SEQUOIA: Fazirsiran Reduces Serum, Liver Z-AAT Concentrations, Improves Hepatic Globule Burden


Findings from a phase 2b study demonstrate fazirsiran’s dose-dependent impact on Z-AAT concentrations and histological measures of liver disease in patients with AATD.

Virginia Clark, MD | Credit: University of Florida Health

Virginia Clark, MD

Credit: University of Florida Health

New phase 2 data are shining light on the impact of treatment with fazirsiran on serum and liver concentrations of mutant misfolded Z alpha-1 antitrypsin (Z-AAT) as well as histological measures of liver disease in adult patients with the PiZZ genotype of alpha-1 antitrypsin deficiency (AATD) and liver fibrosis.1

One-year findings from the ongoing randomized, placebo-controlled, phase 2 SEQUOIA study highlight sustained, dose-dependent reductions in Z-AAT concentration and improved histological findings, including periodic acid-Schiff staining with diastase digestion (PAS+D) globule burden, a hallmark of AATD-associated liver disease, with fazirsiran.1

A genetic disorder resulting in low levels of AAT, AATD is caused by genetic changes in the SERPINA1 gene and is inherited in a codominant manner. It can cause a shortage of AAT in the lungs and a buildup of AAT in the liver, potentially leading to AATD-associated liver and/or lung disease.2

“Lung disease can be managed by lifestyle changes (e.g. cessation of smoking) and AATD augmentation therapy to slow disease progression,” Virginia Clark, MD, associate professor of medicine in the division of gastroenterology, hepatology, and nutrition at the University of Florida, and colleagues wrote.1 “However, no currently available treatment can prevent or reverse the progression of AATD-associated liver disease.”

A hepatocyte-targeted investigational RNA interference therapeutic, fazirsiran contains a synthetic, double-stranded, small interfering RNA duplex and was designed to degrade AAT and Z-AAT messenger RNA in hepatocytes, subsequently reducing protein synthesis and inhibiting further accumulation of Z-AAT polymers to allow normal cellular mechanisms to dispose of mutant proteins.1

An ongoing, placebo-controlled, dose-finding, phase 2 study, SEQUOIA was conducted at 21 centers in Germany, Italy, the Netherlands, Portugal, Spain, and the United States and enrolled 40 adult patients with the PiZZ genotype and liver fibrosis. Participants were randomly assigned to treatment with subcutaneous placebo (n = 14) or fazirsiran 25 (n = 9), 100 (n = 8), or 200 mg (n = 9).1

Participants received a liver biopsy at screening to determine the presence of fibrosis. Patients without fibrosis received a total of 2 doses of study drug on day 1 and week 4 and were followed up to week 64 without a second biopsy. Patients with fibrosis were treated on day 1, week 4, and every 12 weeks thereafter for up to 18 total doses to a maximum treatment duration of 196 weeks. At week 48, a second liver biopsy (post-dose biopsy) was performed only for patients with baseline fibrosis.1

The primary endpoint was percentage change in serum Z-AAT concentration from baseline to week 16, measured using liquid chromatography-tandem mass spectrometry (LC/MS). Secondary endpoints included change from baseline in serum Z-AAT over time; change from baseline in total liver Z-AAT as well as the soluble and insoluble fraction at post-dose biopsy measured by LC/MS; change from baseline in liver function tests at week 16 and over time; and change from baseline in meta-analysis of histological data in viral hepatitis (METAVIR) fibrosis stage at post-dose biopsy.1

In total, 58 patients were screened and 40 were enrolled, including 25 participants with fibrosis. Per local baseline read, 64% (n = 9) of patients receiving placebo and 62% (n = 16) of patients receiving fazirsiran had fibrosis. Per central biopsy read, 57% (n = 8) of patients receiving placebo and 54% (n = 14) of patients receiving fazirsiran had fibrosis.1

At week 16, least-squares mean percent differences in serum Z-AAT concentrations compared with placebo were −61% (95% CI, −73% to −49%) for the 25 mg dose, −83% (95% CI, −95% to −70%) for the 100 mg dose, and −94% (95% CI, −106% to −81%) for the 200 mg dose (P <.0001 for all comparisons). Among patients with fibrosis who continued to receive fazirsiran every 12 weeks after week 16, reductions in serum Z-AAT concentrations were sustained through week 52. Among patients without fibrosis who received 2 doses of fazirsiran, serum Z-AAT concentrations gradually increased toward baseline but still showed a 44% reduction from baseline at week 52.1

At post-dose biopsy, all doses of fazirsiran significantly reduced total liver Z-AAT by a median of 87% to 94% compared with a median increase of 26% for placebo. Of note, least-squares mean percent differences in liver Z-AAT concentration at post-dose biopsy were all significant (P <.0035) compared with placebo.1

Additionally, investigators observed reductions in hepatic PAS+D globule burden with fazirsiran treatment (mean score, 5.9; standard deviation [SD], 2.24 at baseline and 2.3; SD, 2.24 at post-dose biopsy) compared with relatively small change for placebo (mean score, 6.9; SD, 1.76 at baseline and 6.6; SD, 2.13 at post-dose biopsy), and all patients receiving fazirsiran had at least a 1-point improvement in hepatic PAS+D globule burden at post-dose biopsy.1

Portal inflammation improved in 42% (n = 5) of patients treated with fazirsiran compared to no patients in the placebo group at post-dose biopsy among patients with a score > 0 at baseline. Among patients with fibrosis >F0 at baseline, investigators pointed out > 1 point improvements in histological METAVIR score in 50% (n = 7) of patients in the fazirsiran group compared to 38% (n = 3) in the placebo group.1

Fazirsiran was well tolerated with generally similar frequencies of treatment-emergent adverse events in the fazirsiran and placebo groups, none of which led to drug discontinuation, dose interruptions, or premature study withdrawals in any study group. Additionally, investigators observed stable pulmonary function test results for both fazirsiran and placebo over time, with no apparent dose-dependent effects.1

Limitations highlighted by investigators included the small sample size of the placebo group; the short study duration; and the imbalance in prognostic factors between study groups, with more males than females in the placebo group having fibrosis at baseline.1

“Results from this trial and the previously reported open-label study are encouraging and provide the basis for a large, ongoing, placebo-controlled, phase 3 study to confirm the treatment effect of fazirsiran in adults with AATD-associated liver disease with METAVIR fibrosis stage F2–F4,” investigators concluded.1


  1. Clark VC, Strange C, Strnad P, et al. Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA). Gastroenterology (2024). doi:
  2. Genetic and Rare Diseases Information Center. Alpha-1-antitrypsin deficiency. June 2024. Accessed July 9, 2024.
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