatic Z-alpha-1 antitrypsin (Z-AAT) protein. 2. To evaluate the impact of fazirsiran versus placebo on modulating disease progression as defined by progression to cirrhosis or decompensating liver-related clinical events. 3. To evaluate the safety and tolerability of fazirsiran compared with placebo with an emphasis on monitoring lung function, lung injury, and associated symptoms. 4. To evaluate the PD effect of fazirsiran via measurement of serum Z-AAT. 5. To evaluate the efficacy of fazirsiran compared with placebo at reducing histologic evidence of portal inflammation and Z-AAT polymer burden in the liver. 6. To use noninvasive measures of liver fibrosis (including biomarkers) to evaluate the efficacy of fazirsiran compared with placebo. 7. To evaluate the pharmacokinetics (PK) of fazirsiran

Conditions and MedDRA coding

Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda’s data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5 ). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. The participant must have a diagnosis of the PiZZ genotype AATD. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and protease inhibitor Z alleles) at screening. PiMZ or PiSZ genotypes are not permitted. 2. The participant, of any sex, is aged 18 to 75 years, inclusive. 3.The participant has evidence of METAVIR stage F2, F3, or F4 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading of a previous biopsy conducted within 6 months before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual. 4. The participant has a pulmonary status meeting the criteria listed on the Protocol

Exclusion criteria 1

1. 1. The participant has a history of liver decompensating events (overt hepatic encephalopathy [West Haven Grade ≥2] documented by a physician, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy). 2.The participant has a history of the presence of medium or large varices or varices with red wale signs based on a previous EGD within 6 months before the estimated enrollment date. 3. The participant has portal vein thrombosis. 4.The participant has a prior transjugular portosystemic shunt procedure. 5. The participant has evidence of other forms of chronic liver diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis. 6. The participant has a history of malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and a greater than 1-year disease-free interval may be entered after approval by the medical monitor.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of this study is decrease from baseline of at least stage of histologic fibrosis (Meta-Analysis of Histological Data in Viral Hepatitis [METAVIR] staging) in the centrally read liver biopsy done at Week 106 in AATD-LD with METAVIR stage F2 and F3 fibrosis (Yes/No).

Secondary endpoints 8

1. 1. Percent change from baseline in intrahepatic Z-AAT protein at Week 106 in AATD-LD with METAVIR stage F2 to F3 fibrosis.
2. 2. Decrease from baseline of at least 1 stage of histologic fibrosis (METAVIR staging) in the centrally read liver biopsy done at Week 202 in AATD-LD with METAVIR stage F2 to F4 fibrosis (Yes/No)
3. 3. Disease progression, which is defined as progression to cirrhosis or any of the qualifying liver-related clinical events by Week 202 in AATD-LD with METAVIR stage F2 to F4 fibrosis, including the occurrence of 1 or more of the following aggregated liver related clinical events during this period (Yes/No)
4. 4. Change from baseline in serum Z-AAT protein at Week 202 in AATD-LD with METAVIR stage F2 to F4 fibrosi
5. 5. Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by periodic acid Schiff plus diastase (PAS+D) staining in Week 202 liver biopsy in AATD-LD with METAVIR stage F2 to F4 fibros
6. 6. Change from baseline in intrahepatic portal inflammation in Week 202 liver biopsy in AATD-LD with METAVIR stage F2 to F4 fibrosis.
7. 7. Change from baseline in vibration-controlled transient elastography (VCTE)-derived liver stiffness at Week 202 in AATD-LD with METAVIR stage F2 to F4 fibrosis.
8. The secondary PK endpoints are: 1. Observed plasma concentrations of fazirsiran on Day 1 (predose, 2, 4, and 6 hours postdose), and predose and 2 hours postdose at Weeks 4, 16, 28, 40, 52, 76, 100, 124, 148, 172 and 196 and anytime at Weeks 106, 202, and safety follow-up.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Nirav Desai

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 16

Locations

13 EU/EEA countries · 38 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 401 files

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

Application history

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