Start-up Profiles

Nature Biotechnology  20,  BE16-BE17 (June 2002)

Axxima Pharmaceuticals

Creating a firewall against infection

Axxima's Martinsried, Germany headquarters

When pathogens infect a host, they must manipulate its signal-transduction pathways—the intracellular circuits that transmit extracellular signals from the cell's surface to the nucleus, where cellular change can be realized—to survive. Axxima intends to prevent pathogens from hijacking these pathways by using inhibitors of kinases, enzymes that play key roles in cell signaling, to generate a "firewall" against infection. (Click here for company profile.)

Because disturbed kinase activity is known to lead to cellular malfunction, and thus to disease, kinases have become popular targets of drug development, especially in the areas of cancer, immunosuppression, and inflammation. Despite competition in this field, Axxima Pharmaceuticals was set up five years ago to develop small-molecule kinase inhibitors, which can block specifically those signal transduction pathways involved in infectious disease.

What also distinguishes Axxima from the crowd, according to its chairman of the board Jürgen Drews, is that the company focuses its efforts not on kinases in pathogens (although it does some research in this area) but on kinases in the host. "Usually, when you think about a target in infectious diseases, you assume that the target will be in the infectious agent that needs to be eliminated," he says, "but host kinases can be manipulated in such a way that the cell is no longer infected and actually the agent is eliminated—that's a new approach."

Bert Klebl, vice president of research, says this "host approach" works because Axxima checks for toxicity to identify redundancy in pathways. "The cell usually has a few salvage pathways that it can use in the case you block a kinase." This means that a drug can block a particular host kinase in a non-infected cell without producing any toxic effects in the cell and harming the host.

Another reason why Axxima targets host-cell kinases is to avoid the problem of resistance. "Usually, with the typical anti-infectives [that act on the pathogen], you'll get resistance formation at a certain frequency [through spontaneous mutation]," says Klebl. "Tackling a host-cell kinase means that the pathogen most likely will not develop resistance to it [the pathogen would have to find a novel means of infecting the cell]! That's the new mode of action!"

Axxima is searching for antimicrobials that are effective against HIV, hepatitis B and C, influenza, human cytomegalovirus, and tuberculosis. Axxima takes the same approach, regardless of the pathogen: it identifies targets using state-of-the-art genomic and proteomic tools, validates the targets in a relevant pathogen model, and then conducts biochemical and whole-cell screening of the compounds followed by chemical lead optimization using structure–activity prediction.

Drews says that although Axxima is young, it does have "something that can be regarded as a pipeline." This includes several projects at the lead optimization stage in each of the different pathogen areas, the most advanced being an anti-HIV product, AXD-455, acquired from Cytokine Pharma Sciences (King of Prussia, PA), that is in phase 2 trials.

Although the company is building a broad and solid intellectual property portfolio, "it's still early days," says Drews. "The compounds that are being designed or acquired are, of course, patented."

Drews says that an important figure in the company is cofounder Axel Ullrich, who is among the world leaders in this particular area. He was previously at Genentech (S. San Francisco, CA) and was then involved in starting up Sugen (S. San Francisco, CA), before establishing Axxima and bringing with him a very rich scientific background.

A third round of financing recently raised 34.4 million—sufficient to last the company one and a half to two years. The company's strategy is to partner out some of its compounds to generate sufficient resources to allow Axxima to carry one or two compounds through to market itself. "There is not yet the pharmacological deal or the pharmaceutical deal that the company needs in order to develop and bring a compound to the market with royalties," says Drews. "But that's going to come next." ED