REHOVOT, Israel ¿ Control of chronic epilepsy without side effects may have come closer to realization this week as D-Pharm received approval from an ethics committee in the U.K. for Phase I trials of DP-VPA, the company¿s drug derived from the leading anti-epileptic drug, valproic acid (VPA), using D-Pharm¿s drug-delivery technology platform.

The technology, called Regulated Activation of Prodrug (RAP), covalently binds a moiety of VPA to a lipid carrier, particularly phospholipids of membranes, enhancing penetration into cells. The cleavage of DP-VPA and liberation of active valproic acid is highly selective and disease-dependent, triggered by an enzyme characteristically elevated in an epileptic seizure, but absent in normal cells.

Epilepsy is second only to stroke in neurological disorders, estimated to affect between about 4 million people in the U.S. and 2.5 million in Europe. Between 70,000 and 130,000 new cases are diagnosed every year in the U.S. The market for anti-epileptics or anti-convulsants is estimated at $2 billion annually, and is expected to grow to $4 billion worldwide by the year 2000. VPA now commands about 30 percent of the anti-epileptic drug market, generating sales of $700 million in 1997, but the introduction of DP-VPA is expected to turn market share around.

The Phase I trials will demonstrate decisively the safety and pharmacokinetics of DP-VPA in healthy volunteers. ¿We believe that the high efficacy at lower doses of DP-VPA will lead to a major breakthrough in anti-epilepsy therapy, providing patients with the full benefits of valproic acid, but in a safe, non-sedative manner,¿ said Alex Kozak, president and CEO of D-Pharm. ¿More so, we see this as treatment for the large cohort of therapy-resistant patients who have no recourse at present but to suffer.¿

In animal models, when compared with VPA, DP-VPA was shown to be 50 to 80 times more effective and eight times longer lasting in its protective effect.

In contrast to other drug targeting approaches, designer RAP drugs such as DP-VPA are activated by enzymatic hyper-activity pulses triggered by the pathological process itself, and are thus switched on only within the diseased cell and only for as long as the pathological condition is active.

Once the drug takes effect and the cells return to their normal state, the enzyme level subsides and drug activation is switched off, affording double on- and off-control over drug action.

Itzchak Angel, vice president of research and development at D-Pharm, said all preclinical studies showed DP-VPA ¿was very safe and devoid of major side effects, including those associated with the parent valproic acid. Epileptic stimuli and genetic predisposition to epilepsy were demonstrated to enhance the potency and duration of the protective effect of DP-VPA, as compared with healthy animals.¿

In the company¿s pipeline are new-generation novel drugs and ¿re-engineered¿ known drugs, including DP-b99 for neuroprotection in ischemia-related disorders; derivatives of methotrexate and non-steroidal anti-inflammatory drugs for neuro-inflammatory and oncology indications; and derivatives of antiviral drugs, such as AZT and ddI, for AIDS. n