New medicines for neglected diseases

Close collaboration

Many of NITD’s key scientific partnerships have been forged within Novartis, reflecting the intense focus on translating basic science into drug discovery. For example, close collaboration with other Novartis research units was instrumental in the discovery and early preclinical development of a promising compound against malaria.

When NITD launched its malaria program, the Natural Products unit of the Novartis Institutes for BioMedical Research (NIBR) agreed to screen its compound library for possible activity against Plasmodium falciparum, the parasite that cause the most severe form of the deadly disease. The assay used in the screening program was developed by the Genomics Institute for the Novartis Research Foundation (GNF), based in La Jolla, California.

A natural product-like molecule from a chemical class known as the spiroindolones showed activity against P. falciparum and preliminary evidence suggested that this so-called “pathfinder” compound might work through a novel molecular mode of interaction. NITD initiated a lead optimization program in December 2007 with the goal to further improve antimalarial activity and pharmacological properties of the spiroindolone class.

Back in Basel, Switzerland, chemists from the Natural Products unit dug more deeply into the unusual chemical structure of the pathfinder molecule. “It’s a synthetically derived molecule, but one that started from two natural precursors,” says Frank Petersen, Head of NIBR’s Natural Products unit. “It looks like a natural product which is why it wound up in our library.”

Interestingly, the pathfinder actually comprised a mix of so-called isomers, molecules with an identical number and types of atoms but mirror-image structures that can affect their activity. When the isomers were separated by a NIBR team in Basel, one turned out to be inactive but the other isomer was highly active against malaria parasites.

Now scientists at both GNF and the Basel-based Swiss Tropical Institute are racing to determine the exact mechanism of action of a lead compound – known by the research number NITD609 and synthesized by NITD chemists. So far, there has been no evidence of cross-resistance with other existing antimalarial drugs – an indication that the target is potentially novel.

NITD609 has passed several key preclinical checkpoints and if ongoing toxicology studies are successful, the drug could begin full development before the end of 2010. That would represent a significant milestone for NITD but years of clinical testing would still be required before the compound could reach patients. Nevertheless, NITD609 was named Project of the Year 2009 by MMV, which manages a portfolio of projects and provides funding for partners from academia and industry.

“NITD609 is a great example of how Novartis makes available the best resources from across the organization to support our programs,” says Manos Perros, a virologist who joined Novartis as new Head of NITD in March 2010. “It underscores the unique contribution a major pharmaceutical company can make to neglected disease research. I don’t know of any academic institution that could match the know-how and experience that Novartis collectively brings to NITD’s malaria program.”