Takeda Pharmaceutical, Arrowhead announce topline results from SEQUOIA study

Takeda (TAK) and Arrowhead (ARWR) announced topline results from the Phase 2 SEQUOIA clinical study of investigational fazirsiran for the treatment of liver disease associated with alpha-1 antitrypsin deficiency, or AATD-LD. The companies also provided an outline of a Phase 3 study that was co-developed by Takeda and Arrowhead and will be conducted by Takeda. Additional SEQUOIA study results are planned to be presented at a future medical meeting and submitted for publication. Arrowhead will host a webcast call for investors at 8:30 a.m. ET to review the Phase 2 data. Patients receiving 25 mg, 100 mg, or 200 mg of fazirsiran who had baseline fibrosis demonstrated a dose dependent mean reduction in serum mutant alpha-1 antitrypsin protein, or Z-AAT, concentration at week 48 of 74%, 89%, and 94%, respectively. All three doses led to a dramatic reduction in total liver Z-AAT with a median reduction of 94% at the postbaseline liver biopsy visit. In addition, PAS-D globule burden, a histological measure of Z-AAT accumulation, was reduced from a baseline mean of 5.9 to a post baseline mean of 2.3 at the postbaseline liver biopsy visit. Improvement in portal inflammation was observed in 42% of patients while only 7% showed worsening. Lastly, 50% of patients achieved an improvement in fibrosis of at least one point by METAVIR stage. In contrast, by week 48 patients receiving placebo who had baseline fibrosis saw no meaningful changes from baseline in serum Z-AAT, a 26% increase in liver Z-AAT, no meaningful change in PAS-D globule burden, no placebo patients experienced an improvement in portal inflammation while 44% experienced worsening, and 22% of placebo patients experienced worsening while 38% experienced an improvement in fibrosis at the postbaseline liver biopsy visit. This finding highlights the known variability on histologic fibrosis assessment. With a larger sample size, like in the planned Phase 3 study, the rate of improvement in patients receiving placebo may more closely approximate results from natural history studies of untreated patients with AATD-LD. Fazirsiran has been well tolerated with treatment emergent adverse events reported to date generally well balanced between fazirsiran and placebo groups. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or premature study withdrawals in any study group. Compared with placebo, no dose-dependent or clinically meaningful changes were observed in pulmonary function tests over 1 year with fazirsiran. These data are consistent with results from the Phase 2 AROAAT-2002 open-label study that were previously published in The New England Journal of Medicine. Additional details on the SEQUOIA study will be provided at a future scientific meeting.