Currently available pharmaceutical therapies for many chronic illnesses leave much to be desired. Although considerable progress in therapeutics has been made in recent years, available treatments usually do not provide a definitive cure. The goal of current therapy is usually more modest—symptom relief or delay in disease progression.
Many of today’s drugs are also often quite expensive and often must be taken over a long period of time. Therapy with currently available medications is often hit-or-miss, because we cannot accurately predict a patient’s response to a drug or if side effects will occur. Thus, selection of a therapeutic agent for an individual patient is usually marked by a frequently time-consuming and expensive process of trial and error. Often, the first drug chosen is not effective or is not tolerated due to side effects.
All medications approved for marketing by the FDA have been shown, through well-controlled randomized studies, to be statistically effective for large groups of test subjects. However, these drugs are often not effective for some individuals in these groups. Absent or incomplete efficacy in individual patients is very common among major drug classes. The cost of this failure to effectively treat is very high.Into the Future
Due to recent advances in several fields of biomedical research, we will soon be able to identify those patients for whom a drug will be effective. We are on the threshold of major breakthroughs in individualized patient care as a result of new and anticipated advances in molecular biology, genomics, pharmacogenetics, biomarkers, and other biomedical disciplines.
Key to these changes is our growing understanding of the genetic factors that underlie disease and patients’ responses to medications. Pharmacogenomics blends pharmacology with genomic science to study how drug response is influenced by inherited variations in genes and the proteins they produce. Pharmacogenetics is expected to have a profound effect on the individualized treatment of complex, multigene disorders. Recent advances in genomic research have enabled new strategies to determine how individual genetic differences may be responsible for variability in response to drug treatment.
Ongoing studies are finding links between a patient’s specific genotype and the likelihood that a specific agent will be effective or that an adverse effect will occur. Subtle variations in genes can affect expression of specific protein targets, such as receptors, transporters, and cell signaling pathways, all of which play an important role in response to medications. Future therapies will often be based on the identification of which molecular pathway is disrupted in a given patient. This emphasis on diagnostics represents a sea change in the focus of the healthcare industry from a clinical definition of disease and diagnosis to a molecular definition of diagnosis and predisposition.
A major limitation of current therapeutics is the relatively small number of known “drugable targets” at the molecular level. It is anticipated that advances in genomics will greatly expand the amount of targets. The number of targets “hit” by all drug substances marketed today is only about 200, but the number of potential targets for small molecule drugs is estimated to be about 3,000. Therapies that impact biological activity at these targets will greatly expand our therapeutic armamentarium with agents that are selective for the disease process, with limited side effects.
These advances will usher in a new era of effective and truly personalized treatment for major diseases. The considerable “noise” that now exists, in the form of non-response to treatment and adverse drug effects, will be reduced as therapies are channeled to patients for whom they will be safest and most effective, improving
quality and quantity of life.Individual Drug Effectiveness
Studies of twins and blood relatives have shown that genetic factors are important determinants of the normal variability of drug effects. For example, genetic variations appear to underlie differences in the effectiveness of the beta-agonist albuterol used in the treatment of asthma. Different haplotypes (groups of genetic variations) are associated with patients’ varying responses to the medication.
Haplotype 4 is associated with depressed responsiveness and haplotype 2 with increased responsiveness to this agent. Similarly, there is considerable variation in clinical response to antipsychotic agents. For example, the response rate for clozapine varies between 30% and 60%, a diff erence believed to reflect variation in genes governing neurotransmitter-receptor-drug relations. An optimal combination of six specific gene variations (across multiple genes) has been associated with a maximal (77%) success rate with clozapine. Other antipsychotic agents may be relatively more effective in patients with other gene-variation combinations.