Pre-clinical studies carried out by Pharmos show that Cannabinor is as potent as morphine and other pain killers in providing pain relief and has a longer duration of action.

Attendees at last month's BIO in Philadelphia - the largest annual biotechnology conference in the world - could have been excused if they did a double take upon seeing the presence of Israeli biotech company Pharmos.

After all, the company's highly touted drug dexanabinol - based on cannabis-like molecules - failed to show efficacy in a clinical trial for traumatic brain patients last year. But while the trial results had a negative effect on Pharmos' share price, it failed to diminish CEO Prof. Haim Aviv 's enthusiasm for developing cannabinoid drugs.

And today, Pharmos finds itself again at the crossroads of two major trends sweeping the drug development world.

One is the greater-than-ever need for pain relief drugs after the withdrawal of several leading pain drugs from drugstore shelves during the past year because of safety concerns; the other is a surge of interest in cannabinoids for a wide variety of therapeutic uses.

Pharmos President Gadi Riesenfeld gave a presentation at BIO showing the progress the company has made in developing a new synthetic cannabinoid drug for pain relief called cannabinor. The company expects to begin human trials this summer.

"The withdrawal of Merck's Vioxx, a blockbuster pain drug that was found to raise the risk of heart attacks and stroke, is now being accompanied by similar questions concerning Celebrex and Bextra," says Aviv, adding that these concerns come on top of the problems relating to the abuse and potentially life threatening side effects of narcotic painkillers like OxyContin.

Ironically, the search for new treatments for the $26 billion global pain market has led scientists back to a natural substance in use since antiquity - the cannabis plant. But rather than extracting ingredients from cannabis plants, drug makers are now designing drugs using synthetic substances that amplify the therapeutic characteristics of cannabis by selectively activating the CB2 component of the system while minimizing the unwanted effects associated with the CB1 component.

The new synthetic cannabinoid drugs seem to be particularly promising because what scientists have going for them now is a better understanding of both the molecular mechanisms by which pain is perceived and of the pathways in which cannabinoid substances exert their therapeutic affect both in the brain and in other parts of the body.

"There is a very close relationship between the pathways that carry pain sensations in the body and the role played by the cannabinoid receptor system, which is modulated by endogenous cannabinoids during pain conditions, " says Dr. Seth Kindler, Medical Director at Pharmos, (NasdaqSC:PARSD), which carries out its R&D activities in Rehovot, Israel while maintaining its head office in Iselin, New Jersey.

Kindler points out that studies have shown that the pain relief experienced by people who smoke marijuana derives from the influence of substances found in cannabis that activate the cannabinoid receptor system.

"Selectively activating the cannabinoid receptor system disrupts the flow of chemical communications in the body which lead to a sensation of pain," explains Kindler, adding that the therapeutic use of natural cannabis is limited due to the psychoactive affect of the compound which is associated with activation of the CB1 component of the cannabinoid system.

"Cannabinor, our new synthetic drug compound, selectively activates the therapeutic component of the cannabinoid system, called the CB2 receptor, and as such does not produce the non-therapeutic effects of cannabis, " says Kindler, pointing out that cannabinor does not cause any of the psychoactive effects associated with the use of natural cannabis.

Pre-clinical studies carried out by Pharmos show that Cannabinor is as potent as morphine and other pain killers in providing pain relief and has a longer duration of action.

"But unlike morphine and other drugs on the market today, Cannabinor does not show any of the side effects, including constipation, drowsiness and addiction, associated with these drugs," says Kindler.
The development of Cannabinor comes at a time when there is extensive interest in cannabinoids in the pharmaceutical world. Dozens of companies are developing cannabinoid drugs for medical uses that include the treatment of cancer nausea, spastic disorders, epilepsy and sleepwalking.

These drugs leverage recent scientific findings that show that the body produces molecules known as endocannabinoids that are similar to those found in cannabis. The cannabinoids are designed to either amplify or block the activity of those molecules. One of the most advanced is a cannabinoid drug being developed by Sanofi-Aventis for obesity that works by blocking the natural molecule associated with a sensation of hunger.
Despite the intense competition in this field, Pharmos has an edge over others as the company was the first to utilize the seminal research carried out into the medicinal uses of cannabis by Prof. Raphael Mechoulam of the Hebrew University of Jerusalem.
Mechoulam, a world renowned medicinal chemist and a pioneer in the field of cannabinoids who carried out his original cannabis laboratory experiments in the 1960s using contraband supplied by the Jerusalem police force, was the first scientist in the world to isolate THC - the active ingredient in cannabis. He also is credited with identifying the first endogenous cannabinoid.

Pharmos has worked closely with Mechoulam, licensing and refining a library of cannabis-like molecules from his Hebrew University lab. The company became one of the first to recognize the commercial potential of cannabinoid drugs when it developed dexanabinol, a cannabinoid drug currently being studied for use in the prevention of brain damage during open heart surgery.

Following the failure of Pharmos's clinical trials on dexanabinol last year, CEO Aviv, one of the founders of Israel's biotech industry and a serial entrepreneur who has launched several biotech companies, decided to focus on Cannabinor only after conducting an extensive worldwide search for other drug candidates that could be in-licensed.

"No other molecule that we saw showed nearly as much potential, " says Aviv, whose war chest includes more than $50 million in cash reserves, derived in part from the proceeds of three original FDA-approved eye drugs that Pharmos developed and sold to US healthcare giant Bausch & Lomb.

One reason for Aviv's confidence in Cannabinor lies in the fact that it has shown across-the-board robust pain relief in numerous animal models including acute, chronic and visceral pain models with minimal side effects.

So far the results have been quite compelling and the company expects to begin human trials in the next few months.

"In the first study, as is customary in pain drug development, we plan to treat patients experiencing acute pain following the removal of wisdom teeth. Following that we will be ready for trials with patients suffering from chronic pain conditions such as neuropathic pain (sciatica herpetic and diabetes ) and cancer," says Aviv.

Bernard Dichek is the publisher of www.bioisrael.com, a monthly magazine on the Israeli life sciences.
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