14 November 2018 - - US-based RNAi-based therapeutics developer Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) has presented clinical data from a Phase 1 study of ARO-AAT, the company's second generation subcutaneously administered RNA interference therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency, at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Disease (AASLD), being held in San Francisco, the company said.

In the AROAAT1001 study, 45 normal healthy volunteers received a single dose of ARO-AAT, three monthly doses of ARO-AAT, or placebo. Key data presented include the following:

ARO-AAT at single- and multiple-doses produced robust and consistent reductions in serum AAT levels

Single-doses of 200 and 300 mg resulted in greater than 91% serum AAT reduction, with 3 of 4 subjects having concentrations below the level of quantitation.

In 200 and 300 mg single-dose cohorts, an average serum AAT reduction of greater than 90% was sustained for 6 weeks.

In the multiple-dose cohorts of 200 and 300 mg, for subjects receiving all 3 doses, an average of greater than 90% reduction in serum AAT was sustained for longer than 14 weeks.

The maximum NADIR reduction is 94%.

Monthly serum AAT follow up is ongoing with 9 of 10 subjects at BLQ in the multiple-dose cohorts, including 100% of subjects from the 300 mg cohort.

Duration of response indicates that quarterly or less frequent dosing appears feasible.

ARO-AAT has been well tolerated at all doses tested (up to 300 mg) given three times every 28 days.

The most common adverse events were upper respiratory tract infection and headache.

AROAAT1001 (NCT03362242) is a Phase 1 randomized, double-blind, placebo controlled single-ascending dose and multiple-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and effect of subcutaneous doses of ARO-AAT on serum alpha-1 antitrypsin levels in healthy adult volunteers.

The SAD portion of the study included four cohorts at dose levels of 35, 100, 200, and 300 mg and the MAD portion of the study included three cohorts at dose levels of 100, 200, and 300 mg.

Additional cohorts were planned at a dose of 400 mg, but were deemed unnecessary based on observed activity at lower doses. AROAAT1001 enrolled 45 healthy volunteers.

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them.

Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes.

RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein.

Arrowhead's RNAi-based therapeutics leverage this natural pathway of gene silencing.