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Arrowhead Adds Alpha-1 Antitrypsin Deficiency-associated Liver Disease to Pipeline

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NEW YORK (GenomeWeb) – Arrowhead Research this week unveiled its newest pipeline program, a treatment for alpha-1 antitrypsin (AAT) deficiency-associated liver disease that will be developed with the support of a group called the Alpha-1 Project (TAP), which focuses on improving research into the condition.

Notably, Alnylam Pharmaceuticals, which is developing its own RNAi-based AAT therapeutic called ALN-AAT, this week announced its own partnership with TAP.

AAT deficiency is a genetic disease that leads to decreased activity of the protease inhibitor alpha-1 antitrypsin (A1AT) in the blood and lungs causing lung dysfunction. It can also feature the accumulation of a mutant AAT protein known as Z-AAT in liver tissue, which leads to liver injury, fibrosis, cirrhosis, and potentially liver cancer.

"We've got several potential [pipeline] candidates … and this made a lot of sense to be our next candidate," Arrowhead President and CEO Christopher Anzalone said of ARC-AAT during a conference call held to discuss this week's announcement.

Firstly, he said, Arrowhead has generated encouraging preclinical data around the disease. In experiments in a mouse model that expresses human Z-AAT, ARC-AAT was able to cut levels of circulating AAT by more than 95 percent after a single dose. Following eight weeks of treatment in multi-dose studies, soluble and insoluble forms of Z-AAT were found to be "greatly reduced" in the animals' livers, according to Arrowhead.

"In addition, liver globule burden was substantially reduced from baseline levels and in comparison to treatment with saline, which showed progressive globule formation," the company said.

AAT deficiency is also a rare disease, Anzalone added, which may allow Arrowhead to obtain orphan drug status for ARC-AAT. Further, AAT deficiency-associated liver disease is an unserved medical need. "The world has made great progress in the lung disease component in alpha-1 antitrypsin, but nothing for the liver has been approved."

Arrowhead additionally views AAT deficiency-associated liver disease as having an "attractive target risk," Anzalone said. "We see a fairly straight line [between] reducing gene expression of a certain gene product and a clinical outcome.

"Finally, given the dynamics of the disease and of our therapy, we can have early clinical proof of concept," he said.

ARC-AAT includes unlocked nucleobase analog (UNA) modifications that the company said helped slow the rebound production of AAT as compared to treatment with standard siRNAs, while "substantially" boosting the drug's duration of effect. In non-human primate testing, ARC-AAT-mediated knockdown of AAT in serum persisted for more than 10 weeks with greater than 80 percent knockdown observed at the six-week time point.

UNAs relate to acyclic ribonucleoside analogs in which the bonds between C2' and C3' atoms are broken. The resultant change in sugar structure is designed to make the analog flexible and reduce the binding affinity of siRNAs' strands.

The technology was originally developed by RiboTask but exclusively licensed to Marina Biotech predecessor MDRNA in 2009. Marina later licensed to the technology to a number of companies including Roche, and eventually handed off its ownership of the UNA technology to startup Arcturus Therapeutics. Arrowhead's access to the technology stems from its acquisition of Roche's RNA drug assets in 2011.

ARC-ATT is delivered intravenously using Arrowhead's dynamic polyconjugate technology, which was also acquired from Roche.

Arrowhead said that it expects to file an investigational new drug application for ARC-AAT by the end of the year. Initial clinical testing will be conducted in adults with AAT deficiency who show signs of liver injury, with the goal of preventing additional injury and improving liver histology.

Future studies may focus on children with the condition, including ones with severe hepatic disease who may otherwise require liver transplant, the company added.

To assist in its development of ARC-AAT, Arrowhead said that it has inked a deal with TAP, the venture philanthropy subsidiary of the non-profit group Alpha-1 Foundation, which is tasked with supporting organizations developing cures and treatments for AAT deficiency disorders.

TAP will partially fund the drug's development and make its scientific advisors available to Arrowhead, as well as assist in patient recruitment for clinical trials.

Alnylam, too

Concurrent with Arrowhead's announcement that it had added AAT deficiency-associated liver disease to its pipeline, Alnylam disclosed that it had also struck an alliance with TAP for ALN-AAT.

Similar to the Arrowhead arrangement, the deal calls for TAP to provide an undisclosed amount of funding toward the development of Alnylam's drug. Additional terms were not provided.

ALN-AAT, which is subcutaneously administered using Alnylam's next-generation GalNAc conjugate technology, is on track for an IND filing in mid-2015. In a statement regarding the TAP partnership, the company highlighted its own preclinical studies showing that ALN-AAT could knock down levels of Z-AAT in the livers of rodent models, while improving liver function.

The company added that non-human primate studies indicate that ALN-AAT can achieve target gene knockdown at less than 1 mg/kg with a once-a-month dosing regimen.

As one of Alnylam's genetic medicine programs, ALN-AAT is covered by the company's recently announced partnership with Genzyme.

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