Made to Measure

By Marie Shields, Editor

With pipelines running dry and fortunes flagging, the pharmaceutical industry is casting about for a savior. Could individually tailored treatments be the answer?

“100 Americans a year die from adverse reactions to medications, and more than 2 million are hospitalized”
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The pharmaceutical industry is at a crossroads. Business models are changing, and smart companies are looking for ways to maximize their R&D investment. As blockbusters fall by the wayside, or at the very least become much less common, what will take their place? One answer could lie in the rapidly emerging field of personalized medicine.

This is not personalized medicine as it is often defined in healthcare - the need to consider an individual patient's unique lifestyle and medical history, and how this impacts on his or her response to treatment - rather, this type of personalized medicine aims to develop drug therapies that have efficacy within narrowly targeted groups of patients, based on each person's genetically programmed reaction to the drugs.

Why can two people take the same medication, and have completely different responses? One may have severe side effects, and the other none at all. Or the treatment may lead to remission in one, and seem to have no effect in the other.

One of the reasons behind this variety of results is the variations we inherit in our genetic make-up. Pharmacogenomics uses this genetic information to study how individuals react to medications. Variations in genes can determine how we respond to treatment, in a similar way that genetic variations cause differences in eye or hair color. For example, if you have a genetic variation that causes a drug to stay in your body longer than normal, this may cause unwanted side effects.

Researchers are working to identify these genetic variations, and then match them with responses to medications, so that physicians can take this into account when prescribing drugs. In addition to the usual information such as weight, age, medical history and how any relatives may have reacted to the same medication, doctors in the future may be able to take into account your own personal genetic make-up.

Growth area

The field of personalized therapies - and the diagnostics used to develop them - is growing so rapidly that PricewaterhouseCoopers recently released Diagnostics 2009, the first in a series of annual reviews of deal activity in the in vitro diagnostics sector and significant events for personalised medicine.

According to Tony Pillari, PwC's Director, Healthcare Advisory Services, the report was developed for three key reasons. First, the level of deal activity in that sector, which PwC feels is significant and likely to increase in the coming years and create a multitude of business opportunities.

Second, the growing importance of diagnostics in the practice of medicine and in the emergence of personalized medicine. And third, the many exciting advances, such as the recent announcement by Complete Genomics of the $4000 genome, which that have been made in recent months in the field of personalized medicine, including those related to diagnostics.

In PwC's definition a personalized medicine diagnostic as any tool that allows for the generation of data that are then used to tailor strategies for prevention and care to the needs of the individual. Such tools would include companion diagnostics, early diagnostics and prognostics.

Tailoring the treatment to the patient is not an entirely new idea. What's different about this new definition, says Pillari, is the specificity and accuracy that advances in genomics and proteomics and a whole host of related technologies now make possible.

"We now have a much deeper understanding of many diseases, including complex diseases like cancer, at the molecular level, and our knowledge continues to grow," he says. "That kind of understanding simply wasn't possible before. As a result, the way we treat disease, including how we design treatment options for patients, has changed to a point where trial and error will hopefully be replaced by trial and success."

Pharmaceutical companies looking to maximize success rates will be able to determine which subsets of patients would be more likely to respond positively to their drugs. This happens to some extent already, with companies often targeting subsets of patients if initial trials with larger groups don't yield the expected results. AstraZeneca, for example, did this with its anti-cancer drug Iressa. In 2004, a large randomized study failed to demonstrate a survival advantage for the drug in the treatment of non-small cell lung cancer, but it has since been shown to be effective in patients with mutations relating to epidermal growth factor receptor.

Ideally, as AstraZeneca's EVP for Discovery Research Jan Lundberg points out, R&D organizations should work out beforehand which groups of patients are likely to benefit, rather than waiting until the drug has been developed and then looking for people it can help.

PwC's Pillari believes specialized therapies can help pharmaceutical companies improve their bottom line. "The blockbuster model has been the predominant model in the pharmaceutical industry for quite some time and until recently, has been very successful. However, the poor return on R&D investment realized by that model over the past few years, in terms of new drugs developed and introduced into the marketplace, has been well documented, as has the number of drugs coming off patent in the next few years.

"As a result, and quite understandably, pharmaceutical companies are very concerned about pipelines and future revenues. In this context, the move to specialized therapies is relevant to the pharmaceutical industry for two reasons. First, is the potential to reduce drug development time and costs and increase success rates through enriched clinical trials.

"These are trials that only include those people who, based on the analysis of their make up at the molecular level, are most likely to respond to a given drug. Second is the opportunity to move to a 'niche buster' model, that is, one that generates revenue because of the value a specialized therapy delivers to a specific subset of patients."

Mixed feelings

There are some within the industry who see a potential downside to the advent of personalized medicine. David Lathbury, AstraZeneca's Director of Process Chemistry, believes it will only help big pharma improve its business models if it translates to a much more reduced cost of development. If it doesn't do this, he says, the simple net present value calculation means that companies won't make money. "If you can very quickly identify the target groups, if you can get through phase III with, for example, 200 patients, then absolutely it will be a benefit. But if you've got to go through the same process before you identify that population, it could be very difficult."

