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Pharmaceuticals Develops First Novel Oral Compounds Which Demonstrate Regenerative Activity In Animal Models of Parkinson's Disease Three posters to be presented today .. Source: PR Newswire BALTIMORE, Md., Nov. 18 /PRNewswire/ via Individual Inc. -- Guilford Pharmaceuticals Inc. (Nasdaq: GLFD) reported that it will present data today at the Society for Neuroscience Meeting in Washington D.C. on a novel class of orally active small molecule compounds the company has discovered, the neuroimmunophilins, which for the first time demonstrate a potent regenerative effect in rodent models of Parkinson's Disease. "Parkinson's Disease is considered to be one of the most debilitating neurodegenerative disorders, and is believed to affect over 800,000 Americans. Previously, protein-based neuronal growth factors, such as NGF and GDNF, have been shown to increase neuronal cell growth in animal experiments of Parkinson's Disease. However, proteins and peptides are very difficult to administer for neurodegenerative disorders, because they are not orally active, and do not get into the brain," commented Dr. Peter Suzdak, Vice President of Research at Guilford Pharmaceuticals. The animal models of Parkinson's Disease studied by Guilford involve administration of one of two neurotoxins, either MPTP or 6-hydroxydopamine, to rats or mice. These neurotoxins selectively destroy the parts of the brain which deteriorate in Parkinson's Disease, and are thus used as animal models to study the effects of potential therapeutic drugs for Parkinson's Disease. The first of Guilford's presentations, scheduled for 1:00 p.m. today, will show the effects of a novel, orally active Guilford compound, GPI-1046, in various experiments administering either MPTP to mice or 6-hydroxydopamine to rats. The experiments were conducted in two ways. First, with simultaneous administration of GPI-1046 with a neurotoxin, to evaluate the neuroprotective effect, and second, administration of GPI-1046 some time after the neurotoxin, to evaluate the neurotrophic, or regenerative effect. In all experiments, GPI-1046 was administered systemically, including by oral administration. The results of the first series of experiments showed that simultaneous oral administration of GPI-1046 with MPTP produced approximately an 85% neuroprotective effect. "To our knowledge, these results are the most significant neuroprotective effect ever demonstrated in this animal model of Parkinson's Disease, and appear to be much greater than has been previously demonstrated with protein growth factors," commented Dr. Suzdak. The second series of experiments involved administering GPI-1046 some period of time after either MPTP or 6-hydroxydopamine, also including with oral administration. The significance of these experiments is that Guilford's neuroimmunophilin compound was given for the first time after the degeneration in the brain had occurred. In the first set of this series, GPI-1046 was administered to mice 8 days after MPTP, and produced an approximately 45% regeneration of dopaminergic neurons. In the second set of experiments, GPI- 1046 was given to rats either one week or one month after 6-hydroxydopamine. 6-hydroxydopamine is a very potent neurotoxin, which experimentally results in an extremely severe lesion and destruction of almost all of the nigro-striatal dopaminergic neurons in the rat brain. The results of these experiments showed that GPI-1046 produced approximately a 40% regeneration of dopaminergic nerve terminals in the striatum in the brain, regardless of whether it was given one week or one month after the 6-hydroxydopamine. Furthermore, GPI-1046 was also able to improve the functional recovery of the rats. In assessments of various behavioral effects of 6-hydroxydopamine, GPI-1046 appeared to produce near-normal behavior. "The results obtained with GPI-1046 are to our knowledge unprecedented and the first ever demonstration of a nerve regenerative effect with an orally active small molecule," commented Dr. Suzdak. "I know of nothing which has previously demonstrated both such a potent regenerative effect on damaged brain neurons, and a near-normalization of animal behavior, as we have shown with GPI-1046. These results may have potentially significant implications for the treatment of neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease in people. If we are able to demonstrate a similar regenerative effect in humans, for the first time ever we may be able to slow the deterioration, or even reverse some of the effects and restore functioning, to patients with these debilitating degenerative disorders. Some of our newer series of neuroimmunophilin compounds, all synthesized by Guilford, are even more potent