Allosteric modulation company Addex Pharmaceuticals announced that the second preclinical milestone has been achieved in an exclusive collaboration and license agreement with Merck & Co, Inc (through its affiliate Merck Sharp & Dohme Research Ltd).

The collaboration is focused on developing an emerging type of drugs, called allosteric modulators, for treatment of Parkinson's disease and other undisclosed indications. Allosteric modulators have broad potential to address important therapeutic targets; this collaboration with Merck is focused on developing drugs that specifically activate the metabotropic glutamate receptor 4 (mGluR4). The preclinical study showed the desired non-dopaminergic activity profile after oral administration of mGluR4 positive allosteric modulator (PAM) in an animal model of Parkinson's disease.

"We are pleased that these preclinical data show such promise in the animal model used," said Emmanuel Le Poul, head of the CNS Business Unit at Addex. "This work is a further validation of the target and the strength of our collaboration, as both teams have contributed to this achievement."

"Innovative non-dopaminergic therapies represent a significant opportunity to address an important unmet medical need in Parkinson's disease patients," said Vincent Mutel, CEO of Addex. "We are proud that our allosteric modulation drug discovery and development platform has generated highly innovative products in Parkinson's disease in addition to other important indications with unmet medical need including: gastroesophageal reflux disease, migraine, schizophrenia and anxiety."

Addex will receive $500,000 for achieving the second preclinical milestone. Addex received $250,000 after achieving the first preclinical milestone during the first quarter of 2008. Under the terms of the agreement, first announced in December 2007, Addex received $3 million upfront and is eligible for 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 is developed. Addex is eligible to receive undisclosed royalties on sales of any products resulting from this collaboration. Merck is responsible for clinical development.

mGluR4 may play an important role in Parkinson's disease, which is a debilitating movement disorder. Current treatments focus on dopamine-replacement strategies, however most patients reach a stage where dopaminergic treatments are no longer effective. There can also be debilitating side effects with dopaminergic treatments and many patients limit doses so their side effects will be less cumbersome. The recent success of surgical approaches suggests that bypassing the dopamine system may provide a more effective treatment strategy. It is believed that selective activation of mGluR4 is one way to do this and could correct the circuitry that modulates motor excitability. This has the potential to provide significant benefit in Parkinson's disease.

Published research shows that mGluR4 activators, like those in development at Addex, could work via two distinct mechanisms to alleviate symptoms of Parkinson's disease and, potentially, even slow the progression of the disease - 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.

Glutamate, like dopamine and serotonin, is a key neurotransmitter in the human brain, an important signalling molecule involved in control of multiple brain functions ranging from motor control to mood. Although marketed drugs modulate specific receptors involved in both the dopaminergic and serotinergic systems, it has been difficult to develop drugs that can selectively target specific receptors of glutamate, which has many different receptors, some of which can cause serious side effects if improperly modulated.

Merck has been a pioneer in research on mGlu receptors and the metabotropic glutamatergic system for multiple indications. For example, research by Merck scientists provided the first evidence that mGluR4 activation has potential for treatment of Parkinson's disease. However, a remaining challenge has been to make drug-like molecules that activate mGluR4 in a specific fashion. Addex is a pioneer in developing allosteric modulators, truly selective small molecule drug candidates, for human health.

Addex Pharmaceuticals discovers and develops allosteric modulators for human health.