Targeted therapy

Risk of disease and response to treatment vary significantly from person to person, mainly as a result of variation in human genetic coding, interactions between a person's genes and environment over a lifetime and the unique signature of the immune system. The basic human phenomenon of each human being unique by nature or nurture spurs tremendous opportunities for the emerging field of personalised medicine. Such treatments may include drugs or cell therapies tailored to a patient's history, genes and immunology.

Information portals have been abuzz with concepts and terminologies around the field of personalised medicine, so it is a worthwhile exercise to demystify some of these terms, namely companion diagnostics, theranostics and stratified medicine.

A companion diagnostic taken at face value means just that; it is a diagnostic test that accompanies something else, in this case a drug. It is a test or tool that is used to help in prescribing some drugs with greater accuracy. At present, companion diagnostics aid physicians in doing six main things: they help in selecting a particular drug for a patient; they check for the efficacy of a particular drug on a patient; they check for relapse risk; they help decide the right dosage for the drug; they check the disease status before prescribing drugs and check for predisposition to some diseases.

Theranostics is the science of convergence of therapeutics and diagnostics and the diagnostics aspect of it is called companion diagnostics.

Stratified medicine is the process of using biomarkers to select patients for clinical trials. It is taking companion diagnostics one step higher and implementing it in the process of drug development for clinical trial selection. Using biomarkers for this purpose is called stratification and the science is called stratified medicine.

All of these different components come together to achieve the common goal of personalising or individualising medicine, so they all fall under the ambit of personalised medicine.

Stakeholder imperatives
Personalised medicine involves seven key stakeholders: the pharmaceutical company; the diagnostic manufacturer; the patient; the physician; the payer; the testing laboratory and the regulatory authorities. For a companion diagnostic or theranostic to become a success, its clinical utility is of the greatest importance to all of these stakeholders. Any companion diagnostic should have a clearly defined clinical utility.

This is important for the pharmaceutical company to adopt it, for the diagnostic manufacturer to make it, for the physician to prescribe it, for a patient to use it, for the payer to reimburse it, for the testing laboratory to promote it and for the regulatory authorities to approve it. Other key imperatives include cost, pricing and reimbursement, labelling and establishing standards for regulatory approval.

Market direction
The pharmaceutical industry's blockbuster model has consistently earned companies huge revenues from drug sales over the years. However, this model also brings other issues like very high drug development costs caused by drugs failing at phase II and III, when a significant amount has already been spent. Over the past few years, the industry has come to realise that incorporating biomarkers into the drug development process can help it identify drugs that are potential winners and losers early on, to help it decide whether to go ahead.

Also, through the application of biomarkers and the principles of personalised medicine, it will be able to develop drugs that are more effective and can help significantly reduce the number of adverse reactions reported as a result of prescribing drugs that are not suitable for some. So, although the blockbuster model is an established revenue generator, there is much hope and scope for the personalised medicine route.

Personalised medicine brings the important benefits of improving the design, power and predictability of a clinical trial which, in turn, helps achieve better outcomes, in less time. It helps reduce subject recruiting time in clinical trials, improves drug response and, as mentioned, minimises adverse reactions. It also leads to fewer misdiagnoses. In addition, it helps in developing better differentiated drug products, aided by the process of labelling.

Drug against mutated target
Herceptin, developed by Genentech/Roche, was the first clinically approved drug against a mutated target. It is a humanised monoclonal antibody generated from mouse antibody, which is reactive against HER2. Research proved that HER2 gene amplification is an indicator of prognosis and also the basis for targeted therapy for breast cancer. Since more than 25 per cent of breast cancer patients exhibit HER2 gene amplification, the availability of Herceptin and the HER2 companion diagnostic test has helped breast cancer patients with better prognosis and targeted therapy.

Herceptin received fast-track approval by the US Food and Drug Administration (FDA) in 1998 for the treatment of metastatic breast cancer patients. Genentech collaborated with Dako to develop a theranostic test, known as the HercepTest, which is an immunohistochemical test to measure HER2 activity.

This test was also approved along with the drug. In 2002, a second diagnostic test was approved by the FDA. This test was developed by Vysis, which was acquired by Abbott in 2001. Herceptin received approval in record time in the European Union for use in early stage breast cancer, backed by pressure from National Health Service (NHS) patients in the UK.

The success story of Herceptin proves that the intervention of patients along with the clinical utility of a test in the efficacy of a drug can carve the way to faster regulatory approval and acceptance. This can be attained through marketing strategies that will push patients to demand a genetic test. An effective therapy in a disease area like cancer will also be popular with physicians and help gain their endorsement.

Herceptin also ensures high RoI; in other words, it targets a specific set of the patient population who cannot be prescribed the drug without the supporting test and the company's business needs are also thus fulfilled. Herceptin logs annual sales of about $1.3bn, which is comparable to a blockbuster. This demonstrates the power of personalised medicine.

Impediments
Though this market is sure to grow significantly in the coming years, one main problem that will impede the success of theranostics and personalised medicine is a general absence of harmony between the diagnostic and pharmaceutical companies.

The lack of hybrid skills and the unwillingness of many in the pharmaceutical industry to restructure for a better, holistic adoption of personalised medicine are causes for concern. Currently, personalised medicine relies largely on the diagnostic-pharma collaboration model. This is gaining momentum, but it is moving too slowly. For personalised medicine to be awarded a central role in the healthcare delivery system, it needs to develop other strategies that do not rely on pharmaceutical alliances.

Although companies such as Roche and Abbott have evolved as integrated diagnostic and pharmaceutical companies, the key revenue is still generated through two separate revenue streams. It is unlikely that big pharma or large diagnostic companies will rebrand themselves as theranostic or personalised medicine companies.

Some of the key drivers of the field of personalised medicine include the emergence and availability of advanced technological tools to support the discovery and development of new biomarkers and the lowering of overall drug development costs through implementation of biomarkers.

Theranostics is a method that supports the needs of the medical community. The patient wants an efficient therapy with minimal side effects and the physician needs the right type of drug with maximum therapeutic efficacy. Both of these goals can be achieved through personalised medicine from an end user's perspective and this is an important success factor.

In conclusion, the personalised medicine arena is bound for tremendous growth as there is a paradigm shift in the way diseases are treated, from a one-size-fits-all concept to one where therapies are customised to suit the individual's genetic make-up.

The Author
Rasika Ramachandran is senior research analyst, life sciences, at Frost & Sullivan

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