EMERGING TECHNOLOGIES

Keep an Open Mind Glutamate-targeting Drugs Show Potential in Multiple Indications Advances in glutamate research are opening up new possibilities for developing drugs with potential for treating a wide range of neurological conditions including depression, anxiety, psychotic disorders, epilepsy, drug addiction and neurodegenerative disorders such as Alzheimer and Parkinson disease. Glutamate is the brain’s main excitatory neurotransmitter, with virtually all brain cells possessing receptors that allow them to respond to it. In addition, more than 50% of brain neurons generate glutamate. In the past, this all-pervasive nature of glutamate has not endeared it to neurobiologists who were of the opinion that developing glutamate-targeting drugs would generate positive and negative effects all over the brain. Indeed, glutamate-stimulating drugs can induce seizures and glutamate itself is the cause of much of the neurological damage that occurs after stroke. It is probably also the chief culprit in causing neuron death in amylotrophic lateral sclerosis (Lou Gehrig’s disease) and some other neurodegenerative diseases.

Thus, it is entirely probable that targeting one receptor subtype will produce a far more specific effect and have little or no effect on other receptors. One of the most clinically advanced compound targeting mGlu receptors is eglumegad, developed by Eli Lilly and Company and currently in phase II trials in the US in patients with panic disorder. The drug targets group II mGlu receptors and acts by dampening glutamate output and excitability when levels get too high, but has no influence on normal glutamate expression. Promising results were generated from a trial involving about 600 patients with anxiety disorders. In this trial, eglumegad showed similar efficacy to benzodiazepines, but without the adverse effects or withdrawal problems associated with benzodiazepines.

Research programs target wide range of indications A number of pharma companies have established drugdevelopment programs targeting the mGlu receptor, which are focused on a wide range of potential indications. In March 2001, NPS Pharmaceuticals, Inc. Glutamate Research Recharged and AstraZeneca plc started a 5-year collaboration to Prior to the 1990s, it was thought that all glutamate develop small-molecule therapies for the treatment of actions were mediated by ion channel receptors, of various disorders of the CNS. Under the terms of the which there are 3 subtypes named according to which collaborative agreement, NPS licensed its specific agonist activates them: NMDA, proprietary technology related to mGlu AMPA and kainate. However, with the receptors and molecules that act at these discovery of an entirely new class of receptors to AstraZeneca. NPS has glutamate receptor, the metabotropic With the discovery options to co-promote or to receive glutamate (mGlu) receptors, a host of new of an entirely new royalties from products resulting from possibilities for targeting specialized class of glutamate the collaboration and has secured rights receptors in specific parts of the brain receptor, the to co-promote products in North America began to be realized, and research efforts metabotropic with AstraZeneca. Currently, NPS is in the glutamate field have been glutamate (mGlu) conducting preclinical studies of NPS recharged [see table 1]. Unlike ion channel receptors, research 2390, a selective group I mGlu receptor receptors, mGlu receptors activate efforts in the antagonist, for the treatment of epilepsy, biochemical processes within cells rather glutamate field have pain and stroke. than opening ion gates and are capable of been recharged. subtle modulatory activities. Moreover, Prescient NeuroPharma Inc., a Canadian distinct mGlu receptor subtypes are biopharmaceutical discovery company, distributed within different brain regions. has synthesized a library of rationally Call +1 267-757-3400 or write to Pharmaceutical & Diagnostic Innovation for additional information

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Keep an Open Mind

Table 1. In the pipeline Drug

Company

Status

Mechanism(s)

Indication(s)

AMP 397

Novartis AG

Phase II

AMPA receptor antagonist

Epilepsy

AZD 4282

AstraZeneca

Preclinical

NMDA antagonist

Neuropathic pain

Besonprodil

Pfizer Inc.

Phase I

NMDA antagonist

Parkinson disease

CGX 1007

Cognetix, Inc.

Phase I

NMDA antagonist

Epilepsy; also pain (preclinical)

CNS 5161

CeNeS Pharmaceuticals Plc

Phase II

Glutamate antagonist

Neuropathic pain

CX 516

Cortex Pharmaceuticals, Inc., Servier

Phase II

AMPA receptor agonist, AMPA receptor antagonist, Glutamate agonist

Alzheimer disease, attention-deficit hyperactivity disorder, autism and schizophrenia; also mild cognitive impairment (clinical) and stroke (preclinical)

Eglumegad

Eli Lilly and Company

Phase II

Glutamate agonist

Panic disorder

LY 293558

Eli Lilly and Company, Neurogenetics Inc.

Phase II

AMPA receptor antagonist, Pain Kainate receptor antagonist

LY 544344

Eli Lilly and Company

Preclinical

Neramexane

Merz + Co.

Phase II

Glutamate antagonist

Alcoholism; also pain (phase I) and neuroprotection (preclinical)

NS 1209

NeuroSearch, Shire Pharmaceuticals Group plc

Phase II

AMPA receptor antagonist

Epilepsy and stroke

ORG 24448

NV Organon

Phase II

AMPA receptor agonist, Glutamate agonist

Schizophrenia

S 189861

Servier

Phase I

Glutamate agonist

Alzheimer disease

Generalized anxiety disorder

SIB 1893

Merck & Co.

Preclinical

NMDA antagonist

Neuroprotection

Talampanel

IVAX Corporation

Phase II

AMPA receptor antagonist

Epilepsy, Parkinson disease and brain cancer; also multiple sclerosis (clinical) and neuroprotection (preclinical)

UK 240455

Pfizer Inc.