and appear significantly more effective in animal models than GPI-1046." Guilford Pharmaceuticals and its academic collaborators has been conducting research with the neuroimmunophilins since the early 1990's, beginning with the observations of neurotrophic effects with some commonly used immunosuppressive compounds, such as FK-506 and cyclosporin. In May 1996, Guilford made the first public presentation of scientific data on the neuroimmunophilins at the IBC Neurotrophin Meeting in London, England. At that meeting, Guilford disclosed that it had discovered the novel mechanism of action responsible for the neurotrophic effects of the neuroimmunophilins, a cascade of events initiated by inhibition of FKBP-12 mediated rotamase (peptidyl-prolyl isomerase) enzyme activity. Guilford also disclosed at that meeting that its scientists had discovered and demonstrated for the first time a separation of the neurotrophic and immunosuppressive effects of this class of compounds. The second of Guilford's three posters to be presented at the Society for Neuroscience Meeting will show experimental data on GPI-1046 in a cell culture model designed to assess the potency of the compound. In this experiment, using chick dorsal root ganglia cells (sensory neurons), GPI-1046 demonstrated an ED50 (effective dose to achieve a 50% maximal effect) of 53 picomolar. "These results show that not only are our compounds very effective in animal models, but they are also extremely potent -- even more so than protein neuronal growth factors such as NGF, which in our experiments has an ED50 of approximately 300 picomolar", continued Dr. Suzdak. The third of Guilford's poster presentations will describe the discoveries first made by Guilford scientists in separating the neurotrophic from immunosuppressive effects of compounds such as FK-506, and the discovery of FKBP-12 mediated rotamase inhibition as the novel mechanism of action that produces the neuronal growth effects. "Guilford is committed to the development of novel, orally active neurotrophic agents for a wide range of neurodegenerative disorders," said Dr. Craig Smith, Guilford's President and C.E.O. "In studies over the past several years, we previously demonstrated the neurotrophic and neuroprotective activity of our novel compounds in a variety of other earlier animal models, such as the sciatic nerve crush in rats, a model of peripheral nerve injury. In these studies, our compounds appeared to produce a near-complete restoration of both nerve structure and behavioral function. We also demonstrated for the first time a potent effect of our compounds to restore myelin levels, which are necessary for normal functioning of neurons. Other experiments we performed showed that our compounds have regenerative effects on other types of brain neurons, such as serotonergic and other neurons. We also have an extensive intellectual property portfolio, with numerous patent applications dating back to the early 1990's. Based on our promising results, we are moving forward with further research and development of our novel neuroimmunophilin compounds for Parkinson's Disease, Alzheimer's Disease, multiple sclerosis, peripheral neuropathies, traumatic head and spinal cord injuries, and stroke. We now have a library of several hundred active compounds, and are currently conducting studies in primates. We intend to initiate clinical studies with the first of our neuroimmunophilin ligands by the end of 1997 or early 1998." Guilford Pharmaceuticals Inc. is a biopharmaceutical company engaged in the development of polymer-based therapeutics for brain and other cancers, and novel products for the diagnosis and treatment of neurological diseases, including Parkinson's disease, Alzheimer's disease, stroke, 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 most recently filed SEC documents, such as the Forms 10-K and 10-Q and its 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, the pre-clinical results are based on a limited number of animal models, and there can be no assurance that the company will be able to successfully develop one or more of its compounds into a safe and effective FDA-approved drug. While the company has filed numerous patent applications in the U.S. and abroad, the patentability, validity, enforceability, and non-infringement of claims made in such applications cannot be assured. Guilford Pharmaceuticals press releases available through Company News On- Call by fax, 800-758-5804, ext. 112882, or at http://www.prnewswire.com SOURCE Guilford Pharmaceuticals /CONTACT: Angela Webber of Guilford Pharmaceuticals Inc., 410-631-6449; or Brad Miles (media) of Ted Klein & Company; or Jonathan Fassberg (investor) of The Trout Group, 212-477-9007/ (GLFD) [11-18-96 at 13:34 EST, PR Newswire]