Fazirsiran ‘quite amazing’ in treatment of alpha-1 antitrypsin deficiency liver disease
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Fazirsiran effectively reduced the production and accumulation of a protein that causes alpha-1 antitrypsin deficiency and subsequent liver fibrosis in a small subset of patients, according to data in The New England Journal of Medicine.
“We had strong evidence from preclinical studies and the phase I that fazirsiran would knock down [alpha-1 antitrypsin] mRNA in the liver,” senior author Jeffrey Teckman, MD, director of pediatric gastroenterology and hepatology and professor of pediatrics and biochemistry at Saint Louis University School of Medicine, told Healio. “The surprise was to see that nearly half the participants had reduced liver fibrosis after only 24 to 28 weeks of treatment. This was much more rapid that expected and is really quite amazing, given other information about liver fibrosis from diseases like [hepatitis] C.”
![“Nearly half the participants had reduced liver fibrosis after only 24 to 28 weeks of treatment. This was much more rapid that expected and is really quite amazing, given other information about liver fibrosis from diseases like [hepatitis] C.” -- Jeffrey Teckman, MD](/~/media/slack-news/gastroenterology/misc/infographics/2022/0822/hgi0822strnad_graphic_01.jpg?w=800)
According to a related university press release, the liver creates and releases large quantities of the protein alpha-1 antitrypsin (AAT), which serves as a protectant for warding off infections. Alpha-1 antitrypsin deficiency is caused by a homozygous SERPINA1 “Z” mutation (proteinase inhibitor [PI] ZZ), which produces a variant protein that can lead to progressive liver disease and fibrosis. The condition is typically treated only by liver transplantation.
To test the safety and efficacy of fazirsiran (Takeda, Arrowhead Pharmaceuticals), an RNA interference therapeutic, Teckman and colleagues conducted an open-label, phase 2 trial and enrolled 16 adults with PI ZZ genotype and F1 to F3 liver fibrosis. Participants were divided into three cohorts and received fazirsiran subcutaneously on day 1, week 4 and then every 12 weeks. Cohort 1 (n = 4) and cohort 2 (n =8) received 200 mg fazirsiran and cohort 1b (n =4) received 100 mg.
The primary outcome was change in Z-ATT concentrations from baseline to week 24 for cohorts 1 and 1b or week 48 for cohort 2, assessed via liver biopsy samples obtained at each visit. Participants in cohort 1 and 1b could enter an extension period at week 24, as could cohort 2 at week 48.
According to study results, all patients had reduced Z-AAT accumulation in the liver (median percentage change = –83.3%; 95% CI, –89.7 to –76.4) at week 24 or 48, as measured by liquid chromatography-mass spectrometry, and all had improved liver enzyme concentrations. Researchers reported fibrosis regression in seven of 12 patients in cohorts 1 and 2 and fibrosis progression in two patients in cohort 2.
There were no deaths, discontinuations of treatment or dose interruptions in the 1.5-year study period, and serious adverse events, which included viral myocarditis, diverticulitis, dyspnea and vestibular neuronitis, were resolved.
“These findings are very high impact but still preliminary,” Teckman told Healio. “We need a more extensive phase 3 study to really know how long to treat, the preferred dose and the expected benefits.”
According to Teckman, although “the safety profile is excellent so far — nearly the same as placebo,” future studies will help establish the efficacy and safety of fazirsiran in an even broader population. “The next trials will be longer and also include patients with established cirrhosis at some point,” he said. “Also, this disease can cause liver damage in children, so a pediatric arm will open in the coming year or two, hopefully, so that we can meet the needs of patients of all ages.”
He added, “These results should spur clinicians to test more frequently for alpha-1 disease specifically, so patients can be directed to trials and studied in detail for future benefits.”
Reference:
- Saint Louis University and industry partners discover treatment for rare, genetic liver disease. https://www.slu.edu/news/2022/july/teckman-research.php. July 8, 2022.
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