Symphony Pharmaceuticals Inc. has begun Phase I trials of its firstcompound, a neuroprotective agent. The Malvern, Pa., company hasbegun a tolerance and dose-escalation study of amino cyclopropanecarboxylic acid (ACPC) in 40 healthy volunteers in the UnitedKingdom.

ACPC is a partial agonist of the glycine site on the NMDA receptor,Symphony's chief executive officer, Maria-Luisa Maccecchini, toldBioWorld. According to the company, animal testing hasdemonstrated that ACPC is well-tolerated at high doses andbioavailable to the brain in therapeutic amounts following eitherintravenous or oral administration, and that it has neuroprotectiveproperties.

In the animal models, the company tested the agent's ability to blockdamage against simulated stroke. By cutting off blood flow to thebrain either totally (for severe stroke) or partially (for partialstroke), Symphony was able to measure the ability of ACPC toprevent death or brain damage. When administered after simulatedsevere stroke, ACPC was able to reduce death by 80 percent,Maccecchini said. In partial stroke, she continued, animals treatedwith ACPC exhibited 60 percent less brain cell death. If administeredbefore blood supply was reduced or cut off, she added, ACPC wasable to prevent almost all brain damage.

According to Maccecchini, all neuroprotective drugs previously testedhave been associated with some kind of psychotic events, memoryloss and learning disability. Symphony believes that since ACPC onlypartially inhibits the release of neurotransmitters and glutamate inthe brain, it will not cause these complications. The Phase I trial,however, will include a battery of neurological evaluations such asmemory and learning tests.

After the Phase I study, Symphony hopes to test ACPC in patientsundergoing coronary artery bypass graft (CABG). Maccecchini saidthat anywhere from 5 to 25 percent of patients undergoing CABGexhibit lasting neurocognitive decline after the surgery. The companybelieves ACPC can mitigate this effect.

A Phase II trial aimed at establishing a CABG indication for the drugwill be organized by Dennis Mangano of the department ofanesthesiology at the University of California, San Francisco. Manganohas established a link among 25 centers in the U.S. to recordneurocognitive decline associated with CABG.

The CABG study would provide a clear, "laboratory-like" setting tostudy ACPC's efficacy, since patients would be given either the drugor placebo before surgery and evaluated through a series ofneurocognitive tests afterward. The company also plans to pursue asecond indication (and ultimately file a second new drug application)for the use of ACPC in palliating the neuronal effects of stroke.Maccecchini said a study of ACPC in stroke will be more difficultbecause the company will not be able to evaluate neurocognitiveproperties of subjects before the event.

Privately held Symphony was founded in 1992.

-- Karl A. Thiel Associate Editor

(c) 1997 American Health Consultants. All rights reserved.