The biopharmaceutical companies Arrowhead and Takeda announced positive topline results from a phase 2 study of fazirsiran, which is being developed as a treatment for alpha-1 antitrypsin deficiency (AATD)-associated liver disease. 

Fazirsiran is a potential first-in-class investigational RNA interference therapy. Its key goal is to reduce the production of the mutant alpha-1 antitrypsin protein (Z-AAT); studies indicate that pathological Z-AAT accumulation can drive progressive liver disease in patients with AATD. Researchers believe that reducing the production of Z-AAT may halt liver degeneration and give the liver space to regenerate and repair. 

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In the study, patients who had baseline fibrosis were randomized to receive either 25 mg, 100 mg, or 200 mg of fazirsiran. The research team reported that all 3 doses caused drastic reductions in the total liver Z-AAT, with the median reduction being 94% at the postbaseline liver biopsy visit.

Individuals who were in the placebo group demonstrated no meaningful changes in their serum Z-AAT levels from baseline. In addition, the researchers reported that the treatment was safe and well-tolerated. 

“These consistent phase 2 data give us additional confidence that fazirsiran has the potential in the future to provide physicians with the first therapeutic strategy to treat AATD-associated liver disease in their patients,” Arrowhead chief medical officer Javier San Martin, MD, said. 

In phase 3 of the study, researchers aim to evaluate the safety and efficacy of fazirsiran in treating AATD-associated liver disease with METAVIR F2 to F4 fibrosis. The research team intends to recruit 160 patients who will be randomized 1:1 to take either fazirsiran or a placebo. The primary endpoint will be whether there will be significant improvements in histological fibrosis METAVIR staging. 


Arrowhead and Takeda announce topline results from SEQUOIA phase 2 study of fazirsiran in patients with alpha-1 antitrypsin deficiency—associated liver disease. News release. Takeda Pharmaceutical Company Limited; January 9, 2023.