PARIS - Disorders of the central nervous system are one of two priority therapeutic areas, along with metabolic disorders, on which the French genomics company Genset S.A. is increasingly focusing its research and development effort.

It has decided that the market opportunities in these areas are large enough to justify substantial investment in R&D programs that will come to fruition only in the medium to long term.

According to Genset, both areas are characterized by four key factors: they encompass pathologies in which there are substantial unmet medical needs; they represent markets that are potentially worth tens of billions of dollars a year; they involve medical conditions that are imposing a growing financial burden on national healthcare systems; and, above all, they are pathologies in which genomics has a proven competitive advantage since therapies addressing the genetic origins of these diseases can be more specifically targeted, more cost effective and better tolerated than conventional therapies.

There has thus been a gradual shift in Genset's corporate strategy over the past two or three years, although its growing commitment to these two areas has in no way impinged on ongoing research programs in three other areas - cancer, cardiovascular diseases and age-related diseases. But this new priority was reflected in the company's decision in the second half of 1998 to expand its research and development facilities and launch more gene discovery programs.

The resulting increase in R&D spending in the fourth quarter of last year had the effect of reversing the downward trend in quarterly losses and meant the company will attain profitability several years later than originally planned. Little more than a year ago Genset was still expecting to break even in 1999 and show a profit in 2000.

Disorders of the central nervous system (CNS), such as schizophrenia, Alzheimer's disease and depression, are known to have a significant genetic component, as tests on twins have demonstrated. Some of these disorders have been identified only recently and most are not very well understood, since they are highly heterogeneous in their manifestation. The lack of physically measurable symptoms makes CNS disorders difficult to diagnose and measure, and even more difficult to treat. Therapies take a relatively long time to generate a response, and only when they do can doctors be sure they have correctly identified the disease and prescribed the appropriate therapy.

One consequence of the complex nature of these pathologies, as Genset's marketing manager, Agnhs Le Saux-Narjoz, pointed out, is that "the cost of developing a new CNS drug is around $1 billion, compared with $500 million to $600 million for other drugs." Genomics could help cut those development costs, she added, because it "could provide insight into understanding these diseases and finding therapeutic remedies."

Genset has some experience with CNS diseases - it has been engaged in a research program to discover genes associated with schizophrenia since September 1996, when it signed a collaboration agreement to that end with Johnson & Johnson. During the course of that ongoing research program, Genset has delivered periodic research results to J&J, although those results have not been disclosed or published. Since last fall, when the original two-year agreement expired, it has been rolled over every quarter, but Genset's chief financial officer, Deborah Smeltzer, told BioWorld International the two companies were presently in negotiations with a view to putting their collaboration onto a broader footing.

Genset has not concluded any more research collaborations in the CNS area since then, but over the past year or so it has embarked on three in-house programs aimed at identifying the genes associated with schizophrenia, Alzheimer's disease and manic depression. Then last May it signed agreements with two North American institutions, which are providing it with the clinical samples it requires for two of those CNS research programs.

The first was with Johns Hopkins University School of Medicine, which is giving the French company access to its bank of 1,800 DNA samples collected from more than 300 families with one or more schizophrenia sufferers. Genset has started analyzing them with the help of its proprietary SNP (single nucleotide polymorphism) technology and is carrying out linkage disequilibrium association studies to search for significant genetic linkages indicating susceptibility to schizophrenia.

The second agreement was signed with Canada's Alghne Biotechnologies, which has since changed its name to SignalGene. In that case, Genset not only has access to SignalGene's collection of DNA samples from Alzheimer's patients, but also has a license to exploit the Canadian company's proprietary gene mapping results. Genset is drawing on its own integrated genomics technology to generate biallelic markers in the chromosomal regions identified by SignalGene, perform high-throughput genotyping of the complete sample collection and analyze the resulting association data.

Smeltzer declined to put a figure on Genset's financial commitment to CNS, saying only that "we have more internally funded programs in CNS than in anything else." But she pointed out that Genset would soon be concluding more research collaborations with pharmaceutical companies to obtain external funding for these programs, since it did not want to increase its internal funding commitments beyond existing levels.

Before it can interest big pharma in the programs, however, the company needs to have completed a certain amount of fundamental genomics research to give it "a minimum set of tools," as Le Saux-Narjoz put it. At the same time, pharmaceutical companies have to beat their own path to the door of biotechnology-based therapies. For them, teaming up with a genomics company is a major innovation and may require both a cultural and a scientific leap forward on their part, according to Smeltzer. "Pharmaceutical companies have to develop internal capabilities to incorporate genomics into their drug development strategies," she said.

The important thing was "to have something concrete to show partners, rather than just concepts," and in that regard, Smeltzer went on, "we feel we have a strong portfolio now, especially in CNS disorders." Genset is negotiating with "a lot of pharmaceutical companies interested in the CNS ... but these agreements can take 18 to 24 months to negotiate." Nevertheless, she said, "we expect to close some new deals before the end of this year," one or more of which could be in the CNS area.