Merck & Co. has decided to continue its research collaboration with Addex Pharmaceuticals for an additional year. The partnership is focused on developing positive allosteric modulators (PAM) of the metabotropic glutamate receptor 4 (mGluR4) for the treatment of Parkinson disease and other undisclosed indications.
The decision follows a report earlier this year from Addex that a preclinical study with an orally available mGluR4 PAM showed efficacy in an animal model of Parkinson. With the extension, Addex will recognize $1.8 million in research funding over the next 12 months in addition to the original financial terms.
As per the exclusive collaboration and license agreement announced in December 2007, Addex received $3 million up front. Since then the company has been paid two preclinical milestones of $250,000 and $500,000. Addex is eligible to receive up to $106.5 million in research, development, and regulatory milestones for the first product developed for multiple indications.
Additional milestones of up to $61 million would be payable if a second and third product are developed. Addex will also receive royalties on sales of any products resulting from this collaboration.
Glutamate, like dopamine and serotonin, is a key neurotransmitter in the human brain, an important signaling molecule involved in control of multiple brain functions ranging from motor control to mood. In Parkinson the death of dopamine-producing neurons leads to excess glutamate signaling.
Current treatments focus on dopamine-replacement strategies. Yet, most patients reach a stage where dopaminergic treatments are no longer effective. There can also be debilitating side effects with dopaminergic treatments. It is believed that selective activation of mGluR4 is one way to bypass the dopamine pathway and could correct the circuitry that modulates motor excitability via a nondopaminergic mechanism.
Research shows that mGluR4 activators could work via two distinct mechanisms to alleviate symptoms of the disease and, potentially, even slow the progression of the disease, according to Addex and Merck. mGluR4 activation triggers a compensatory mechanism that may spare or potentiate the use of dopamine-receptor activators. And mGluR4 activation may have a neuroprotective effect that helps to preserve the brain's dopaminergic neurons.
Addex has an mGluR5 NAM candidate called ADX10059 in Phase IIb testing for GERD and migraine prevention. The mGluR5 NAM ADX48621 has completed Phase I for levodopa-induced dyskinesia related to Parkinson. Also, Addex’ partner, Ortho-McNeil-Janssen Pharmaceuticals, is performing a Phase I study of another mGluR2 PAM, ADX71149, which has potential in anxiety and schizophrenia.