'A New Hope' for Rare, Deadly Liver Disease

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An investigational, potential first-in-class RNA interference (RNAi) therapy showed promise for treating patients with liver disease associated with alpha₁-antitrypsin (AAT) deficiency, results of a phase II trial suggested.

All 16 patients treated with fazirsiran experienced reductions in mutant AAT protein in both the liver and serum as well as reductions in globule burden, and patients' liver enzymes reached normal levels by the end of the study, reported Pavel Strnad, MD, of the University Hospital Rheinisch-Westfälische Technische Hochschule in Aachen, Germany, at the European Association for the Study of the Liver meeting.

At 24 or 48 weeks, seven patients on the higher dose of fazirsiran studied experienced regression of their liver fibrosis, though two had progression, and reductions in liver stiffness were seen with the higher dose, according to findings that were simultaneously published in the New England Journal of Medicine.

"The results from the AROAAT-2002 study provide multiple lines of evidence that preexisting liver damage in these patients may be meaningfully improved following treatment with fazirsiran," said Strnad at a late-breaking presentation. "We have a great drug candidate, but we will only be able to bring this drug in the clinic when we understand the disease much better."

According to background information in the publication, AAT is encoded by the SERPINA1 gene and protects lung tissue; low levels of AAT in circulation can result in lung disease. AAT deficiency is caused by a homozygous "Z" mutation -- proteinase inhibitor (PI) ZZ -- and retention of Z-AAT in the liver can result in liver injury, inflammation, and fibrosis, which in turn can progress to cirrhosis, portal hypertension, hepatic decompensation, or hepatocellular carcinoma.

"The study offers a new hope for a successful treatment for this rare, but potentially fatal disease," said Omar Massoud, MD, PhD, of the Cleveland Clinic in Ohio, who was not involved in this study.

Massoud said the cases of fibrosis progression will need to be evaluated. He also cautioned that as fazirsiran decreases production of both AAT and Z-AAT, "there is a concern that this may lead to worsening of lung disease."

There were no deaths in the study, and no adverse event (AE) led to treatment discontinuation. Overall, 56% of AEs were deemed treatment-related, with common AEs including arthralgia (25%), increased blood creatine kinase (25%), and 19% had pain in the back or chest, diarrhea, dizziness, dyspnea, headache, or nasopharyngitis.

Four serious AEs occurred -- diverticulitis, viral myocarditis, dyspnea, and vestibular neuronitis -- but all resolved and "didn't seem to be related to the treatment," said Strnad.

The open-label phase II study enrolled 16 patients with liver disease associated with AAT deficiency (PI ZZ genotype) at four centers in Europe. Patients received subcutaneous fazirsiran on day 1, week 4, and then every 12 weeks. Four patients in cohort 1 and eight patients in cohort 2 received a 200-mg dose, while four patients in cohort 1b received a 100-mg dose.

For the primary endpoint, researchers measured changes in liver Z-AAT concentrations on liquid chromatography-tandem mass spectrometry: from baseline to week 24 for cohorts 1 and 1b, and until week 48 for cohort 2.

As noted, all patients experienced a reduction in mutant AAT at 24 or 48 weeks, with a median decline of 83% (95% CI -89.7 to -76.4). Histologic globule burden decreased by 69% from baseline.

Patients ranged in age from 18 to 75 (mean 52 years), 88% were men, and most had fibrosis stages F2 (38%) or F3 (25%) disease. One patient did not have fibrosis. Mean body mass index was 25.5. Six patients, four with emphysema, were receiving AAT augmentation therapy.

A larger phase II study -- SEQUOIA -- is examining the effect of fazirsiran versus placebo in patients with liver disease associated with AAT deficiency.