[Stitcher]

Brainstorm at Roche Leads to New Valium-Like Drugs (Update2)

By Dermot Doherty
http://www.bloomberg.com/apps/news?p...nsY&refer=home

Nov. 13 (Bloomberg) -- Vincent Mutel saw so much potential in a new way of tweaking the brain's circuitry that he left a job he'd had for 15 years to bet his future on a start-up.

The ability to move fast and take a risk on a hunch in his six-year-old venture, Geneva-based Addex Pharmaceuticals Ltd., is paying off. The company has signed licensing deals with Johnson & Johnson and Merck & Co. to make schizophrenia and Parkinson's disease medicines, and Addex's first pill, a treatment for migraine and heartburn, may be introduced in 2012.

The Addex approach represents a promising way for creating medicines at a time when the pharmaceutical industry is struggling to find new products. Its potential has attracted the attention of Pfizer Inc., Novartis AG and Roche Holding AG, Mutel's former employer, which say the drug-hunting method may lead to safer, more effective therapies.

``Addex has done with a fairly small company what in many cases larger companies have failed to do,'' said Darryle Schoepp, head of neuroscience research and development at Whitehouse Station, New Jersey-based Merck. ``They've done the best job of taking the technology and turning what is a compound into what might be a drug.''

Most modern medicines work by mimicking or blocking the action of molecules in the body that help carry out chemical reactions linked to a disease. Addex's treatments differ in that they are designed to regulate or fine-tune the molecules' activity. Researchers say this softer approach may cause fewer side effects than conventional drugs.

Valium

The concept, known as allosteric modulation, isn't new. Roche introduced the tranquilizer Valium in 1963, and although scientists didn't fully realize it at the time, the pill works in a similar way to Addex's drugs. It wasn't until three decades later, when a new way of screening compounds became common, that researchers saw that many such therapies may be possible.

The first medicine to use the approach to act on a family of proteins targeted by about half of all new drugs was Amgen Inc.'s Sensipar for kidney-disease complications. The treatment won U.S. approval in 2004 and had sales of $161 million during this year's third quarter, a 32 percent gain over the same period in 2007.

``Sensipar does appear to be the validation of the concept because it's safe, has fewer side effects and represents a significant advance on whatever else is available,'' said Arthur Christopoulos, professor of pharmacology at Monash University in Australia. He has worked as a scientific adviser on the approach to Addex, as well as Pfizer, Amgen and GlaxoSmithKline Plc.

Experimental Drugs

Still, most experimental medicines fail to make it through the three phases of clinical testing needed for marketing approval, and the U.S. Food and Drug Administration cleared just 19 new medicines in 2007, the fewest in 24 years.

Since its founding in 2002, Addex has burned through 141 million Swiss francs ($120 million) and had 143 million francs in cash and marketable securities as of June 30. The stock has lost about half of its value since its May 2007 initial public offering, and has declined about 9 percent this year. Prominent investors include London-based Glaxo, which owns about 5 percent of the Swiss company. Addex has had licensing revenue of about 40 million francs.

The shares increased 1.1 francs, or 3.1 percent, to close at 37.05 francs.

Addex's initial focus on brain disorders stemmed from Mutel's time at Basel, Switzerland-based Roche, where he searched for compounds to regulate the activity of glutamate, a chemical linked to schizophrenia and Parkinson's disease.

Cell Surfaces

Drugs work by interacting with protein molecules that sit on the surfaces of cells. Binding, or receptor, sites have a specific structure and chemicals have to fit precisely onto these spots in order to bind to a protein and turn it on or off and have an effect. Mutel and his colleagues tried to find medicines that would attach to a G-protein coupled receptor -- a type of protein active in almost every organ system in the body -- for glutamate.

The team discovered a compound that fit to the receptor's so-called allosteric site, rather than the point that most modern drugs target. This allowed the chemical to modulate the glutamate receptor's activity rather than just switching it on.

``One of the biggest difficulties in drug development is that if you completely block or activate the body's own chemical systems, it can lead to side effects,'' Mutel, 50, said in an interview. ``What we're doing is not to turn the body's own systems on or off like a normal light switch, as most drugs do, but to control the amount of light in the room like a dimmer.''

`Lab Curiosity'

The drug also kicked into action only when the body's own messengers signaled a need, more closely mirroring the peaks and troughs of the body's own systems. The receptor's allosteric site was unusual in structure, making the medicine that fit it less likely to bind to and affect other proteins.

``With a typical drug on the market, if you want to target a particular site on a protein in the brain, the drug will also target the same site on a related protein in the heart,'' Christopoulos said. ``It's like turning on all the lights in the house when you just want to turn on the light in the kitchen.''

Except for the work on Amgen's Sensipar, modulating the receptors in this way had been considered a ``lab curiosity,'' Mutel said. The discoveries at Roche and crosstown rival Novartis in 2001 ``completely changed the whole perception of the field,'' he said.

Such development now focuses mostly on diseases of the brain and central nervous system. Addex has two drugs in human studies, the most advanced of which is in the second of three stages of testing generally needed for approval.

Pfizer, Novartis

Mutel says the technology's potential goes beyond the central nervous system. The company and plans to explore rheumatoid arthritis and obesity, among other ills.

Other companies are forging ahead too. Roche has several compounds in animal and human tests for psychiatric disorders such as schizophrenia, while Novartis is seeking to use the technology to treat Parkinson's disease. Pfizer used the approach to develop its Selzentry HIV treatment and also wants to market the drug for rheumatoid arthritis. The New York-based company is also working on a hepatitis C treatment that uses the technology.

``We certainly have significant interest in this field and are looking at several approaches,'' said Will Spooren, project leader in the Roche research unit that focuses on the central nervous system. ``It's a big theme in general both in biotech as well as big pharma.''

Other characteristics of such compounds suggest additional potential uses. The molecules don't interfere with the active sites of the receptors, so they may someday be combined with conventional medicines to minimize side effects and make them more targeted, Christopoulos said. The technique may also make it possible to develop substitutes for medicines that now have to be injected. One oral compound in Addex's early-development program appears to mimic the activity of Eli Lilly & Co.'s Byetta shot for Type 2 diabetes.

``There are many fantastic drug targets for which the pharma industry hasn't been able to develop good compounds yet,'' Mutel said. ``We believe that this approach is the solution to many of those targets.''

To contact the reporter on this story: Dermot Doherty in Geneva at Ddoherty9@bloomberg.net

Last Updated: November 13, 2008 12:19 EST