April 1, 2007 (Vol. 27, No. 7)

Although Robust Growth Is Predicted in the Next Five Years, Mainstream Adoption Is Unclear

Pharmacogenetics (PGx), the application of genetic variation to understand variability in medicinal response, has been heralded as the facilitator of personalized medicine and targeted therapies with the potential to alter the healthcare landscape. Key benefits of PGx tools include:

· Reducing adverse reactions, enabling selection of optimal therapy, and increasing patient compliance

· Enabling development of safer, more effective drugs

· Capable of reviving drugs that failed clinical trials or were withdrawn from the market

· Reducing time, cost, and failure rate of clinical trials

In recent years, it has become increasingly apparent that dozens of human drug metabolism polymorphisms exist and that inter-individual variability in drug metabolism is caused by these polymorphisms. Differences in drug responses can be attributed to differences in genes that code for the production of drug-metabolizing enzymes, drug transporters, or drug targets.

Variations in genes coding for key enzymes such as P450, N-acetyl-transferases, vitamin-K-metabolizing enzyme, glutathione-S transferase, and dehydrogenases lead to decreased or increased metabolism of drugs.

PGx tests that measure these variations are capable of reducing adverse reactions associated with most blockbuster drugs and helping physicians select optimal therapy and the most-effective dosage for various subpopulations. For example cytochrome P450 tests provide critical information on individual dosing and therapeutic efficiencies of drugs such as antidepressants, antipychotics, anticoagulants, anti-arrthymics, b-blockers, and oncologics.

PGx tests correlate with clinical factors, such as disease state, prediction of future disease states, drug response, and treatment prognosis, to help physicians individualize treatment for each patient.

Oncology was the first beneficiary of PGx testing, but another area that is now benefiting from PGx tests as well is antiretrovirals. For example, PGx tests to quantify HIV disease progression and tests that measure variations in various genes are playing a crucial role in development of new HIV inhibitors that are tailored to the subset of patients who respond.

Notable Trends

One emerging trend in the PGx space is the desire of both physicians and payers to have a panel PGx test that evaluates patients not just for a particular drug, but for all the drugs that could be given to a patient for a given condition.

Developing a new drug is a costly and lengthy process. Theoretically, using PGx tests to preselect patients most likely to respond to a drug or least likely to suffer side effects for studies could reduce the size, time, and expense of clinical trials. For example, results of a Phase III clinical trial for the drug Tykerb (lapatinib) in treating a genetically defined subset of patients with breast cancer were so compelling that researchers terminated the trial early.

There are no examples today in which a drug has been resurrected based on PGx tests after having been withdrawn for serious adverse events. However, AstraZeneca is trying to revive its drug Iressa (gefitinib) by attempting to develop a genetic test that might better define the subset of patients who respond to the drug.

With the blockbuster model broken, recent drug withdrawals, patent expirations, and declining new drug approvals, the pharmaceutical industry seems to be in deep peril and frantically searching for a turnaround. The key to pharma’s future success could likely be the ability to identify subpopulations and develop drugs for them by combining drug candidates with PGx tests.

Pharma needs to be attentive to the availability of numerous PGx tests that predict drug safety and efficacy as the perceived market, commercial, and clinical success of their existing drugs and drug candidates in the pipeline will change drastically.

Massachusetts Institute of Technology recently performed a study to analyze the potential value of PGx tests in clinical practice, using insurance claims for asthma patients to determine the economic impact of a hypothetical diagnostic test used to predict drug response. Assuming that the diagnostic test was accurate and economical, the study found that the use of such a test would offset costs for payers and reduce asthma-related healthcare costs.

Demise of Blockbuster Model

Although there is mounting evidence that PGx tools will be vital to pharma’s growth in the future, much of its promise and many of its challenges remain untested. One of the reasons for pharma’s reluctance in adopting PGx tests widely is fear that PGx will lead to the demise of the blockbuster model. We believe these fears are unfounded and that PGx will present opportunities to increase sales by defining new uses for products, rescuing drugs in the pipeline, reducing time and size of clinical trials, and dominating niche markets.

Unlike the reimbursement conditions, the U.S. regulatory climate has been very supportive of PGx. The FDA has increasingly pushed toward personalized medicine through its critical path initiative and its process to submit PGx information for informal review. Recently, the agency announced that it expects to see PGx information front and center on drug labels. The FDA is expected to release guidelines on this new drug label format soon.

The degree to which the medical community will accept PGx tests will be limited by their knowledge of the subject and their awareness of available tests and treatments. Most of the medical educational curricula today do not include PGx, this is likely to hinder acceptance furthermore. Additionally, PGx tests raise public policy concerns such as ethical, legal, and societal questions. For example, how should test results be protected to prevent employers from misusing the information and insurance companies from denying coverage?

Scientia believes that the next five years will likely see robust growth in PGx tests; however, mainstream adoption will depend on market surveillance studies, clinical research studies, and clinical trials to prove its ability to reduce healthcare spending and address the unmet needs of patients and physicians.

Harry Glorikian is managing partner at Scientia Advisors. Web: www.scientiaadv.com.
E-mail: [email protected].

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