Fazirsiran lowers serum, liver concentrations of Z-AAT in alpha-1 antitrypsin deficiency
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Key takeaways:
- Least-squares mean percent differences in serum Z-AAT concentrations with fazirsiran 25 mg, 100 mg and 200 mg vs. placebo were –61%, –83% and –94%.
- Fazirsiran improved portal inflammation and interface hepatitis.
In a dose-dependent manner, fazirsiran reduced serum and liver concentrations of Z-AAT and also improved histological measures in patients with homozygous ZZ alpha-1 antitrypsin deficiency-associated liver disease, according to data.
“Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by mutations in the coding sequence of the SERPINA1 gene,” Virginia C. Clark, MD, associate professor of medicine at the University of Florida, and colleagues wrote in Gastroenterology. “In the classic form, AATD is caused by homozygous Glu342Lys substitutions of the Z allele (PiZZ), resulting in production of mutant misfolded Z alpha-1 antitrypsin (Z-AAT) proteins.”
They continued: “Fazirsiran is a hepatocyte-targeted investigational RNA interference therapeutic that contains a synthetic, double-stranded, small interfering RNA duplex. The drug was designed to specifically degrade AAT and Z-AAT messenger RNA in hepatocytes, thus reducing protein synthesis.”
In the ongoing, phase 2, placebo-controlled SEQUOIA trial, researchers randomly assigned 40 adult patients with PiZZ genotype and liver fibrosis to subcutaneous fazirsiran 25 mg, 100 mg or 200 mg (n = 26; 35% men) or placebo (n = 14; 64% men). At baseline, local biopsy readings showed 62% of patients receiving fazirsiran had fibrosis vs. 64% receiving placebo. According to central biopsy readings, 54% and 57%, respectively, had fibrosis.
Patients with fibrosis underwent treatment on day 1, week 4 and every 12 weeks thereafter, with a second liver biopsy performed at or after weeks 48, 72 or 96. Patients without fibrosis received two treatment doses on day 1 and week 4.
The primary endpoint was change in serum Z-AAT concentration from baseline to week 16, measured by liquid chromatography-tandem mass spectrometry.
Results demonstrated a dose-dependent reduction in serum Z-AAT concentrations in patients treated with fazirsiran, with significant differences observed between all doses of fazirsiran and placebo through week 16. Compared with placebo, least-squares mean percent differences at week 16 were –61% (95% CI, –73 to –49) with fazirsiran 25 mg, –83% (95% CI, –95 to –70) with 100 mg and –94% (95% CI, –106 to –81) with 200 mg.
After week 16, patients with baseline fibrosis who continued treatment with fazirsiran every 12 weeks sustained reductions in serum Z-AAT concentrations through week 52.
According to post-dose biopsies, all doses of fazirsiran significantly reduced total liver Z-AAT by a median of 87% to 94% vs. a median increase of 26% with placebo.
Fazirsiran also improved portal inflammation and interface hepatitis in 42% and 58% of patients, respectively, vs. none with placebo. Among patients with at least FI fibrosis at baseline, histological METAVIR score improved by one point or more in 50% treated with fazirsiran vs. 38% on placebo.
Researchers reported that no adverse events led to study discontinuation.
“The results of this study show that fazirsiran reduced serum and liver concentrations of Z-AAT and improved histological measures of liver disease,” Clark and colleagues wrote. “This ongoing study is a comprehensive trial that will not only evaluate the effects of fazirsiran on liver inflammation and fibrosis, but also evaluate the long-term safety and efficacy on liver- and lung-related clinical events.”
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