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Medco, SureGene to Validate SULT4A1 Variants for Gauging Patient Response to Antipsychotic Drugs

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By Turna Ray

Medco is expanding its personalized medicine research efforts into antipsychotic drugs, a highly variable class of therapies to which industry and academic researchers are increasingly applying pharmacogenomic strategies.

Medco Research Institute announced this week that it will work with SureGene to investigate genetic variations that may be used to administer antipsychotic drugs to patients most likely to respond to them.

"The results of this research could help provide evidence supporting the development of genetic tests that would assist doctors to make more precise prescribing decisions, leading to improvements in outcomes, compliance, and safety for these mental health patients," Medco said in a statement.

Bryan Dechairo, senior director of Medco Personalized Medicine, told Pharmacogenomics Reporter that the alliance aims to validate whether polymorphisms identified by SureGene in the SULT4A1 gene can be used to stratify best responders to the four most widely prescribed atypical antipsychotics.

Medco and SureGene will conduct the REST study — Relative Effectiveness of Schizophrenia Therapy — a prospective trial that will explore how the SULT4A1 variants are linked to the safety and efficacy of quetiapine (AstraZeneca's Seroquel), risperidone (Janssen's Risperdal), olanzapine (Eli Lilly's Zyprexa), and ziprasidone (Pfizer's Geodon).

Medco will collect 2,000 DNA samples from plan members who consent to participate in REST. Additionally, although SureGene's initial investigations on the SULT4A1 polymorphisms focused specifically on schizophrenia patients, the study with Medco will extrapolate those gene markers into patients with bipolar disorder as well.

"The REST study provides us an exciting opportunity to validate our technology in a real-world setting. It has the potential to move us closer to making a real difference in the lives of people suffering from serious psychiatric illnesses using genetic information to guide drug selection." said Mark Brennan, SureGene’s chief scientific officer, in a statement.

Although genomic strategies to improve the safety and efficacy of antipsychotics are gaining interest in industry and academia, PGx research in this field is challenged by the variable nature of drugs currently on the market.

While most drug classes bind primarily to a single receptor, Dechairo noted that atypical antipsychotics bind to numerous receptors in the brain. As a result, "each individual drug within the atypical antipsychotics class of drugs has very different safety and efficacy profiles," creating an acute market need for PGx tests to guide treatment decisions.

Cost Conscious

Since the objective of Medco's personalized medicine effort is to administer cost savings to its payor clients through more efficient administration of drugs, the study with SureGene will also evaluate the cost effectiveness of using SULT4A1 polymorphisms routinely in the care of mental health patients.

Healthcare costs related to lack of response and adverse reactions to antipsychotic treatments are high. Schizophrenia patients have a particularly poor compliance record while on antipsychotic drugs, with 50 percent of patients discontinuing treatments within six months of starting a prescription, which often results in hospitalization.

"It was due to this great variability in atypical antipsychotic safety, tolerability, and efficacy that we decided to focus on this area of personalized medicine research," Dechairo said. "We chose to focus on schizophrenia and bipolar since these are the indications for which all atypical antipsychotics are approved and labeled for use in the US by the [Food and Drug Administration]."

The worldwide market for atypical antipsychotic drugs is expected to be around $18.5 billion this year and to dip below $15 billion in 2014, when many drugs in the class are expected to lose patent exclusivity. Seroquel's US patent is expected to expire in 2012; Janssen's exclusive marketing rights for Risperdal expired in 2004, and many generics are available; Zyprexa's patent is slated to run out next year; and Geogon's exclusivity period is expected to expire in two years.

Medco stands to gain financially if the REST study yields gene markers able to guide treatment with these drugs, since the bulk of the pharmacy-benefit manager's revenues come from the dispensing of generic drugs.

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As part of its effort to drive down healthcare costs and incur savings for its customers from greater use of generic drugs, Medco last year launched the Genetics for Generics program, which aims to use genetic testing to increase healthcare savings in the administration of certain generic drugs (PGx Reporter 10/07/09). In 2009, Medco's generic dispensing rate increased 68 percent, whereas in 2008 generic dispensing increased by 65 percent.

Growing Research

Of course, Medco isn't the only one embarking on genomics research to better characterize schizophrenia and improve drug response.

Earlier this month, PGx Reporter sister publication In Sequence reported that Merck recently used RNA-seq to measure allele-specific expression in 20 human samples with schizophrenia. The exercise yielded 170,000 variants associated with neurodegenerative disease, cytoskeleton remodeling, and neurofilament development. Merck researchers plan to probe further in this area by conducting additional RNA-seq studies by year end (IS 08/10/10).

An industry-academic partnership focused on the genomics of schizophrenia was announced in May, when Life Technologies partnered with EdgeBio and Virginia Commonwealth University to embark on a genome-wide sequencing and methylation study involving 1,500 individuals. Promising markers from this study will be validated in a cohort of 1,600 patients and controls. "This study in particular has significant implications for the development of personalized genomic medicine, and we look forward to seeing the results of this research," John Miller, president of Life Technologies' Genetic Systems Division, said in a statement at the time.

The University of California San Diego announced earlier this month that it is using a $10 million grant from the National Institute of Mental Health to study the genetic underpinnings of schizophrenia. The 12-year study hopes to study "the genetics of brain-based deficits" related to schizophrenia, and identify gene targets for drug development.

Finally, last year, Roche, Rules-Based Medicine, and RBM's subsidiary Psynova Neurotech announced an exclusive agreement to discover, develop, validate, and commercialize diagnostic immunoassays to "differentiate" schizophrenia treatments being developed by Roche (PGx Reporter 12/09/09).

Medco's study with SureGene is the PBM's first foray into personalized medicine research in the area of mental illness. Previously, Medco conducted an observational study with the Mayo Clinic to study the clinical utility of PGx-guided dosing for warfarin. Medco is also conducting personalized medicine research for the antiplatelet drug Plavix, for statins, and tamoxifen.

In working with SureGene, Medco is making good on its promise to work with small diagnostic firms to gather clinical utility data on promising genetic tests that can guide treatment in major disease markets.

According to previous comments by Dechairo, Medco is interested in working with small diagnostic firms that have pharmacogenomic tests analyzed in independent sample sets and in CLIA-certified labs. The PBM will help these firms obtain clinical utility and cost effectiveness data for their tests within its network of pharmacists, doctors, insurers, and patients. Having collected this cost-effectiveness and clinical utility data, which often pose the greatest barrier to adoption, Medco can then introduce these tests to its customers (PGx Reporter 04/14/10).

Medco appears to be entering its PGx collaboration with SureGene in the mental illness market with some confidence. SureGene's initial findings on SULT4A1's association to atypical antipsychotic response has been observed in two other schizophrenia studies performed by researchers collaborating with the company.

"Medco's research partnership with SureGene could help provide evidence supporting the development of a genetic test that may assist physicians to make a personalized treatment decision for patients with these serious diseases," Felix Frueh, Medco's VP of personalized medicine R&D, said in a statement.

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