Arrowhead, Shire Ink Targeted Peptide-Drug Conjugate Deal
By Marie Powers
Less than a year after the acquisition of Alvos Therapeutics Inc. gave Arrowhead Research Corp. a library of 42,000 individual targeting sequences, the company has attracted a second research collaboration and license deal.
Shire plc will use Arrowhead's human-derived homing peptide platform to develop and commercialize targeted peptide-drug conjugates (PDCs) using Shire's therapeutic payloads.
In April, Arrowhead bought Alvos, of Waltham, Mass., in an all-stock deal valued at about $2.1 million, plus additional stock worth up to $23.5 million based on the achievement of clinical and regulatory milestones.
The targeting sequences, which Alvos had licensed from the University of Texas MD Anderson Cancer Center (MDACC), are broken into groups of 300 to 1,000 peptide sequences that can be conjugated to drugs and targeted directly to some 30 specific tissues or organs. MDACC researchers used phage display in terminally ill cancer patients to establish a library of peptides that targeted not only tumors but also specific healthy tissue.
Arrowhead had originally licensed one of the peptides discovered by MDACC in 2010 to target its obesity drug, Adipotide, to receptors specific to white adipose tissue. One beauty of the technology is that most of the targeting sequences were developed in humans, enabling Arrowhead to skip animal trials and the related qualms about translational breakdowns, explained Chris Anzalone, Arrowhead's president and CEO.
In August, Arrowhead struck a deal with Merck & Co. Inc., of Whitehouse Station, N.J., to evaluate a monoclonal antibody candidate the big pharma may later choose to license. (See BioWorld Insight, Aug. 20, 2012.)
Compared to that deal, where "the economics will be determined as we move down the road," the Shire roadmap is better defined, Anzalone said.
Arrowhead, of Pasadena, Calif., will receive undisclosed research funding and is eligible for development, regulatory and commercialization milestone payments of up to $32.8 million for each candidate, plus additional milestone payments for a second indication and royalties on worldwide sales. The companies did not disclose additional financial terms for agreement, which contains no development deadlines.
Shire, of Dublin, Ireland, did not name the target but indicated the platform technology will potentially enable the company to move into a wider range of orphan diseases.
"The tissue type is not our core focus but will enable us to build out our expertise in targeting that tissue on their dime," Anzalone told BioWorld Today.
In addition to research funding, the Shire partnership helps to validate Arrowhead's technology, Anzalone added.
"We view this as a very important and wide-ranging asset," he said. "We're going to use it to target our own RNAi therapeutics as well as more traditional small-molecule drugs, and we're going to enable partners to build on this."
Enabling Arrowhead's RNAi Therapeutics
The first step in the Shire partnership is to interrogate the database. Once the companies identify sequences that target the tissue of interest, they can winnow prospects into a manageable group for initial testing.
"This is a bit of proof of concept for the type of partnerships that we want to do," Anzalone said. "We are hopeful that, as we do more partnerships, the economics will grow. But first we need to show the world that peptide-drug conjugates really are next-generation antibody-drug conjugates."
Internally, Arrowhead's lead obesity drug candidate, Adipotide, uses the peptide-targeting technology to selectively destroy the blood supply that supports the growth of unhealthy fat by inducing apoptosis in the vasculature of adipose tissue. The peptide consists of two functional domains. The homing domain targets a membrane-associated protein, Prohibitin, on adipose vascular endothelial cells, while the membrane-disrupting domain causes apoptosis by disturbing mitochondrial membranes inside the cells.
The targeting peptide sequences also can be linked to Arrowhead's siRNA delivery vehicles, giving the company flexibility to design, chemically tune and develop RNA therapeutics optimized for each target. Behind Adipotide, the company is developing ARC-520, an RNAi-enabled therapeutic in hepatitis B based on a formulation of its dynamic polyconjugate siRNA delivery vehicle and two siRNA sequences that target different regions of the viral genome. Arrowhead currently is conducting investigational new drug-enabling studies and is on track to begin a Phase I study in mid-2013, Anzalone said.
Last year, Arrowhead acquired the RNAi therapeutics assets from Roche Holdings AG, of Basel, Switzerland, including Roche's research site in Madison, Wis. At the time, Roche took a minority stake in Arrowhead and obtained rights to negotiate for certain future products, milestone payments and royalties on sales. (See BioWorld Insight, Dec. 5, 2011.)
At the time, Anzalone prophesied that big pharma would eventually come back to license delivery technologies from companies that proved successful in RNAi. In fact, the Alvos technology was acquired specifically to support Arrowhead's RNAi platform, he said.
In addition to its PDCs, Arrowhead could join the growing ranks of biotechs wooing pharmas back to RNAi. The goal is for partnering deals to provide sufficient nondilutive funding to propel the company's internal pipeline.
Although Arrowhead hasn't disclosed a target number for future deals, "we hope each partnership will teach us more about this platform," Anzalone said. "The Shire collaboration, over the next couple of quarters, is going to inform how quickly we can move on these deals."
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