Arrowhead Pharmaceuticals has dosed the first patient in SEQUOIA (AROAAT2001), a potentially pivotal Phase 2/3 clinical study of ARO-AAT, the company’s second generation subcutaneously administered RNA interference (RNAi) therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD).
“ARO-AAT is the first RNAi therapeutic derived from our proprietary Targeted RNAi Molecule, or TRiM™, platform to reach a potentially pivotal study,” Bruce Given, M.D., chief operating officer and head of R&D at Arrowhead, said. “This is a significant milestone for Arrowhead and, more importantly, it represents potential hope for patients living with alpha-1 liver disease, who currently have no available treatment options other than liver transplant.”
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SEQUOIA (NCT03945292) is a placebo-controlled, adaptive design Phase 2/3 study to evaluate the safety, efficacy, and tolerability of ARO-AAT administered subcutaneously to patients with AATD associated liver disease. SEQUOIA is designed to enroll 120 patients who will receive at least 9 doses, or approximately two years of treatment, with ARO-AAT or placebo. Doses will be administered on day 1, 29, and approximately every 12 weeks thereafter. The four-arm placebo-controlled Part A component of the study will feed seamlessly into a two-arm placebo-controlled Part B component. The primary objective for Part A is to select a single dose level for use in Part B of the study based on a combined evaluation of safety and pharmacodynamic dose response in each Part A cohort using change from baseline in soluble liver mutant AAT (Z-AAT), insoluble liver Z-AAT, and serum AAT levels as pharmacodynamic metrics. The primary objective for Part B is to evaluate efficacy, as assessed by the proportion of ARO-AAT treated patients relative to placebo achieving a 2-point improvement in a histologic grading scale of AATD associated liver disease, and no worsening of liver fibrosis on end of study biopsy.