Lathbury says that where personalized medicine could make a difference is in dosing regimens, which could help drive through a better result. "We tend to give everyone an average dose, that's the way most clinical programs are designed. If better titration of dose will reduce adverse events, increase compliance and get a better return on the drug, those steps I think we can take."

Then there's the view we could go much further. Dorman Followwill. Partner and VP, Healthcare EIA for Frost & Sullivan, describes his idea of the ultimate version of personalized medicine. "if you're really talking about the holy grail of personalized medicine, it would be walking into a physician's office, pulling out a smart card that has your genotype on it, and having them plug it into their system and then diagnose you or, dispense medication for your genotype." In the course of his travels around the world, Followwill has asked many people in the industry when they think that day will come, and has received answers as varied as in 10 or 15 years to as long as 100 years.

The version of personalized medicine as it exists today has proven popular with regulators. In some cases, they now insist on biomarker testing to guide drug prescribing. Tony Pillari believes their main concern is efficacy. He points the testing for infection by a specific HIV subtype that is required prior to the use of Pfizer's Selzentry treatment, which he says is based on the fact that Selzentry blocks the specific receptor that HIV subtype uses to attach to and infect white blood cells.

"Similarly," he says, "testing for epidermal growth factor receptor (EGFR) expression is required prior to the use of Erbitux because Erbitux binds to EGFR and blocks certain growth factors that ultimately promote the expansion and spread of tumors. We believe this practice will become more common, as everyone in the healthcare value chain, from regulators to pharma to providers to patients to payers, appreciates the benefits of improving drug efficacy as well as reducing the frequency of adverse events.

Yet despite the fact that the clinical case for developing companion diagnostics is strong, the PwC report points out that there has yet to be significant deal-flow between the pharmaceutical and diagnostics industries, because while the existing pathway for drug approval and reimbursement is clear and well-established, this is less so for diagnostics and even less so for drugs and diagnostics developed in tandem.

Pillari does point out that there are a number of encouraging initiatives underway, including by the FDA and the Critical Path Institute, to better define the pathway for drug and companion diagnostics development. As this pathway becomes clearer, and the risks associated with such strategy are mitigated, he expects deal-flow between the two to increase.

Frost & Sullivan's Followwill points out that personalization is a mega trend in many sectors, including healthcare, automotive, transportation, environment and building technologies. For this reason he predicts that personalization will be also increase within the pharmaceutical industry, as it strives to find new business models to secure its future.

Reaping the benefits

The potential benefits of pharmacogenomics could include:

• The ability to make better medication choices.
  Each year, roughly 100,000 Americans die from adverse reactions to medications, and more than two million are hospitalized. Pharmacogenomics may be able to reduce the number of adverse reactions by predicting who is mostly likely to react badly to a particular drug.
• Safer dosing options.
  Standard doses used today can prove toxic to those with certain genetic make-ups. Using pharmacogenomics, doctors may be able to predict which dose will work for which patients.
• Improvements in drug development.
  Pharmacogenomics may help drug companies better focus their drug development programs, by predicting in advance which people will have adverse reactions to a drug before it is tested. These people can then be excluded from clinical trials.

[Source: www.mayoclinic.com]

Testing time

The following genetic tests are currently in use. They help guide dosing and prevent toxic levels of medication from building up in patients who lack certain enzymes.

Cytochrome P450 test. This group of enzymes are responsible for metabolizing more than 30 types of medications. The test can determine dosing and effect of some antidepressants, anticoagulants, proton pump inhibitors and a number of others.

Thiopurine methyltransferase test. This enzyme breaks down the chemotherapy drug thiopurine, which is used to treat leukaemia and autoimmune disorders.

UGT1A1 TA repeat genotype test. This test detects a variation in a gene that affects the UGT1A1 enyme, which determines how the body breaks down irinotecan, a drug used to treat colorectal cancer.

Dihydropyrimidine dehydrogenase test. This enzyme breaks down the drug 5-fluorouracil is a commonly used chemotherapy medication.

[Source: www.mayoclinic.com]

Up and coming

PricewaterhouseCoopers' Tony Pillari's pick of the significant events for the development of personalized medicine that have occurred during the past year.

1. The announcement in early September by Complete Genomics, a genome sequencing company based in California, that it had completed the sequences of 14 individuals for the price of about $4000 per genome in the space of just a few months. This is a big step toward the dream of fast and cheap genome sequencing: the ability to sequence whole genomes at costs as low as the $100 to $1000 range and in a matter of days or even hours.

This means that the day when rapid, affordable genome sequencing is accessible to all patients is that much closer. It also means that we are that much closer to amassing quickly and affordably the number of sequences needed to truly understand the genetic basis of disease.

2. The expansion of Medco's Personalized Medicine Program. The Program was created in 2008 with the goal of improving patient care by requir­ing genetic tests to determine the correct dosages for certain medicines. Medco began this program with two drugs, tamoxifen, a breast cancer treatment, and warfarin, a blood thinner, and recently announced plans to add two more prod­ucts later this year and another in 2010.

This program is a very exciting example of pharmacogenomics (the science of understanding how an individual's genomic profile influences drug response) in action and its expansion speaks to Medco's faith in personalized approaches to medicine. Given how many individuals Medco serves, its expansion should have a real impact on the practice of medicine.