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Resistance is futile
ATLANTAŚNeurOp Corp. recently announced a collaboration with Bristol-Myers Squibb Co. (BMS) focused on the development of NeurOp's proprietary small molecules for use in the treatment of major depression and other central nervous system disorders.
According to BMS spokesperson Jennifer Fron Mauer, "BMS was attracted to NeurOp's molecular understanding of the target we are interested in, the NR2B receptor, and its collection of 400 compounds aimed at that target. We have established a working group with leadership from both companies to manage day-to-day activities. Both parties will work to identify new compounds active against the receptor, and then advance both new hits and early leads to a clinical candidate."
Under the terms of the agreement, BMS has agreed to pay NeurOp an upfront fee of $1.5 million and to fund a two-year research collaboration. In addition, NeurOp is eligible to receive up to $74 million in potential milestone payments for the successful development of a compound in major depression and royalties on worldwide sales of commercialized compounds. The compound class to be developed comprises NR2B subunit-specific N-methyl-D-aspartate (NMDA) receptor antagonists.
From NeurOp's end, the collaboration was spearheaded by George "Barney" W. Koszalka, who joined the company in March as president and CEO. He notes that other NR2B therapies have fallen out of the clinic due to unacceptable side effects, which he is confident NeurOp has designed out. NeurOp's compounds have minimal activity in healthy (normal pH) tissue, he explains, but are "turned on" and become potent NMDAR antagonists when needed in regions of low pH caused by focal ischemia or rapid neuronal firing. Additional selectivity is achieved by binding only NMDAR containing the NR2B subunit as noncompetitive, allosteric antagonists. This offers regional selectivity and also preserves some NMDA receptor activity, as opposed to a complete antagonism caused by many previous generation antagonists.
NeurOp's most promising compounds are up to 60 times more potent at pH 6.9 than at pH 7.6 in protecting neurons from glutamate-induced cell death in vitro, show good efficacy in the in vivo models tested and show high margins of safety, Koszalka says.
"The side effect profile at normal pH should be mineral," he says. "We are excited about the research agreement with Bristol-Myers Squibb because of their commitment to neuroscience drug development. We believe they are the ideal collaborator to help develop the potential of our NR2B program in depression. This alliance validates the pioneering work of NeurOp's scientific founders, Dr. Raymond Dingledine and Dr. Stephen Traynelis of Emory University and Dr. James McNamara of Duke University."
Previously under development for ischemia and neuropathic pain, this is the platform's first application to depression.
"There are many, many types of depression," Koszalka notes.
The currently available SSRI-type therapies are not responded to by all patients and typically can take four to six weeks to elicit improvement even in responsive individuals. NeurOp's most advanced compounds modulate the NMDA receptor in a manner designed to enhance therapeutic benefit while alleviating side effects associated with previous-generation NMDA receptor antagonists. Koszalka says therapeutic effect is notable 24 to 48 hours after the first dose.
Multiple scaffolds of molecules are under evaluation, Koszalka says, each of which has particular characteristics.
"The idea is to find the right balance," he notes.
BMS will conduct the lead identification and evaluate compounds for safety panel testing prior to Phase I clinical trials.