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February 3, 2005 RATIONALE FOR GDNF THERAPY From Phase 1 and 2 clinical trial doctors Don M. Gash, Ph.D.1; John Slevin M.D.1; Steven Gill, Neurosurgeon2; Michael Hutchinson, M.D., Ph.D. 3; Byron Young, M.D.1; Greg Gerhardt, Ph.D. 1; Richard Penn, M.D. 4 1. University of Kentucky Medical Center;, 2. Frenchay Hospital, Institute of Neuroscience, Bristol England; 3. New York University School of Medicine; 4. University of Chicago On September 1, 2004, Amgen decided to discontinue three small ongoing clinical trials testing the continuous infusion of a human protein (glial cell line-derived neurotrophic factor, GDNF) into the brain for the treatment of advanced Parkinson’s disease in about 50 patients. The decision was made because of concerns that had arisen about the safety and efficacy of the drug. Many of the patients receiving GDNF felt that the drug was a “godsend,” providing relief from the pain and suffering while promoting significant improvements in their parkinsonian condition. Many of them have adamantly expressed their desire to begin receiving the drug again. Many of the investigators conducting the trials also feel that the drug has great promise. The scientists and physicians listed above have provided this consensus statement addressing concerns Amgen has about GDNF. We strongly support making the drug available to the patients. CONCERN: Alternative therapy to GDNF is available for advanced Parkinson’s disease patients. RESPONSE: GDNF has the potential to revolutionize the treatment of Parkinson’s disease. In contrast to other available therapies including Deep Brain Stimulation (DBS), GDNF promises to significantly slow disease progression and promote restoration of function in moderate to advanced Parkinson’s disease patients. CONCERN: Gene therapy and stem cells are better methods to deliver GDNF. RESPONSE: Direct infusion of GDNF into the brain is a technology that can be used today to treat hundreds of thousands of advanced Parkinson’s disease patients. It is the bird in the hand. This is of utmost importance for today’s advanced Parkinson’s patients and their families as other methods for delivering the drug are five to ten years or more away. By the time these methods are available, it will be too late for many. They will be either dead or totally debilitated! CONCERN: GDNF does not work. This has been shown in a Phase 2, double-blind clinical trial. RESPONSE: Efficacy of GDNF is directly related to dose and tissue distribution. Infusion procedures using Convection Enhanced Delivery to increase GDNF penetration into surrounding brain tissue is crucial for the direct infusion approach to work properly. The methods used in the two Phase 1 studies achieved this goal, with 15 out of 15 advanced Parkinson’s disease patients showing significant functional improvements. The Phase 2 study did not replicate the Phase 1 studies in these two key parameters. CONCERN: GDNF is unsafe to give to patients. RESPONSE: GDNF can be safely delivered within the clinically effective dose range. Despite the fact that GDNF was safe and well tolerated in the Phase 1 and 2 trials, two safety issues have arisen. Cerebellar toxicity was seen with very high doses of GDNF in rhesus monkeys and GDNF antibodies have been expressed in some patients. While they remain a concern, it is important to place them in perspective. First and foremost, to date none of the patients have shown evidence of cerebellar toxicity or autoimmune symptomatology. Cerebellar toxicity in rhesus monkeys occurred outside of the clinically relevant dose range. Antibody expression frequently occurs with other proteins used to treat diseases of the brain, such as b-interferon therapy for multiple sclerosis, without producing recognizable clinical autoimmune disease and without precluding clinical treatment. While both safety issues dictate that the patients receiving GDNF be closely monitored, further testing is needed to determine their relevance, if any, in clinical treatment. CONCERN: It is not economically feasible to develop GDNF as a drug. RESPONSE: Development of the direct infusion approach for GDNF delivery is economically feasible because GDNF qualifies as an “orphan drug” for treating a subset of persons with Parkinson’s disease. This subset consists of non-demented patients with progressive, advanced, life-threatening Parkinson’s disease. These patients may have pronounced ON-OFF responses and debilitating side effects, such as hallucinations and dyskinesis, to conventional anti-parkinsonian medications. The drug would have intended effects for fewer than 200,000 people a year in the United States. It is understood that companies must make business decisions about product development. If Amgen decides not to continue to develop the intraputamenal infusion approach for GDNF therapy, they should license this approach to another company that can take this promising therapy forward. from:http://www.pdpipeline.org/focus_updates.htm ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn