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Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA). Gastroenterology Clark, V. C., Strange, C., Strnad, P., Sanchez, A. J., Kwo, P., Pereira, V. M., van Hoek, B., Barjaktarevic, I., Corsico, A. G., Pons, M., Goldklang, M., Gray, M., Kuhn, B., Vargas, H. E., Vierling, J. M., Vuppalanchi, R., Brantly, M., Kappe, N., Chang, T., Schluep, T., Zhou, R., Hamilton, J., San Martin, J., Loomba, R. 2024

Abstract

Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT mRNA, reducing deleterious protein synthesis.This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg. The primary endpoint was percentage change in serum Z-AAT concentration from baseline to Week 16. Patients with fibrosis on baseline liver biopsy received treatment on Day 1, Week 4, and then every 12 weeks, and had a second liver biopsy at or after Weeks 48, 72, or 96. Patients without fibrosis received two doses on Day 1 and Week 4.At Week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83% and -94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001). Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden. Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively. Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation and pulmonary function tests remained stable.Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292).

View details for DOI 10.1053/j.gastro.2024.06.028

View details for PubMedID 38964420