Protecting Human Subjects And The Ethics Of Clinical Trials
ASENT 4th Annual Meeting
Thursday, March 14 - Saturday, March 16, 2002
Capital Hilton Hotel Washington, DC
Speaker Abstracts: Proof Of Concept Trials In NeuroScience
FROM SYNTHESIS TO FIRST IN HUMANS: PHARMACOLOGY & CHEMISTRY
Edward D. Hall, PhD, Senior Clinical Director
Pfizer Global Research & Development
Ann Arbor Laboratories
Drug discovery in the current era is mechanism driven rather than empirical. The initiation of a drug discovery project begins with some level of understanding of the role of the particular target mechanism in the disease in question. Initial target validation studies have already verified that the target receptor or enzyme is probably involved in the disease, and if possible, there has been a demonstration in either cell-based or in vivo disease models that a prototype pharmacological compound known to interact with the putative drug target can ameliorate the disease mechanism. Once this has been achieved, high throughput screens (HTS) are developed and appropriate compound libraries are screened. The "hits" from the screen are then triaged by chemists to identify the best templates for chemical synthetic programs, and their activity at the target site is confirmed by secondary screening. Through an iterative process, compounds with high affinity and selectivity for the target mechanism, good pharmaceutical and pharmacokinetic properties and pharmacological activity are then entered into preclinical development (i.e. toxicology). If they are demonstrated to possess a practical therapeutic index (safety margin), they are then graduated into Phase I studies to assess safety and pharmacokinetics in human volunteers upon single and multiple dose administration. If no problems are encountered, the compound then moves into Phase II development to determine safety in patients suffering from the target disease. A second goal of Phase II testing is to determine whether the compound possesses the expected disease-modifying efficacy. In the case of novel or unprecedented mechanistic targets, the observation that compounds which selectively target the putative disease mechanism are indeed therapeutic in animal disease models and/or humans represents proof of concept. In other words, if the compound works and can be demonstrated to be operating by the intended mechanism, this constitutes reasonable proof that pharmacological modification of the target is associated with attenuation of the disease or its symptoms. At present, there is increasing emphasis on the identification and use of either biochemical markers of disease and drug mechanism or imaging technologies that can demonstrate that the disease mechanism is effectively being modified and/or the drug is working by its intended mechanism.
In order to illustrate this proof of concept process at both the laboratory and clinical level, the development of the concept of the role of oxygen radical-induced lipid peroxidation (LP) in the context of acute spinal cord and brain injury will be reviewed together with the discovery that administration of the glucocorticoid steroid methylprednisolone in doses that inhibit post-traumatic LP is able to protect the injured spinal cord and brain and promote functional recovery in animals and man via inhibition of LP. Additional proof of the concept that LP inhibition was the explanation for the neuroprotective effects of high dose methylprednisolone therapy was later provided by the observation that the 21-aminosteroid tirilazad, which completely lack glucocorticoid activity, is equally effective with high dose methylprednisolone in protecting the injured spinal cord (and brain). The importance of lipid peroxidative events in acute ischemic and hemorrhagic stroke and other neurodegenerative models has been illustrated by the finding that tirilazad as well as newer non-steroidal antioxidant compounds are also neuroprotective in those instances. The use of LP-related biomarkers in plasma or CSF to facilitate further proof of concept in acute CNS injury will also be discussed.
PROOF OF CONCEPT IN PHARMACEUTICAL RESEARCH
Scott A. Reines, MD, PhD, Merck Research Laboratories, West Point, PA 19486 USA
A critical element of drug development in neuroscience is bridging the preclinical - clinical gap that exists for novel therapeutic agents. Animal models in psychiatry, and to a lesser extent in neurology, lack adequate validation as predictors of useful treatments for human illnesses. Negative trials often go unpublished, creating an overly optimistic body of literature that over-emphasizes successful results. Recent experience in our Substance P antagonist program includes Proof-of-Concept studies in patients with various types of pain, headache, motion sickness, chemotherapy-induced emesis, schizophrenia, or depression. A study in a human model of motion sickness was also conducted. Although each of these potential indications was supported by preclinical efficacy models of uncertain predictive value, some (e.g. antagonism of cisplatin-induced emesis in ferret) had more obvious face validity than others. In another program we utilized a human model of anxiety to support further trials with a novel anxiolytic drug. Perspectives obtained from these programs will be discussed during the Panel Discussion.