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Research Results of Guilford's Neuroimmunophilin Ligands Published in Proceedings of the National Academy of Sciences First Orally Active Neurotrophic Agents to Demonstrate Nerve, Re-Growth .. Source: PR Newswire BALTIMORE, March 4 /PRNewswire/ via Individual Inc. -- Guilford Pharmaceuticals Inc. (Nasdaq: GLFD) today announced the publication of research results on GPI-1046, one of the lead compounds in Guilford's program to develop drugs to promote nerve growth, in today's issue of the Proceedings of the National Academy of Sciences (U.S.A.), Volume 94, number 5, pp. 2019-2024, 1997. The results of this research demonstrate that GPI-1046 can protect nerves from damage and cause brain cells to regenerate in animal models of central nervous system and peripheral nerve damage. The paper, communicated by Dr. Solomon Snyder of The Johns Hopkins University School of Medicine, presents the results of experiments with GPI-1046, an orally active neuroimmunophilin ligand that crosses the blood- brain barrier. The studies show that GPI-1046 promotes both morphologic and functional recovery in animal models of both peripheral nerve injury and Parkinson's disease. Immunosuppressive drugs such as cyclosporin A and FK-506 are known to bind to intracellular proteins called immunophilins. Scientists at Johns Hopkins and Guilford have previously discovered that immunphilins 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, such as GPI-1046, which possess the neurotrophic activity of FK-506, but are devoid of immunosuppressive activity. In a mouse model of Parkinson's disease, GPI-1046 showed a potent neuroprotectant effect on the nigral-striatal dopamine system, an area of the brain damaged in Parkinson's disease. In these studies, the neurotoxin MPTP was administered to severely damage nigral-striatal dopamine neurons and mimic the damage caused by Parkinson's disease, simultaneously with GPI-1046. Compared with the MPTP/control group, GPI-1046 protected more than 80% of nigral-striatal dopamine neurons. "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. Peter Suzdak, Vice President of Research at Guilford Pharmaceuticals Inc., and an author of the paper. The studies went one step further in an attempt to more accurately model human Parkinson's disease by administering GPI-1046 after damage of the nigral-striatal dopamine neurons had taken place by the administration of two different neurotoxins, either MPTP or 6-hydroxydopamine. In these experiments, GPI-1046 was administered up to one month after striatal dopamine neurons were destroyed by the neurotoxin. GPI-1046 significantly increased the number of functional dopamine terminals in the striatum at doses as low as 4 mg/kg. Administration of GPI-1046 was also shown to significantly improve both neuronal dopamine levels and turnover, indicating physiological recovery. Furthermore, administration of GPI-1046 was also shown to significantly improve functional behavior in the rats, as measured by apomorphine or amphetamine induced rotational behavior. The studies looked at other neurological models in addition to Parkinson's disease and also found protective and regenerative effects using GPI-1046. In animals whose sciatic nerves were crushed, GPI-1046 accelerated functional recovery of the damaged nerves. The compound was able to regenerate the myelin sheath over the nerves, a characteristic critical to nerve re-growth and recovery of function. "To our knowledge, we believe our experiments are the first demonstration of such a significant neuronal regenerative effect with an orally-active non- immunosuppressive small molecule. We believe that our findings are also particularly important in that they are the first demonstration of both physiological and behavioral recovery following oral administration of a small molecule neuroimmunophilin ligand in this animal model of Parkinson's disease," commented Dr. Suzdak. "One of the most striking features of the neurotrophic actions of these neuroimmunophilin ligands is their efficacy and potency," commented Dr. Joseph Steiner, Senior Scientist and Head of Biology for the neuroimmunophilin program at Guilford Pharmaceuticals, and an author of the paper. "GPI-1046 has produced significant enhancement of neurite outgrowth in sensory ganglia at concentrations as low as 1 picomolar. This means its neurotrophic potency is greater than that of nerve growth factor itself." "Another potential advantage of GPI-1046 is that it is orally active and crosses the blood-brain barrier. Thus, it should not be limited by the drug delivery problems associated with protein or peptide growth factors," said Dr. Greg Hamilton, Principal Scientist and Head of Chemistry for the neuroimmunophilin program at Guilford Pharmaceuticals, and an author of the paper. "Based on our experiments to date, we are actively investigating our neuroimmunophilin ligands as potential treatments for a range of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, traumatic head and spinal cord injuries, stroke, and peripheral neuropathies such as diabetic neuropathy. If continued pre- clinical development proceeds favorably, we hope to begin clinical trials as soon as possible," said Dr. Craig R. Smith, Guilford's President and CEO. 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 Company's current report on Form 8-K filed on September 24, 1996, 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, (i) the pre-clinical results discussed above are based on a limited number of animal models, and there can be no assurance that the company will be able to successfully develop GPI-1046 or one or more of its other compounds into a safe and effective FDA-approved drug, and (ii) the Company's hope to begin human trials is dependent upon factors such as the further pre-clinical development of these compounds, and no assurance can be given that delays may not occur in the Company's current plans. While the Company has filed numerous patent applications claiming neuroimmunophilin ligands for neurotrophic applications in the U.S. and abroad, the patentability, validity, priority, enforceability, and non-infringement of claims made in such applications cannot be assured. SOURCE Guilford Pharmaceuticals Inc. /CONTACT: Angela Webber of Guilford Pharmaceuticals, 410-631-6449; for media, Brad Miles of BMC, or for investors, Jonathan Fassberg of The Trout Group, 212-477-9007/ (GLFD) CO: Guilford Pharmaceuticals Inc. ST: Maryland IN: MTC SU: PDT KS-JA -- DCTU011 -- 4457 03/04/97 09:47 EST http://www.prnewswire.com [03-04-97 at 12:00 EST, PR Newswire]