Shots:
- AATD-associated liver disease is a progressive genetic disorder with no approved therapy, and liver transplantation remains the only option for patients with end-stage disease.
- Fazirsiran is an investigational RNAi therapy designed to treat AATD-associated liver disease by lowering the production of Z-AAT.
- PharmaShots welcomes Dr. Chinwe Ukomadu, Head of the Gastrointestinal and Inflammation Therapeutic Area Unit at Takeda, for an illuminating discussion on the SEQUOIA trial.
Saurabh: Would you elaborate on the study design of open-label extension (OLE) of the SEQUOIA trial?
Chinwe: The SEQUOIA trial is a randomized double-blind study that enrolled 40 adults with a Pi*ZZ genotype to receive the investigational treatment fazirsiran 25, 100 or 200 mg or placebo subcutaneously. Subjects included those without fibrosis (F0) and with fibrosis (stages F1-F3). Patients with F4 (cirrhosis) were excluded. The randomized double-blind portion of SEQUOIA was followed by an open-label extension (OLE) trial where patients received fazirsiran 200 mg SC. The OLE was designed to evaluate the long-term (>1 year) safety and efficacy of the investigational treatment fazirsiran in patients with alpha-1 antitrypsin deficiency (AATD)-associated liver disease. To be eligible for the OLE, patients had to have fibrosis at screening and a post-dose liver biopsy performed at either Weeks 48, 72 or 96 during the double-blind stage. Eligible patients entered the OLE and received fazirsiran 200 mg every 12 weeks for a total treatment period of ≤197 weeks. Overall, 23 patients who received fazirsiran at 25 mg (n=4), 100 mg (n=5), 200 mg (n=5) or placebo (n=9) during the double-blind phase received ≥1 dose of fazirsiran 200 mg during the OLE trial.
Saurabh: What primary and secondary endpoints were you targeting in patients in the OLE of the SEQUOIA trial?
Chinwe: The OLE trial did not measure a primary endpoint. Study endpoints in the OLE included measurements for changes in serum Z-AAT levels, laboratory measures of liver enzymes (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)), safety outcomes and pulmonary functions.
Saurabh: Could you walk us through the findings of the SEQUOIA OLE study?
Chinwe: We’re pleased to share that results from the OLE of the Phase 2 SEQUOIA trial showed the safety and efficacy of fazirsiran, supporting its potential as an investigational treatment for patients with AATD-associated liver disease.
The OLE included 23 patients and reports data for up to 197 weeks – representing the longest Phase 2 trial in AATD-associated liver disease to date. Specifically, findings showed maintained or decreased serum Z-AAT levels, with some trends for laboratory measures of liver health and pulmonary function, which include:
- Maintained reductions in serum Z-AAT levels in the fazirsiran 200 mg/200 mg group (patients who received 200 mg in the double-blind phase of the trial).
- Further reductions in the fazirsiran 25 mg/200 mg and fazirsiran 100 mg/200 mg groups (patients who received 25 mg and 100 mg in the double-blind phase, respectively).
- An 85.5% mean reduction in serum Z-AAT levels in patients new to treatment with fazirsiran in the OLE trial (patients who received placebo in the double-blind phase of the study).
Fazirsiran was also associated with improved laboratory measures of liver health and stable pulmonary function.
Overall, safety findings included:
- 20 patients reported a treatment-emergent adverse event during the OLE trial; of those, most were mild or moderate, four were serious and one led to study withdrawal.
These results add to the evidence base supporting the further clinical development of fazirsiran in patients with AATD-associated liver disease.
Saurabh: Can you elaborate on the P-III REDWOOD study? What primary endpoints are you targeting in this study?
Chinwe: The randomized, double-blind, placebo-controlled Phase 3 REDWOOD study, which is currently recruiting patients, continues our efforts to evaluate the safety and efficacy of fazirsiran in adults with alpha-1 antitrypsin deficiency (AATD)-associated liver disease, with Pi*ZZ genotype. Aiming to enroll 160 participants, the trial will last approximately 4.5 years, including screening (up to 10 weeks), treatment (up to 196 weeks) and safety follow-up (six months).
The primary endpoint will assess the efficacy of fazirsiran 200 mg compared to placebo in improving measures of histologic fibrosis. Additional measures will evaluate the pharmacodynamic effect of fazirsiran compared to placebo on serum Z-AAT, its impact on disease progression, safety and tolerability, reduction of liver inflammation and pharmacokinetics.
Saurabh: Can you give us an insight into the safety and tolerability of Fazirsiran?
Chinwe: Results from the OLE of the Phase 2 SEQUOIA trial showed that fazirsiran was associated with improved laboratory measures of liver health and stable pulmonary function. Overall, 20 patients reported a treatment-emergent adverse event during the OLE trial; of those, most were mild or moderate, four were serious and one led to study withdrawal.
It is important to note that fazirsiran is an investigational product in development for AATD-associated liver disease and its potential efficacy and safety have not been evaluated by any health authority. Open label extension studies have certain limitations, which may affect the interpretation of this data.
Saurabh: How will Fazirsiran change the standard treatment scenario in the case of AATD-associated liver disease? What competitive advantage does Fazirsiran have over other therapies available to treat AATD diseases?
Chinwe: AATD-associated liver disease is an under-recognized, progressive genetic condition with no approved pharmacologic therapies. Liver transplant is currently the only available treatment option for those who progress to end-stage liver disease. Fazirsiran is a potential first-in-class investigational RNAi therapy designed to target the cause of AATD-associated liver disease by reducing the production of Z-AAT. When Z-AAT accumulates in liver cells, it can cause liver damage, leading to fibrosis, cirrhosis and/or hepatocellular carcinoma. Reducing production of the inflammatory Z-AAT protein may stop the progression of liver disease and potentially allow the liver to regenerate and repair.
There are no comparative trials in AATD-associated liver disease at this time. Fazirsiran is the only AATD-associated liver disease candidate to enter into a Phase 3 clinical trial at this time.
Saurabh: When can we expect the completion of phase 3 trials and submission for regulatory review of Fazirsiran?
Chinwe: Takeda is currently aiming to complete the full Phase 3 REDWOOD study in 2029.
It is premature to discuss our plans to pursue the marketing authorization of fazirsiran with any health authorities at this time.
Image Source: Canva
About the Author:
Chinwe Ukomadu
TAKEDA SPOKESPERSON: Chinwe Ukomadu, M.D., Ph.D., Head of the Gastrointestinal and Inflammation Therapeutic Area Unit, Takeda
Chinwe Ukomadu, MD., Ph.D., is a physician-scientist whose career spans academia, clinical care and industry. Chinwe earned his Ph.D. (Physiology) and MD from Yale University and was an internal medicine resident and chief medical resident at Brigham and Women’s Hospital (BWH). He completed sub-specialty training in gastroenterology and a post-doctoral fellowship at BWH before joining the staff of the hospital and Harvard Medical School with roles as an independent investigator, clinician and educator.
In 2021, Chinwe joined Takeda, a multinational company as its head of the GI Therapeutic Area Unit. He is responsible for the gastroenterology pipeline and strategy in research and development and is a member of the Takeda Research and Development leadership team. Dr. Ukomadu serves on the board of several biotech companies.
Related Post: Predicting 2025 Trends: Jesse Mendelsohn from Model N in an Illuminating Discussion with PharmaShots
