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By Nuala Moran
BioWorld International Correspondent
Drug repositioning specialist Pharnext out-licensed its lead program in the chronic neuromuscular disease, Charcot-Marie-Tooth, to Ipsen SA in a deal with a value of at least €91 million ($US126.1 million).
Paris-based Ipsen is taking up convertible bonds of an undisclosed value now, and will pay Pharnext €91 million in milestones, plus royalties on sales, if it decides to take the program forward at the end of Phase II. In this case, Ipsen will have the option to swap the bonds into Pharnext shares.
Pharnext will be responsible for advancing the program, which consists of selected combinations of more than 200 off-patent, approved compounds thrown up by the company's systems biology in silico screening technology, to the end of Phase II. Ipsen will take on subsequent development and marketing costs if it exercises its option.
Although Charcot-Marie-Tooth has orphan classification, Pharnext said there are 30,000 sufferers in France and 3 million worldwide. Currently there is no treatment for the disease, which is triggered by genetic factors. More common peripheral neuropathies, such as those caused by diabetes, affect more than 30 million people worldwide and could be amenable to the compounds uncovered in Pharnext's screen.
Pharnext is one of an emerging band of biotechs that are repositioning drugs by applying advances in systems biology, in which understanding of the biological networks involved in particular diseases states is used to identify existing drugs that act on one or more proteins that are involved in the disease process.
The company was co-founded in June 2007 by Daniel Cohen, a leader in genomics and former chief science officer of Genset SA. That is the company credited with establishing the first deal in pharmacogenomics, in a 1997 agreement with Abbott Inc., to search for single nucleotide polymorphisms associated with drug efficacy and side effects.
The co-founder is France's leading biotechnology entrepreneur Philippe Pouletty, general partner at the venture capital firm Truffle Partners and chairman of the national industry association, France Biotech. Truffle has put in €3.5 million, and Paris-based Pharnext also has received €3.4 million from the French innovation agency, OSEO.
Although the initial focus is on Charcot-Marie-Tooth, Cohen said the technology platform, called pleotherapy, has far wider applications. "We believe that pleotherapy will generate many novel therapies in the central nervous system disease area, and indeed other fields of medicine."
Having identified 200 compounds, which act on proteins that are involved in peripheral neuropathies, and pinpointing some combinations that are active in in vitro and in vivo models of Charcot-Marie-Tooth, Pharnext is widening its search to find drugs that are active in Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia and inherited disorders including cystic fibrosis, Duchenne muscular dystrophy and Down syndrome.
Pharnext is promoting its approach to repositioning as a solution to the industry's productivity problems. While re-positioning accounted for €4 billion in R&D expenditure in 2008, the company is adding another layer of sophistication by looking for combinations of approved drugs.
The industry is being forced to acknowledge the existing discovery model of finding a single, safe and effective drug that can treat disease by increasing or blocking the production of a single protein has been undermined by the intricacies and feedback loops that are being uncovered by systems biology.
Every single biological function depends on multiple, finely-balanced networks, and the same protein is usually involved in several functions.
And since few drugs are target-specific, and since proteins have more than one function, most drugs will have unwanted side effects.
Looking on the positive side, the fact that each protein has more than one function enables the repositioning of drugs from one indication to another. Moreover, combinations of drugs that act on different protein targets are effective at lower doses of each component of the drug cocktail, reducing side effects.
Pharnext first accumulates genetic data relating to a particular disease and uses those to generate a list of proteins involved in the disease state and identify approved drugs that act on any of those proteins.
The screening process takes place in silico over three to nine months. The selected drugs are then screened alone and in combination in models to generate preclinical candidates.
According to Pharnext, the discovery phase is twice as fast and yields less toxic, more effective compounds than traditional methods. The company has conferred with regulators and said that while it is necessary to compare the effect of a mixture with that of each of its components when testing in an established indication, it is not the case in new indications. | 
