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Resistant Depression NEWS & ANALYSIS BIOBUSINESS BRIEFS DEAL WATCH NR2B antagonist pursued for treatment- resistant depression Roche has entered into an agreement with compared with non-selective NMDA receptor Evotec to fund the Phase II clinical development antagonists in preclinical studies. The effects of a selective N-methyl-d-aspartate (NMDA) of other oral, brain-penetrant NMDA receptor antagonist, EVT 101, for patients with receptor antagonists that bind to the treatment-resistant depression. EVT 101 was NR2B receptor subunit (including TXT-0300, originally discovered by Roche and licensed to Traxion Therapeutics; and MK-0657, Merck) Evotec in 2003 for further development. Roche have also been investigated, not only for will also pay Evotec to conduct Phase I safety the treatment of depression, but also pain and tolerability studies for EVT 103, a next and cognitive disorders. However, no generation compound to EVT 101, and an developments have been reported recently. upfront fee of US$10 million for the option to Although it is not well understood why buy back rights to the entire EVT 100 family of NMDA receptor antagonists are effective compounds. The total potential deal value is against treatment-resistant depression, as more than $300 million. Mathew notes, “...the rapid onset of action It is estimated that over 120 million people of these compounds could result in a decrease suffer from depression and that about one-third in long-term morbidity,” and thus warrants of patients treated for major depressive further investigation. Holger Wigström, disorder (MDD) do not respond satisfactorily. Professor at the Institute of Neuroscience and In addition, current therapies, such as selective Physiology, Göteborg University, Germany, serotonin-reuptake inhibitors, typically take who is examining the effects of NMDA several weeks to exert their effects. receptor antagonism on neuronal plasticity, The involvement of non-monoaminergic points out that “...the blocking mechanisms mechanisms in mood disorders is currently an of [ketamine and memantine] versus EVT 101 area of active investigation with the aim to are somewhat different; so the important address these treatment needs. In particular, issue could be achieving a partial block of the the glutamatergic system has attracted NMDA receptors, rather than which receptor attention (Nature Rev. Drug Discov. 7 426-437; subtype is targeted. Certain forms of synaptic 2008). Increased levels of glutamate have been plasticity can be influenced by NMDA found in the frontal cortex of patients with receptor subtype-specific blockers, MDD, and the non-selective NMDA receptor but it is controversial whether this is a antagonist ketamine has shown antidepressant subtype-specific effect or is due to a general effects in patients with treatment-resistant reduction of NMDA-dependent Ca2+ influx, depression within 2 hours. However, its suggesting that there is also still much to be psychotomimetic effects preclude long-term learnt about the role of receptor subunit use. specificity in the therapeutic effects of NMDA These findings, together with the observed antagonists.” differential expression of the various NMDA receptor subunits in individuals with mood disorders, suggest that NMDA receptor subtype-specific antagonists could “...provide a more selective approach, which could potentially capitalize on the therapeutic benefits, while minimising some of the cognitive and psychiatric side-effects associated with broader NMDA receptor blockade,” explains Sanjay Mathew, Director of the Mood and Anxiety Disorders Program at Mount Sinai School of Medicine, New York, USA. In 2005, Evotec initiated a Phase I trial after reporting that EVT 101 showed strong efficacy and an improved side-effect profile NATURE REVIEWS | DRUG DISCOVERY VOLUME 8 | MAY 2009 | 349 © 2009 Macmillan Publishers Limited. All rights reserved.
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