08:29 a.m. Sep 23, 1997 Eastern
By Andrea Orr
BALTIMORE, Sept. 23 /PRNewswire/ -- Guilford Pharmaceuticals Inc. (Nasdaq: GLFD) today announced interim results from an ongoing study in a primate model of Parkinson's Disease. The results of this research demonstrate that one of Guilford's novel FKBP-neuroimmunophilin small molecule neurotrophic agents, GPI-1046, can cause brain cells to regenerate and improve behavioral measures in this primate model of Parkinson's Disease.
These results are from a dose-escalation study using GPI-1046 in a Rhesus monkey MPTP model of Parkinson's Disease, and are the first of an ongoing three-part study being conducted by an academic collaborator. MPTP is a neurotoxin, which when administered to animals, severely and selectively damages nigral-striatal dopamine neurons in the brain, mimicking the damage caused by Parkinson's Disease.
Immunosuppressive drugs such as FK-506 and cyclosporin A are known to bind to intracellular proteins called immunophilins. Scientists at Johns Hopkins University and Guilford have previously discovered that immunophilins are enriched 10-40 fold more in the brain than in immune tissue and that drugs that bind to immunophilins, such as FK-506, produce nerve growth in vitro and in vivo (i.e., they are neurotrophic). Guilford scientists, utilizing structure-based drug design, synthesized a series of novel small molecule neuroimmunophilin ligands, including GPI-1046, which possess the neurotrophic activity of FK-506, but are devoid of immunosuppressive activity.
"The results of the study are impressive. These results and the magnitude of effect we have observed are consistent with the results we have previously seen in our studies in mice and rats. Our compound had striking effects on several monkeys, restoring their ability to feed themselves whereas before treatment they were totally unable to use the affected limb. Based on microscopic examination of the brains, we have also observed apparent corresponding increases in striatal innervation, that is, regrowth of damaged nerve terminals. We believe that the degree of recovery was a function of the magnitude of the lesion. There was a range of effect across the monkeys; however, the results were statistically significant, with improvements in all measures of locomotor activity, neurological outcome, and fine motor control. We consider these findings in the Rhesus monkey to be particularly significant, and based on these very encouraging results, have now initiated the second and third phases of the study," commented Dr. Peter Suzdak, Vice President of Research at Guilford.
"To our knowledge, these experiments are the first demonstration of such a striking neuronal regenerative effect with an orally-active small molecule in this primate model of Parkinson's Disease. We believe that our findings are also particularly important in that they are the first demonstration in primates of both physiological and behavioral recovery following oral administration of a small molecule neuroimmunophilin ligand. These results suggest that neuroimmunophilin ligands, such as GPI-1046, may represent a significant new approach to the treatment of neurodegenerative disorders such as Parkinson's disease," commented Dr. Craig R. Smith, M.D., President & C.E.O. of Guilford.
On Aug. 20, 1997, Guilford entered into a licensing agreement with Amgen, under which Amgen received exclusive worldwide rights to Guilford's FKBP-neuroimmunophilin compounds.
"Based on our experiments to date, we and our partner Amgen are actively investigating the FKBP-neuroimmunophilin ligands as potential treatments for a range of neurodegenerative disorders, such as Alzheimer's Disease, multiple sclerosis, traumatic head and spinal cord injuries, stroke, and peripheral neuropathies such as diabetic neuropathy, in addition to Parkinson's Disease. Subject to successful completion of pre-clinical development, we are both committed to rapid clinical development of neuroimmunophilin ligands as soon as possible," continued Dr. Smith.
This pilot study was an open, uncontrolled study in six Rhesus monkeys, which were rendered hemi-parkinsonian using the MPTP model. The animals were monitored for changes in locomotor activity, neurological outcome, and fine motor control (measured by grasping and feeding behavior). It has been previously demonstrated that MPTP administration in Rhesus monkeys causes a significant decrease in locomotor activity, impaired neurological outcome, and loss of fine motor control. These behavioral deficits begin to develop immediately after administration of MPTP, and reach maximal damage six to eight weeks later. It is generally accepted, based on prior work, that the damage produced by MPTP in this model is permanent, with no spontaneous recovery.
In this first phase of the study, MPTP was first administered to monkeys, followed by the administration of GPI-1046 10 weeks later, to see if the compound could produce a reversal of the behavioral deficits caused by MPTP, and if it could regenerate the dopaminergic nerve terminals in the brain. Based on encouraging results of this preliminary study, the next two phases of the study are being conducted to more extensively examine the protective and regenerative effects of GPI-1046 in this Rhesus monkey model.
GPI-1046 was administered orally once daily. The study was a dose- escalation design using four different doses of GPI-1046 (0.3, 1.0, 3.0, and 10.0 mg/kg), where the dose was increased every two weeks. Positive effects were observed in the study at doses as low as 1 mg/kg. Animals were evaluated for behavioral measures at every dose group, and after completion of the study the brains of the animals were microscopically examined to determine nerve regrowth.
Guilford Pharmaceuticals Inc. is a biopharmaceutical company engaged in the development of polymer-based therapeutics for cancer, and novel products for the diagnosis and treatment of neurological diseases, including Parkinson 's disease, Alzheimer's disease, stroke, severe head trauma, spinal cord injuries, multiple sclerosis, peripheral neuropathies, and cocaine addiction.
This press release contains forward-looking statements that involve risk and uncertainties, including those described in the section entitled "Risk Factors" from the Company's registration statement on Form S-3, declared effective September 17, 1997, that could cause the Company's actual results and experience to differ materially from anticipated results and expectations expressed in these forward-looking statements. In particular, the pre- clinical results discussed above are based on a limited number of animals and animal models, and there can be no assurance that the Company and its collaborative partner will be able to successfully develop one or more of its compounds into a safe and effective FDA-cleared drug; furthermore, the Company's hope to begin human trials is dependent upon factors such as the further pre-clinical development of these compounds and the development program of the Company's corporate partner, Amgen Inc., in this area, and no assurance can be given that delays may not occur in any such trials. SOURCE Guilford Pharmaceuticals, Inc.
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