Phase I

NMDA antagonist

Stroke

Zonampanel

Yamanouchi Pharmaceutical Co., Ltd.

Phase II

AMPA receptor antagonist

Stroke; also neuroprotection and pain (preclinical)

Source: R&D Insight (Adis International)

designed, small-molecule mGlu receptor agonists. The company is interested in the neuroprotectant properties of these molecules. Prescient is currently in the process of selecting subtype-selective mGlu receptor agonists prior to definitively selecting a lead compound for preclinical development. The company reports that one of its candidates, PRE 103, has shown impressive neuroprotective activity in a rat model of global cerebral ischemia. Taisho Pharmaceutical Co, Ltd. has developed a series of mGlu receptor agonists for the treatment of CNS disorders, including schizophrenia. In May 2002, Merck & Co. signed a license agreement with Taisho to develop and market the compounds; the agreement gives Merck exclusive worldwide rights (ex-Japan and 16

China) and co-exclusive rights in Japan. Currently, Taisho has two orally active, selective group II mGlu receptor agonists undergoing preclinical evaluation: MGS 0008 and MGS 0028.

Depression may yield to glutamate-targeting drugs It is likely that depression, the most common psychiatric disorder, may also yield to treatment with drugs targeting mGlu receptors. Scientists have known for many years that NMDA antagonists are capable of inducing antidepressant effects; unfortunately many of them induce unwanted psychoses as well. Many believe that the key to getting successful results with NMDA antagonists is to only partially block the receptor. The other option is to design drugs that stimulate the subtle action of mGlu receptors. Volume 1, Number 2 2003

EMERGINGSPECIAL TECHNOLOGIES REPORT

Schizophrenia is another disorder that may one day be treated by drugs targeting glutamate. When NMDA antagonists such as phencyclidine (PCP) and ketamine are given to healthy subjects, symptoms can be generated that bear a remarkable resemblance to those associated with the disorder. Scientists are, therefore, searching for compounds that can either enhance NMDA receptor function or reduce the excess amount of glutamate released. Merck’s eglumegad may have application here. It has been tested in animal models of the disease where it ameliorated symptoms of acute PCP-induced psychosis and related symptoms in schizophrenia.

Interest is mounting in the NR2B subunit of the NMDA receptor. The expression pattern of this subunit in the nervous system makes it a promising target for Parkinson disease and pain control.

Interest is mounting in a particular subunit of the NMDA receptor known as NR2B. The expression pattern of this subunit in the nervous system makes it a promising target for Parkinson disease and pain control. Pfizer, Inc. and Roche have a number of agents targeting this subunit in development, with Pfizer’s besonprodil completing phase I trials for pain control, while Roche’s programs are focused largely on neuroprotection. Cognetix, Inc. in the US has completed a phase I trial of its mollusc-derived small peptide molecule CGX 1007 in patients with epilepsy and is intending to move the compound into phase II trials. As for the AMPA receptor, research has hardly begun to scratch the surface. There is some evidence that stimulating AMPA receptors increases the neuronal expression of brain-derived neurotrophic factor that

plays an important role in maintaining cell functions. This has implications for depression and conditions involving cognitive deterioration, including Alzheimer disease. Eli Lilly has two AMPA receptor agonists in preclinical development that it is trialing as potential antidepressants and as treatments for cognition disorders.

Earlier this year, Cortex Pharmaceuticals, Inc. received a European Patent (titled `Drugs that enhance synaptic responses mediated by AMPA receptors’) for the use of AMPA modulators for enhancing memory encoding and cognition in humans. In addition to AMPA-targeting compounds being developed by Cortex, the patent includes compounds under development with other companies that work via the AMPA upmodulation or potentiation mechanism; accordingly, these companies would require a license from Cortex prior to commercialization. Similar broad use patents have already been issued to Cortex in the US, Mexico, Australia and New Zealand.

Already, Cortex has entered into an exclusive worldwide license agreement that will allow NV Organon to develop and commercialize its Ampakine® technology for the treatment of schizophrenia. Also, Cortex and Servier are jointly developing AMPA receptor-modulating compounds (ampakines) that could be used for dementias associated with aging and neurodegenerative diseases. Cortex will retain rights to the Ampakine program in the North American market.

Table 2. Global market potential of selected compounds Drug

Indication

Launch date

Peak sales ($US millions)

Year of peak sales

AMP397

Epilepsy

2008

100

2015

AZD 4282

Neuropathic pain

2009

250

2017

LY 544344

Anxiety

2007

500

2015

NS1209

Attention-deficit hyperactivity disorder Stroke

2006 2007

150 100

2010 2013

ORG 24448

Schizophrenia

2008

500

2015

Talampanel

Epilepsy* Multiple sclerosis* Parkinson disease*

2006 2007 2007

150 200 175

2010 2011 2011

Zonampanel

Stroke**

2007

231

2015

* US market only; ** US and EU markets Source: Lehman Brothers International

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17

Keep an Open Mind

The two companies will share costs for the placebocontrolled study in North America and Europe that will evaluate the efficacy of CX 516 in individuals with mild cognitive impairment. Under the terms of the licensing agreement, Cortex will receive an upfront payment of approximately $US5 million. Cortex stands to receive milestone payments on clinical and commercial

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development of CX 516 plus royalties on sales. The potential pay-off for the pharmaceutical industry in developing glutamate-based drugs is huge, but the risks and hurdles for the drug-makers are high also. In the next 3–4 years we may well witness the arrival of a new vanguard of glutamate-based therapeutics on the market [see table 2]. ■

Volume 1, Number 2 2003