AATD-Associated Rare Liver Disease Treatment Shows Strong Activity in Phase 1 Study


A recent phase 1 study evaluating ARO-AAT for the treatment of a rare genetic liver disease associated with alpha-1 antitrypsin (AAT) deficiency boasts positive initial clinical data.

Positive initial clinical data from a recent phase 1 study evaluating ARO-AAT for the treatment of a rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD), was recently presented at the Alpha-1 National Education Conference in San Francisco.

ARO-AAT is a second generation subcutaneously administered RNA interference (RNAi) therapeutic. The treatment has been developed to “knock down the hepatic production of the mutant alpha-1 antitrypsin (Z-AAT) protein,” which is responsible for progressive liver disease in patients with AATD, according to Arrowhead Pharmaceuticals.

The phase 1 single- and multiple-ascending dose study, dubbed AROAAT1001, had a primary focus of evaluating the safety, tolerability, pharmacokinetics, and effect of ARO-AAT on serum alpha-1 antitrypsin levels in healthy adult volunteers.

The study is comprised of 7 cohorts; 16 subjects are receiving placebo and 28 subjects are receiving single or multiple doses of ARO-AAT at doses of 35, 100, 200, or 300 mg. Due to observed activity at lower doses, additional cohorts at a dose of 400 mg were deemed unnecessary.

“The 100 mg open-label, single-dose cohort showed strong activity with a maximum serum AAT reduction of 93%,” said Chris Anzalone, PhD, president and chief executive officer of Arrowhead, in a recent statement.

The data presented at the conference had been collected from 4 subjects who obtained 93% maximum serum AAT knockdown and 87% mean maximum serum AAT knockdown. In addition, a mean serum AAT knockdown remained at 83% remained at 8 weeks post-dose.

Furthermore, the single 100 mg dose of ARO-AAT was reported to equate to an average dose of 1.4 mg/kg (range 1.0-1.6 mg/kg) in study participants whose average weight was 72.9 kg (range 61.8-98.9 kg).

“The duration of effect we’re seeing should enable monthly or less frequent dosing,” added Dr Anzalone. “We are excited by these results and would like to thank the Alpha-1 Foundation for providing us with a forum to discuss the development of ARO-AAT with the Alpha-1 community.”

As of the data cutoff on June 11, 2018, ARO-AAT was shown to be generally well tolerated. In 40 subjects (24 of whom received ARO-AAT and 16 of whom received placebo), no serious adverse events (AEs) were observed, and most AEs were noted to be mild in nature; there was only 1 reported case of mild gastroenteritis. The researchers reported 2 cases of injection site erythema at 100 mg after the first dose but both cases were deemed mild and subsided within 48 hours.

The researchers did not report any adverse change in blood urea nitrogen, creatinine, alanine transaminase, aspartate transaminase or total bilirubin that they considered to be clinically meaningful. No dose-related pattern of adverse laboratory changes was observed as well.

Overall, the phase 1 findings proved to be positive and only further supported the preceding preclinical data conducted in young AAT mutant (PiZ) mice, which found that 8 weeks of ARO-AAT treatment caused reductions in Z-AAT monomer and polymer content and prevented globule accumulation in the livers. Furthermore, 2 doses of 3 mg/kg of ARO-AAT led to a 92% maximum serum AAT knockdown in the nonhuman primates which that lasted for over 7 weeks.

“Based on our experience in primates and prior human clinical studies,” Dr Anzalone said, “we believe this knockdown level represents near full suppression of the liver production of AAT.”

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