AMS ONCOLOGY STUDIES
A New Model for Personalized Medicine
The premise of our approach to personalized medicine is shown in the diagram to the left. A population of patients may produce a wide range of response to the same treatment. This is likely due to the underlying heterogeneity (genetic and environmental) that ultimately drives response. To uncover the pharmacologic basis of response (or lack of response), patients are administered a tracer dose of the treatment drug. The drug is lightly-labeled with 14C to permit detection by AMS. The dose may be reduced to <100 ug to eliminate pharmacologic effect yet provide sufficient mass for assessment of tracer kinetics and target uptake (if tissue is available). Patients are then stratified to ‘high responders’ and ‘low responder’ based on empirical assessment of drug pharmacology. A physician may choose a different treatment modality for patients predicted to have a ‘low response’ to standard therapy.
Phase 3 Patient Selection
Phase 3 trials are performed on a large number of patients, typically 300 to 3,000 or more, using randomized control at multiple medical centers. The ultimate aim of these trials is to provide definitive assessment of drug efficacy in patients. Subject enrollment criteria, however, is rarely based on any patient-to-patient variation in drug pharmacology, such as absorption, metabolism, kinetics or elimination.
Pharmaceutical companies have started to recognize the risks associated with conducting efficacy trials in large heterogeneous populations. Significant effort has gone into pharmacogenomic approaches to aid in patient stratification based on various genomic biomarkers, including variants involved in drug metabolism and drug resistance. DNA samples are now collected and archived in these trials so retrospective genomic screening can aid interpretation of trial results (i.e. why some patients responded and others did not).
We propose a more rational approach towards patient enrollment in Phase 3 trials, one that is based on a pre-trial study to evaluate drug pharmacology, and if possible, drug uptake by the target organ. Patients that show poor drug pharmacology and/or target uptake may be excluded from enrollment in the longer phase of the study. Enrollment of pre-selected patients based on positive pharmacology (efficacy marker) may improve the likelihood of a successful outcome in the larger trial. The approach may also reduce the number of patients required for such a study due to the improved statistical power of the study design. AMS methodology provides a solid scientific basis for the rational enrollment of patients in Phase 3 trials.
Personalized Medicine
A major problem in the current practice of medicine is that not all patients benefit to the same degree when given an approved drug for that disease. Often drugs will only exert the desired therapeutic effect in perhaps 30-70% of patients (Personalized Medicine Market Report - Bharat Book Bureau, 2004). Anti-depressants, for example, are notorious for being successful in only 30% of cases; the other 70% are described as non-responders. Furthermore, drugs may function as predicted in one patient but lead to adverse drug reactions in another. In the US it is estimated that over 2 million people are hospitalized and 100,000 die each year from adverse drug reactions.
This individualized response is due to genetic factors as well as environmental modulators such as age, disease condition, diet and drug-drug interactions. The completion of the initial phase of the Human Genome Project and the development of bioinformatic tools have ushered in the era of pharmacogenomics. The underlying goal of pharmacogenomics is to personalize treatment based on a patient’s genetic makeup.
The major draw-back of these tests and with pharmacogenomics in general, is that they target fairly simple gene-disease scenarios involving a single gene (for example, Her2) or a limited number of genes. Complex pathway feedbacks and genetic networks make development of gene-based predictive tests a truly daunting task. Furthermore, these gene-based tests do not take into account environmental factors that may influence treatment response, factors that may have an equal or even greater impact on response than genetics.
Our approach to personalized medicine is shown in the diagram below. The major advantage of an AMS-based approach is that the test encompasses both genetic and environmental factors that influence drug response and treatment outcome in individual patients. This systems biology approach of ‘pharmaco-phenotyping’ each patient may ultimately address a much wider range of diseases, especially ones that are influenced by complex gene networks, pathways and environmental modulators.
Case Study
Quantitation of 14C-Temozolomide in Tumors of Newly Diagnosed Glioblastoma Multiforme Patients
We are pleased to announce the initiation of an internal clinical study to quantify tumor uptake of 14C-Temozolomide (Temodar) and subsequent 14C-methylation of tumor DNA. The primary objective of the study is to evaluate a series of pharmacologic endpoints (biomarkers) as predictors of Temozolomide efficacy in individual patients. Predictive biomarkers, also known as companion diagnostic tests, help to identify the right treatment for each patient and may help improve overall outcome. Our neurosurgeon collaborator, Dr. Greg Foltz at Swedish Neuroscience Institute in Seattle, is providing surgical expertise and patient care at the Swedish Medical Center located adjacent to Accium's AMS facility.
