Arrowhead and Takeda Announce Topline Results from SEQUOIA Phase 2 Study of Fazirsiran in Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
− Fibrosis regression observed in 50% of patients receiving fazirsiran
− Median reductions of 94% of Z-AAT accumulation in the liver and mean reduction of 68% in histologic globule burden
− Treatment emergent adverse events were generally well balanced between fazirsiran and placebo groups
− Results consistent with AROAAT-2002 open-label study previously published in
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“Currently there is no treatment for liver disease from alpha-1 antitrypsin deficiency. The results presented today from the SEQUOIA study are highly encouraging to physicians and patients in need of a safe and effective therapy for this rare genetic condition,” said
Key SEQUOIA Results
Patients receiving 25 mg, 100 mg, or 200 mg of fazirsiran who had baseline fibrosis (n=16) demonstrated a dose dependent mean reduction in serum mutant alpha-1 antitrypsin protein (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 (n=9) 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
“Patients receiving fazirsiran showed dramatic and encouraging changes in several markers of disease during the treatment period, including fibrosis, Z-AAT accumulation in the liver, PAS-D globule burden, liver enzymes, and other important markers,” said
Advancing the Fazirsiran Phase 3 Study
This month Takeda plans to initiate TAK-999-3001, a randomized, double-blind, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of fazirsiran in the treatment of alpha-1 antitrypsin deficiency–associated liver disease with METAVIR stage F2 to F4 fibrosis. Approximately 160 patients will be randomized 1:1 to receive fazirsiran or placebo. The primary endpoint of this study is a decrease from baseline of at least 1 stage of histologic fibrosis METAVIR staging in the centrally read liver biopsy done at Week 106 in patients with METAVIR stage F2 and F3 fibrosis.
“These compelling Phase 2 data confirm our belief that an RNAi therapy like fazirsiran has the potential to reverse liver disease associated with AATD,” said
Fazirsiran is a potential first-in-class investigational RNA interference (RNAi) therapy designed to reduce the production of mutant alpha-1 antitrypsin protein (Z-AAT) as a potential treatment for the rare genetic liver disease associated with AATD. Z-AAT accumulation is believed to be the cause of progressive liver disease in patients with AATD. Reducing production of the inflammatory Z-AAT protein is expected to halt the progression of liver disease and potentially allow the liver to regenerate and repair. Fazirsiran was granted Breakthrough Therapy Designation (BTD) in
About SEQUOIA Phase 2 Study
SEQUOIA (NCT03945292) is a placebo-controlled, multi-dose, Phase 2 study to determine the safety, tolerability, and pharmacodynamic effect of fazirsiran (TAK-999, ARO-AAT) in 42 patients with AATD-LD. Patients were enrolled in three cohorts to receive fazirsiran at doses of 25 mg (n=9), 100 mg (n=8), 200 mg (n=9), or matching placebo (n=14). All eligible participants received a pre-dose biopsy and those with baseline fibrosis (n=25) received a post-baseline biopsy at week 48. Treated participantswere also offered the opportunity to continue treatment in an open-label extension (OLE).
About Takeda and Arrowhead Collaboration and License Agreement
About Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is estimated to affect 1 per 3,000-5,000 people in
Individuals with the homozygous PiZZ genotype have severe deficiency of functional AAT that may lead to pulmonary disease and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant, with its attendant morbidity and mortality, is currently the only available cure.
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Strnad P, Mandorfer M, Choudhury G, et al. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. N Engl J Med. 2022;10.1056/NEJMoa2205416. doi:10.1056/NEJMoa2205416.
Strnad P. Reduction of intra-hepatic Z-AAT synthesis by fazirsiran decreases globule burden and improves histological measures of liver disease in adults with alpha-1 antitrypsin deficiency. Poster presented at:
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