For people who suffer from Parkinson’s disease, a progressive neurodegenerative condition that manifest itself with telltale tremors as the cells that produce dopamine die off, there are limited choices for treatment. Dopamine helps control muscle movements and the drugs available to treat Parkinson’s seek to replace the lost neurotransmitter. But patients grow resistant to these drugs, which also carry adverse side effects.

 

Two recent agreements—one corporate and the other academic—have researchers working to develop a new class of orally-available drugs that would bypass dopamine neurons. Instead, they would offer a chemical approach to interrupt the same brain circuitry that lies behind the success of deep brain stimulation. Deep brain stimulation  uses a surgically implanted pacemaker-like device to send electrical stimulation to the brain to block the overactive signaling that cause tremors and other Parkinson’s syndromes.

 

This month, drug giant Merck entered into an early stage development deal worth up to $170.5 million with Addex Pharmaceuticals, a small Swiss biopharmaceutical focused on a new class of drugs known as allosteric modulators, to develop new drugs for treating Parkinson’s and for other undisclosed indications. The news was followed this week with the announcement that the Michael J. Fox Foundation for Parkinson’s Research had made a four-year, $4.4-million grant to researchers at Vanderbilt University for pre-clinical development focused on the same target as Merck and Addex. “The ideal outcome would be the development of lead molecules ready to go to the clinic,” said Todd Sherer, vice president of research for the Michael J. Fox Foundation, speaking of the Vanderbilt grant.  

 

With 1.5 million people in the United States afflicted with Parkinson’s and another 60,000 diagnosed each year, sales of drugs to treat the disease are expected to grow to $3.8 billion by 2010, up from $2.5 billion in 2005. If successful in their efforts and a resulting drug could be used in combination with existing therapies to treat both early and late stage patients, analysts said a drug it could represent a billion dollar a year product.

 

At the heart of both agreements is a receptor called metabotropic glutamate receptor or MgluR4. Unlike the active binding sites on cells that constitute the typical target for drugs, MgluR4 is an allosteric target. Rather than acting like a switch that either activates or inhibits activity involved in a disease process, allosteric targets act more like dimmer switches that can modulate the level of activity. 

 

“Merck has been pioneering the MgluR4 field,” said Vincent Mutel, CEO of Addex. “They were the first to demonstrate the potential use of this receptor in the Parkinson’s pathology. They have really opened up the field and been very active on it. It’s great for us to have this collaboration and it’s a recognition of our competence.”

 

Like other allosteric targets, MgluR4 is attractive because drugs that target it have the potential for fewer side effects and have the potential to be used in combination with conventional Parkinson’s drugs because they take advantage of this alternate receptor. But in the case of Parkinson’s disease, MgluR4 is particularly important because researchers have been stymied in efforts to develop small molecule drugs that could safely and effectively target active receptors in brain cells involved in the disease.

 

“It’s a more subtle way of modulating the brain and targeting the things that are more specific to disease versus normal function in the brain,” said Darryle Schoepp, senior vice president and franchise head, Neuroscience, at Merck Research Laboratories.

 

MgluR4 targets neurons involved in the portion of the brain known as the basel ganglia, which is involved in controlling movement. Researchers became interested in MgluR4 because it was seen as a potential way to achieve chemically the effect seen through the invasive process of deep brain stimulation, which though effective, requires the implantation of electrodes into the brain.

 

“Instead of trying to replace the dopamine, we’re trying to change the activity of the circuit in a way that a corrects for the problems that occurred after the dopamine cells were lost,” said Jeffrey Conn, director of the Vanderbilt Program in Drug Discovery and professor of pharmacology Vanderbilt University and lead investigator on the Fox grant. “This is really designed as a pharmacological approach to do the same thing that’s been accomplished with this very invasive brain surgery.”

 

Though the concurrence of the two announcement was described as coincidental by Conn, he worked on developing allosteric modulators where he headed neuroscience efforts for Merck until leaving five years ago. He also serves as a consultant to Merck and is a member of the Addex Scientific Advisory Board.

For Addex, which in May raised $111 million in what was the largest biotech IPO in Europe during the past three years, the Merck deal is further validation of its approach to pursuing allosteric modulators. The Merck agreement follows an earlier deal between Addex and Johnson & Johnson to develop drugs targeting MgluR2 for anxiety and schizophrenia. And Addex is pursuing a range of allosteric modulators in a wide range of disease areas including gastroesophageal reflux disease, migraine, osteoporosis, depression and Type 2 diabetes. 

 

Though MgluR4 drugs are being pursued as a way to improve the symptoms from Parkinson’s disease, some researchers have hope that they may also provide neuroprotective activities. But for now, Addex is being cautious about the potential for any of these drugs.

 

“There are some hypotheses about the potential of slowing down the disease progression, but these are a hypotheses for the time being. We should not give false expectation,” said Addex’s Mutel. “The goal is symptomatic treatment. We will look at the potential of slowing down the disease progression, but the first priority is looking at the symptomatic effects.”