Guilford Pharmaceuticals (Baltimore MD) and Amgen (Thousand Oaks CALIF) announce on-going work on GPI-1046 a novel drug that, taken by mouth, stimulates regrowth of damaged dopamine-producing nerve cells in the brains of monkeys with an animal model of Parkinson Disease (PD).

GPI-1046 is a drug with a chemical structure related to the chemical structure of immunosuppressive drugs, drugs like cyclosporin that block or retard the immune response. The immune response is involved in the rejection of foreign tissue such as transplanted hearts, kidneys, or lungs. Cyclosporin blocks the patient's body from rejecting the foreign heart, kidney, or lung. GPI-1046, however, isn't an immuno-suppressive drug and unlike cyclosporin it DOES NOT block or retard the immune response.

GPI-1046 binds to proteins including proteins in the brain that resemble the proteins involved in the immune response. These brain proteins, called neuro-immunophilins, are highly concentrated in certain brain regions. Drugs like GPI-1046 bind to the neuro-immunophilins and are called neuro-immunophilin-ligand (NL). Such NLs can stimulate regrowth of dopamine-containing nerve cells. Scientists at Guilford recently synthesized a series of such novel Nls including GP!-1046.

Initially, GPI-1046 was shown to be effective in reversing the effects of MPTP, a nerve toxin, in mice and rats. MPTP when injected into mice and rats causes a parkinson-like state. Next, GPI-1046 was studied in Rhesus monkeys made parkinsonian by injecting them with MPTP. MPTP was injected into the right (or left) carotid artery of a monkey resulting in a severe loss of dopamine-containing nerve cells in the right (or left) substantia nigra-a loss mimicking the loss in PD. This results in a permanent parkinson state. If MPTP is injected into the monkey's right carotid artery it causes permanent parkinson state on the left side of the monkey's body: left hemi-parkinsonism. If MPTP is injected into the monkey's left carotid artery it causes a permanent parkinson state on the right side of the monkey's body: right hemi-parkinsonism. MPTP is usually not injected into both carotid arteries simultaneously because it causes a bilateral parkinson state that is so severe the monkey cannot survive. Ten weeks after MPTP had been injected into the carotid artery of several monkeys and each of the monkeys had developed a permanent hemi-parkinson state, GPI-1046 was given by mouth. Four different schedules were used. GPI-1046, administered once/day, was started at 0.3 mg/kg in one group of monkeys, 1.0 mg/kg in a second group of monkeys, 3.0 mg/kg in a third group of monkeys, and 10.0 mg/kg in a fourth group of monkeys. The dose was increased every two weeks in each group of monkeys. Positive results, improvement in parkinson symptoms, were observed in monkeys at GPI-1046 doses as low as 1.0 mg/kg. The monkeys were continuouly evaluated for several weeks and upon completion of the study the monkeys were sacrificed and their brains were examined.

GPI-1046 had a striking effect in several monkeys. Monkeys with difficulty walking, difficulty climbing, difficulty in feeding themselves, regained these abilities. And, under the microscopic, the Guilford scientists observed, in the brains of the GPI-1046 treated monkeys evidence of re-growth of dopamine nerve terminals. The Guilford scientists believe that the observed improvement in walking, climbing, and feeding is related to the re-growth of dopamine nerve terminals. These findings were so encouraging that trials of GPI-1046 in humans with PD will soon begin. The trials in PD will be conducted by Amgen, a major bio-technology company that licensed GPI-1046 from Guilford.

"To our knowledge," said Dr. Craig Smith, President & C.E.O. of Guilford, "these experiments are the first demonstration of such a striking neuronal regenerative effect with an orally-active molecule in a primate model of Parkinson's Disease. We believe that our findings are particularly important in that they are the first demonstration in primates of both physiological and behavioral recovery following oral administration of a neuro-immunophilin-ligand. These results suggest that neuro-immunophilin ligands such as GPI- 1046 may represent a significant new approach to the treatment of neuro-degenerative disorders such as Parkinson disease.

"Based on our experiments to date, we and our partner, Amgen, are actively investigating the NLs as potential treatments for a range of neuro-degenerative disorders (not only PD), disorders such as Alzheimer disease, multiple sclerosis, traumatic head and spinal cord injury, stroke, and peripheral neuropathy."

Promising as these studies are, both Guilford and Amgen emphasize that the above results are based on a limited number of animals and there can be no assurance that the companies will be able to successfully develop one or more of its compounds including GPI-1046 into a safe and effective FDA-approved drug.