Drug reduces mutant protein that can lead to fibrosis in rare genetic liver disease

[June 28, 2022]  By Reuters Staff

(Reuters Health) - The experimental Arrowhead Pharmaceuticals drug fazirsiran can reduce the accumulation of a mutant protein by 83% among people with alpha1-antitrypsin deficiency (AAT) disease, according to results from an open-label phase 2 trial involving 16 volunteers.

The condition is a rare genetic liver disease wherein a mutant protein, known as Z-AAT, accumulates in the liver and can lead to fibrosis, then cirrhosis or portal hypertension, and eventually hepatic decompensation or hepatocellular carcinoma. There is no approved treatment.

Fazirsiran, an RNA interference therapeutic, was given in one of two doses on day 1, week 4, week 16, and then every 12 weeks.

At week 24 and 48, a median 83% of the Z-AAT in the liver was gone.

"Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks," the research team led by Dr. Pavel Strnad of RWTH Aachen University in Germany report in the New England Journal of Medicine.

The team also saw improvements in liver enzyme concentrations.

"Because the liver is a regenerative organ, removal of the Z-AAT hepatic insult is expected to yield clinical benefit," they write.
 

However, "Despite marked reductions in liver Z-AAT concentrations in all the patients, reductions in mutant protein concentrations did not uniformly translate into regression of fibrosis during the first 24 or 48 weeks of treatment," the authors note.

Although no side effects prompted anyone to leave the trial, there were four serious adverse events coinciding with the treatment: diverticulitis, dyspnea, viral myocarditis, and vestibular neuronitis. The Strnad team said all of those problems resolved and "each of the four patients continues to receive fazirsiran treatment in the extension period."

Milder side effects included arthralgia and increased blood creatinine kinase.

A problem was considered an adverse event if it emerged or worsened after the first dose of the drug.

Arrowhead conducted the trial. The company released topline results of the study in November. The updated results were presented Saturday at the annual meeting of the European Association for the Study of the Liver.

Fazirsiran was previously known as ARO-ATT.

SOURCE: https://bit.ly/3ne0DXV The New England Journal of Medicine, online June 25, 2022.

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