REHOVOT, Israel - D-Pharm Ltd. has received U.S. patent approval for a drug it is developing to treat epilepsy.

The patent is based on its regulated activation of prodrugs (RAP) technology for prodrugs of valproic acid (VPA) with enhanced penetration into cells by covalently binding VPA to various lipids, including phospholipids of membranes. This is designed to reduce the side effects and epileptic attacks that patients suffer.

The patent was granted on the basis of animal studies which demonstrated that D-Pharm's prodrugs of valproic acid (DP-VPA) have a therapeutic profile that is superior to conventional compositions. DP-VPA is at least 20 times more effective than the well-known VPA from which it is derived.

Because of its low toxicity, DP-VPA does not cause the adverse side effects associated with VPA, and it also may offer safe treatment of manic-depression and migraine headaches.

Epilepsy is the second leading neurological disorder, exceeded only by stroke. Estimated to affect up to 2 percent of the population, there are about 4 million epileptics in the U.S. and 2.5 million in Europe. Between 70,000 to 130,000 new cases are diagnosed every year in the U.S. alone.

The present market for anti-epileptic drugs, or anticonvulsants, is estimated at $2 billion annually and forecast to grow to $4 billion worldwide by 2000. The current market for VPA alone is $700 million, but introduction of DP-VPA is expected to capture a greater market share.

“The superior safety and efficacy profiles of D-Pharm's line of anti-epileptic drugs are expected to enable these drugs to compete as second-generation drugs in the valproic acid market,“ said Alex Kozak, president and CEO of D-Pharm. “This new family of anti-epileptic drugs emerged from our proprietary Regulated Activation of Prodrugs technology, which is part of our company's innovative drug design program.“

D-Pharm's RAP drug targeting technology exploits pathological metabolic processes themselves to direct the drug's pharmacological activity to the disease-affected site and to control the level of it activity.

“RAP technology enables drugs to be activated only within the cells affected by disease, substantially diminishing the adverse reactions caused when drugs also activate within healthy cells,“ Kozak said. “In contrast to other drug-targeting approaches, RAP does not rely on cell-surface markers, but rather upon functional activation of the prodrug by enzymatic activity characteristically elevated in the diseased cell.“

RAP prodrugs are designed to be susceptible to cleavage by these processes and are thus preferentially switched on within the actual diseased cell for as long as the pathological condition exists. Moreover, once the cells return to their normal state and enzymatic hyperactivity subsides, prodrug activation is switched off, affording double control over drug action.

Other Applications Being Explored

In addition to epilepsy, this core technology is potentially relevant to development of lipid derivatives of widely used drugs for the treatment of ischemia, inflammatory conditions and even certain forms of cancer.

“This core technology will allow us to develop an extended pipeline of drugs based on both proven and new compounds that are therapeutically effective. We expect to develop this pipeline through extensive partnering with pharmaceutical companies,“ said Kozak.

Yaffa Beck, executive vice president and chief operating officer, added, “The granting of the patent will certainly facilitate licensure agreements with other companies, which we are actively pursuing.“

In March, D-Pharm completed a $6 million private placement and directed the funds to accelerated development of its RAP drugs for treatment of epilepsy, cardiac ischemia, brain stroke, cancer and viral diseases.

New investors were Apax-Leumi Israel Growth Fund, an affiliate of the U.K.-based Apax Partners venture capital group; the Vertex Group, an affiliate of Singapore Technologies; and the U.S.-based Medmax Ventures. They joined Israel's Gemini Venture Capital Management Fund and two U.S. venture capital groups, the Advent Venture Fund, of Boston, and the Walden Group, of San Francisco, as supporters of D-Pharm.

The next step for D-Pharm is Phase I/II trials for epilepsy, which are expected to begin in mid-1998. *