Evotec takes on tricky CNS target

The patents relate to a specific receptor for glutamate, one of the principle excitatory neurotransmitters in the CNS and a long-standing target for indications such as stroke, Alzheimer's disease, brain injury, Parkinson's disease and neuropathic pain.

Glutamate has been implicated in a series of events - known as the glutamate cascade - that are thought to be involved in the degeneration of nerve cells after injury or in disease.

A large number of drugs aimed at interrupting this chain by blocking a receptor for glutamate known as the NMDA (n-methyl-d-aspartate) receptor, but to date just one - Merz+Co's memantine - has reached the market. Several have failed in clinical trials for a variety of reasons, but often related to the non-selective inhibition of the receptor which can lead to adverse effects such as altered mental activity. Most of these trials were looking at the use of the drugs in stroke.

Evotec Neurosciences has licensed rights to a patent portfolio covering both oral and injectable inhibitors of a specific subtype of the NMDA receptor known as NR2B . It believes these could be used for the treatment of a variety of CNS disorders, including Alzheimer's disease, neuropathic pain and Parkinson's disease.

The novel compounds are in late preclinical development, and are said to show a considerably improved side effect profile compared to non-selective NMDA receptor antagonists.

That the agreement is with Roche is not wholly surprising, as Evotec Neurosciences' chief executive John Kemp was closely involved in the discovery and development of the compounds in his previous role as the former head of CNS research the Swiss firm's research facilities in Basel. And Roche has retained rights to reacquire the compounds in the future.

Exploring the glutamate cascade

Over-stimulation of the NMDA receptor has been associated with a complex cascade of events, characterized by an influx of calcium ions into nerve cells. For example, after a stroke, the oxygen-starved tissue is stimulated to release glutamate (possibly by blocking the reuptake of the transmitter into nerve cells from the synapse.

This means that more glutamate is therefore available to stimulate the NMDA receptors, leading to over-excitation of neurons and an excessive influx of calcium ions. In turn, this rise in intracellular calcium can lead to the activation of a number of enzyme systems (e.g. protein kinase C, phospholipases, proteases), which have multiple effects including the inhibition of glutamate uptake, which further exacerbates the situation.

These enzymatic processes can also cause the neuron to 'digest itself' by protein breakdown, free-radical formation and lipid peroxidation. Injured neurons then release more glutamate that in turn injures other neighbouring neurons - a classic example of positive feedback. Blocking the NMDA receptor prevents the over-stimulation that kicks of this process and should, at least in theory, preserve the function of nerve cells.

Sees recovery in discovery market​

Meantime, parent company Evotec OAI has reported a 10 per cent growth in revenues in 2003 that suggests - according to the company - that the downturn in spending on drug discovery among the biotechnology and pharmaceutical industries is ending.

Group revenues came in at €77.2 million, up 10 per cent, with the Discovery and Development Services division seeing sales of €61.2 million, up 4 per cent.

The strongest growth came in the Tools and Technologies segment, which saw its turnover rise a whopping 64 per cent to €18.7 million, driven by newproduct launches including Evotec's Opera confocal imaging reader.

Joern Aldag, the company's chief executive, noted that 2003 was another demanding year for the drug industry, with many clients impacted by margin pressures, increasing generic competition and the focus on getting products to market near-term, "which led to some shifting of resourcesinto clinical development and away from preclinical R&D."​

In an encouraging statement, Aldag said: "We believe the tendency of some companies to move away from discovery activities may prove temporary as the pharmaceutical industry needs to balance their preclinical and clinical pipelines."​

Evotec's operating loss was reduced dramatically, falling to €15.8 million in 2003 from €135.5 million in the prior year, although this reflected the absence of a charge for goodwill impairment linked to the acquisition of OAI in 2000. Excluding this, the operating loss narrowed to €5.1 million from €14.1 million, an improvement of 64 per cent.

In common with other companies supplying products and services for drug discovery, Evotec believes that the weakness caused by soft financing markets for biotechnology companies and budget cuts by pharmaceutical companies appeared to bottom out at the end of 2003.

"There are now signs of a recovery, particularly in the US andJapan, with Europe following at some distance,"​ said Aldag, and this should lead to significant revenue growth in the second half of 2004.