3:42 PM
Sep 21, 2018
 |  BioCentury  |  Product Development

Arrowhead refills its quiver

How Arrowhead’s toxicity blowup gave it a jump start on a better RNAi platform

Editor's Note: This article was updated on Sep 24, 2018 at 2:45 PM PDT

Arrowhead Pharmaceuticals Inc.’s tox blowup in 2016 set back its clinical timelines, but it also prompted the company to bring a more versatile platform online faster than originally planned. Early data from replacement candidates suggest management’s choice to scrap its initial programs and instead accelerate development of a next-generation RNAi delivery platform is paying off.

On Sept. 6 at the World Gastroenterologists Summit, the company reported the first efficacy data for a candidate from its new subcutaneous Targeted RNAi Molecule (TRiM) platform. In a Phase I/II study in patients with chronic HBV, 100 mg of ARO-HBV lowered hepatitis B surface antigen (HBsAg) by a mean of 2.0 log10, or a 99% reduction in HBsAg, and a 200 mg dose lowered HBsAg by a mean of 1.4 log10, or 96% reduction.

Arrowhead reported that ARO-HBV was “generally well-tolerated” among 40 patients with chronic HBV. The most common adverse events were injection site reactions associated with roughly 10% of injections.

The company had reported safety data in June from another program to treat alpha α-1 antitrypsin (AAT; A1AT; SERPINA1) deficiency, at the Alpha-1 Foundation National Education Conference. An interim look at the first-in-human study showed no serious or severe adverse events reported among 32 healthy volunteers who received a single dose of ARO-AAT or placebo.

These presentations are the fruits of management’s decision nearly two years ago to abandon its original delivery technology -- and the clinical candidates that used it -- following a preclinical toxicology blowup.

“Sometimes you have to walk into a punch to build the company you want.”

Christopher Anzalone, Arrowhead

On Nov. 8, 2016, Arrowhead announced that FDA placed a hold on a Phase II study of ARC-520 in chronic HBV. The reason was unexplained deaths in non-human primates being treated in long-term toxicity studies with the company’s dynamic polyconjugate (DPC) delivery vehicle for ARC-521, another HBV candidate then in Phase I.

ARC-520, ARC-521 and a third clinical candidate targeting mutant AAT all used the DPC delivery vehicle.

President and CEO Christopher Anzalone said Arrowhead suspected the deaths were species-specific and due to higher doses of DPC than would ever be given in humans. But conducting the studies needed to prove it would have taken at...

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