BioWorld International Correspondent

Merck & Co. Inc. demonstrated its liking for Addex Pharmaceuticals AG's approach to modulating glutamate receptors by entering a second deal with the Swiss firm in consecutive months.

The latest pact is potentially worth up to $702 million in up-front and milestone payments, plus royalties on product sales. It concerns ADX63365, a preclinical positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), and related compounds, in development for treating schizophrenia and other undisclosed central nervous system indications.

Geneva-based Addex would capture the total value of the deal if two products were to gain approval in a total of four indications. It is receiving an upfront payment of $22 million and would gain a further $455 million in milestones based on the first product in the collaboration gaining approval in two indications.

It would gain an additional $225 million if a second product would gain approval in two indications, also. Addex has retained an option to co-promote products in certain European Union member states.

The deal follows a recent pact between the two firms based on the development of a positive allosteric modulator of mGluR4 for treating Parkinson's disease and other CNS indications, worth up to $170 million in up-front and milestone payments. (See BioWorld International, Dec. 5, 2007.).

The emergence of mGluR5 as a potential therapeutic target in schizophrenia is part of a wider revival of the "glutamate hypothesis" in that condition, Addex CEO Vincent Mutel told BioWorld International, following the commercial and clinical success of the dopamine receptor-2 antagonists. Those have dominated the field for more than a decade but shortly will become generics, opening up commercial possibilities for innovative drugs based on new mechanisms.

"Several lines of evidence from work being done by Merck, in particular, and by other groups" support the notion of a role for mGluR5 in the condition, he said. That includes work on transgenic animals, animal models of schizophrenia and pharmacologic work.

Others already have established clinical evidence in support of a role in schizophrenia for a different metabotropic glutamate receptor.

Last September, Indianapolis-based Eli Lilly & Co. published Phase II data in the journal Nature Medicine, which provides clinical proof of concept for LY2140023, a prodrug of a selective agonist of mGluR2/3 called LY404039.

"What we believe is the role of the two receptors is very different," Mutel said. MGluR5 is "very much associated with ion channels - the NMDA class of glutamate receptor," he said. It appears to be linked to cognitive functioning. Addex, Mutel said, is one of the few companies that successfully generated positive allosteric modulators of the receptor, which is difficult to target at its active site. Merck has the tools, research activities, models and development skills to bring that chemistry forward, he said.

The partners are not yet releasing the additional indications covered by the agreement, and in fact, have not identified or finalized them all. "We have made some interesting observations, which will probably guide us to certain indications. Very clearly there is room for exploratory activity as well," Mutel said.

Addex released news of the Merck deal on the same day it disclosed that ADX10059, a negative allosteric modulator of mGluR5, failed to demonstrate efficacy in a Phase IIa clinical trial in anticipatory anxiety.

"What we were betting on was acute anxiety - we were betting that this compound could act like benzodiazapines," Mutel said. It still has potential in generalized anxiety disorder although Addex does not intend to pursue that indication on a solo basis, as it requires large-scale studies that are beyond its capabilities. It is continuing to develop the compound in gastroesophageal reflux disease and migraine.

No Comments