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Kinexis Targets Alzheimer’s Through Amyloid Oligomers

Source: BioWorld Today
By: Trista Morrison
03.10.2008

Since its founding in 2003, Kinexis Inc. has pursued several lead development programs, including prokineticin receptor modulators and melanin concentrating hormone (MCH)-1 receptor antagonists.

But the San Diego-based company's third lead program - licensed from the University of California at Irvine in 2004 - turned out to be the charm. The program was built around a platform to generate antibodies targeting oligomeric conformations of amyloid proteins, which form the hallmark plaques of Alzheimer's disease. And in 2006, the amyloid oligomer program officially became Kinexis's primary focus at the urging of new CEO Kevin Anderson.

Alzheimer's disease affects more than 26 million people worldwide, creating a $4 billion market. Currently available drugs - Aricept (donepezil, Pfizer Inc.), Exelon (rivastigmine, Novartis AG), Cognex (tacrine, First Horizon Pharmaceutical Corp.), Reminyl (galantamine, Shire Pharmaceuticals Group plc) and Namenda (memantine, Forest Laboratories Inc.) - boost memory and cognition but cannot slow the course of the disease.

Much Alzheimer's research has focused on amyloid plaques, but Anderson said recent studies indicated the plaques may not be toxic in and of themselves, and may not be the source of the cognitive defects in Alzheimer's disease. He added that cognitive problems often appear even before the plaques develop, leading researchers to look upstream at the prefibrilar oligomers that eventually form plaques.

Prefibrilar oligomers are cytotoxic and interfere with neurotransmission; they are "pretty universally recognized as the bad actors in Alzheimer's disease," Anderson said.

Yet not many companies are working with the oligomers, Anderson explained, because they are unstable
and will quickly dissociate into monomers or bind to form fibrils. Those conformations are also popular Alzheimer's drug targets: Myriad Genetics Inc.'s Phase III drug Flurizan (tarenflurbil) targets monomers, as does the Phase III monoclonal antibody bapineuzumab (Elan Corp. plc and Wyeth). Elan and Wyeth also have an Alzheimer's vaccine that targets fibrils. (See BioWorld Today, Jan. 13, 2005, and May 22, 2007.)

Yet oligomers are present at a lower concentration than monomers or fibrils, which means they can be targeted with a lower dose of drug, Anderson said. That may avoid autoimmune and inflammatory consequences, he added.

Kinexis' platform identifies antibodies that specifically target amyloid oligomers. The company has parlayed that technology into three programs: vaccines, therapeutic antibodies and small molecules.

The Kinexis vaccine stimulates production of antibodies targeting amyloid oligomers. In preclinical studies, it has "worked at least as well as fibril vaccines," decreasing plaques and increasing cognition and memory, Anderson said. Kinexis is formulating preclinical development plans for the program.

In its therapeutic antibody program, Kinexis demonstrated that polyclonal candidates could decrease plaques and improve synaptic function in animal models. The company has since created two monoclonal candidates and is studying them in animal models, but Anderson said Kinexis will seek a partner for humanizing and further developing the selected antibodies.

Kinexis also used its antibodies to develop assays for small molecules that bind to amyloid oligomers. The company established proof of concept using known binders and is now scaling up for high-throughput screening.

Anderson said the amyloid oligomer approach could "absolutely" modify the course of Alzheimers disease. In theory, it also could be used in combination with both existing drugs and with late-stage candidates like Flurizan, which would decrease the monomers while Kinexis' drug wiped up the oligomers already present.

Thus far, Kinexis has built its programs using $2.8 million in seed funding provided by InvestBio Ventures. But Anderson, who previously served as vice president of business development and research at Chimerix Inc., said the company is looking to close a $10 million venture round in the next six months. That funding will be used to advance the vaccine into clinical trials and select a lead candidate from the antibody program.

Additional funding also may come from future partnerships. In addition to partnering out its antibody program, Anderson noted that amyloid oligomers also contribute to diseases like Parkinson's and Huntington's, and that Kinexis would be interested in exploring and potentially partnering its technologies for such indications.

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