Arrowhead's midstage hep B data shows promise for RNA-based 'functional cure'

Arrowhead CEO Chris Anzalone

RNA interference specialist Arrowhead ($ARWR) presented new data from an ongoing Phase IIa study of its hepatitis B treatment ARC-520, demonstrating a reduction of the disease's surface antigens in what the company says is a first for RNAi.

Arrowhead has been chugging along on its hepatitis B candidate, which makes use of the company's delivery system designed to overcome the vast challenges associated with RNAi. Last year, CEO Christopher Anzalone told FierceDrugDelivery that the polymer-based platform stands apart from other RNA platforms due to its ability to release the genetic material, what they term "endosomal escape." The company's Dynamic Polyconjugate approach allows for a "masking" and "unmasking" process that protects the RNA as it enters the cell, but also allows it to perform its interference duty once inside.

The new human data for ARC-520 showed significant reduction of the hepatitis B surface antigen (HbsAg), according to Arrowhead, as compared to placebo for up to 85 days, with the lowest point at about a month after dosing in the 54-patient study. Back in March, the company called its candidate a "functional cure" due to the presence of an "immunological flare" in primate studies.

In addition to the hepatitis treatment, Arrowhead also has another RNAi candidate for liver disease associated with Alpha-1 antitrypsin deficiency. In preclinical mouse studies, the company's ARC-AAT induced a greater-than-95% reduction in circulating AAT after a single dose. And primates also showed more than 80% knockdown over 6 weeks of treatment, the company said.

Back in February, Arrowhead picked up a $120 million public offering.

"These programs and our expanding pipeline of RNAi therapeutics continue to generate exciting data that further validate the utility of the DPC delivery system," Anzalone said in a statement. "We have seen clear activity across multiple preclinical models and are now seeing activity in humans. We are still dose escalating in the ARC-520 Phase IIa, where dosing is complete in the 3 mg/kg cohort and screening has begun for 4 mg/kg. We believe that the initial data from the first two dose cohorts as well as safety data from the Phase I volunteer study are encouraging and support advancement of the program into multidose Phase IIb studies. We are currently preparing regulatory filings for the ARC-520 Phase IIb and the ARC-AAT Phase I, both of which we expect to be filed this quarter. We intend to initiate those studies soon after receiving regulatory permission to begin."

Today, fellow RNAi specialist Alnylam ($ALNY) added two new early-stage programs for hepatitis to its pipeline, also at the American Association for the Study of Liver Diseases meeting in Boston. Diseases of the liver are a promising target for the treatment paradigm because the organ is amenable to drug delivery of RNAi molecules.

Alnylam, Arrowhead and others are striving for the first clinically viable RNAi treatment, a concept that garnered the Nobel prize in 2006 but has lingered on the fringe of commercialization for almost a decade. Some big names like Merck ($MRK) and Novartis ($NVS) dropped out of the space in the last year, contributing to a loss of faith for some, but the smaller specialists in the arena have forged on. Though still outside the commercial market, analysts recently forecast that RNA-based therapies would generate $1.2 billion in revenue by 2020 with large-scale public and private funding to back it up. So perhaps there's hope after all.

- here's the release
- and here are slides from the presentation (PDF)