Data Support Clinical Validity Of Pharmacogenomic Testing

By Ed Miseta, Chief Editor, Clinical Leader

In 2007, a technical review by the Evaluation of Genomic Applications in Practice and Prevention group (EGAPP) conducted testing that concluded there was insufficient evidence at the time to determine the clinical value of pharmacogenomic testing for adults beginning treatment with SSRI antidepressants.  Since then, extensive new published evidence is available to refute those findings. C. Anthony Altar, chief science officer of personalized medicine company Assurex Health, is the lead author of a study published last fall in the International Review of Psychiatry, which validates the clinical use of pharmacogenomic testing to help predict patient response to psychiatric medications.

Dr. Altar, who has a Ph.D. in psychology with an emphasis in neuroscience, has spent over 30 years working in the life science industry dealing with pharmaceuticals and drug discovery. He was instrumental in the discovery of Abilify, one of the most commonly prescribed antipsychotic medications, and has done extensive work in developing drugs for the nervous system.      

Assurex Health uses pharmacogenomics to test patients’ individual genetic variations that affect their ability to tolerate and respond to psychiatric medications such as antidepressants and antipsychotics. “Basically, we measure the unique differences in an individual’s genes,” he says. “In our current test, called GeneSight Psychotropic, we measure 50 variants of six genes that have been studied extensively for their effect on drug response. Those genes are responsible for metabolism of psychiatric medications in the liver, or are responsible for the brain response to those medications. The variations in the DNA of those genes can also affect the extent to which medications are tolerated. For example, one or more gene variations might result in a patient only being able to tolerate lower doses of a drug, while another patient may require higher doses to achieve the same effect.“

A single gene variation can have profound effects and change the response in the brain of the critical receptor that would normally bind that drug. This can cause the patient to have a decreased response, or conversely to have a much bigger response. This measurement of variations in an individual’s DNA is referred to as pharmacogenomics. By analyzing a relatively small number of genes, Assurex can use the resulting information to accurately predict the response to drugs.

The 2007 report by EGAPP evaluated how earlier pharmacogenomic technology worked in clinical practice, and concluded at that time there was insufficient evidence to support a recommendation for or against the use of measuring gene variations in adults starting antidepressant (SSRI) therapy for depression. Since then, Assurex has assembled significant data from its own laboratory studies, as well as clinical studies conducted in collaboration with the Mayo Clinic, which showed that analyzing a combination of gene variations actually did help adults get on the right medication for treating depression.

“In that 2007 study, EGAPP evaluated limited data for just five SSRI drugs and only two genes, based on only 30 published clinical studies,” says Altar. “In collaboration with our colleagues at Cedar Associates,  we conducted a much more extensive literature review covering published clinical studies through the end of 2013. We identified an additional 163 papers on this topic, and reviewed the literature for 26 antipsychotics and antidepressants and eight genes that have been shown to influence patient response to antidepressants and antipsychotics.”

New Findings, New Results

C. Anthony Altar, chief science officer, Assurex Health

What Altar and his team discovered was a preponderance of evidence supporting the validity of measuring gene variants to predict the outcome of patients who were on psychiatric medications, or the levels of the drugs that end up in their circulation, along with the side effects they might experience in taking those drugs. It was clear to Altar and the team that those events depend upon the gene variations.

“We are convinced by the extensive published data base, as well as our own clinical studies, that sufficient evidence now exists to support using a combinatorial analysis of gene variants to help clinicians select appropriate antidepressants for individual patients,” he says. “The reason we came up with a different conclusion is because substantial data had been developed in the seven years since the EGAPP publication. Psychiatric pharmacogenomics was no longer a fledgling science – extensive clinical data now supported routine clinical use.”

Altar notes the Assurex team conducted clinical studies to obtain the data necessary to confirm the importance of selected genes in determining individual patient response to medications. “We now have three clinical studies that have reinforced the ability of our GeneSight pharmacogenomic test to improve outcomes in patients with depression when clinicians are provided results of the test,” he says. “We have clinical data that show patient symptoms improve when this genetic information is provided to their clinicians who, as a result, switch patient medications to those more concordant with their individual genetic profile.”

“In addition to clinical studies and the more extensive literature review, our test is also able to predict which patients are less likely to do well on their current medications (i.e., those patients taking medications discordant with their individual genetic profiles). When we identify a patient for whom their DNA predicts a mismatch with their genetic profile, clinicians usually end up making changes in prescribing medications that lead to better clinical outcomes.”

Combinatorial Pharmacogenomics Integrates Gene Variants

An additional factor at work here is what Altar refers to as Combinatorial Pharmacogenomics. He states no other group provides this approach to psychiatric pharmacogenomics testing. Single gene analysis does not provide the statistical significance needed to determine appropriate medications for patients taking psychiatric medications. Assurex Health takes all the gene variants, combines them for each drug, and looks at the interrelationship of the gene variants that contribute to statistically significant differences in patient responses to over 95% of the antidepressant and antipsychotic medications prescribed today.

“We have literally thousands of possible genetic outcomes for the genes we analyze that affect response to psychiatric medications,” he says. “For each of those possible outcomes, our analysis asks, “How would Prozac perform for the clinician’s patient? Or “How would Abilify work for them?” This is a powerful technique because it takes the prediction of each of the genes we analyze for the patient and puts them all together into a comprehensive analysis for each available medication. Most studies, including the ones we reviewed, just look at one gene at a time to make some kind of prediction.”

Last year Altar presented at two different conferences and showed that when using the exact same patient data, the new test could predict outcomes that the single gene technique could not.

For pharmaceutical companies and clinical research organizations (CROs), the advances made in the test now enable it to be used for patient stratification. For example, clinical studies for new antidepressants have historically included adult patients with a diagnosis of depression without regard for whether their genetic profile would allow them to tolerate the developmental drug. However, clinical study sites need to know whether a patient in the study is going to be normally, poorly, or rapidly metabolizing the new drug. GeneSight provides drug companies with the means to stratify and select those patients who would likely respond to the medication and exclude those patients who may have an aberrant genotype.

Conversely, the clinical trial can be conducted with all patients, regardless of their genetic profile, and subsequently remove patients who have aberrant genotypes to see how the results are affected. While there may be a desire to remove patients from a study if they are not responding well, another option to this is what Altar refers to as “patient retaining stratification.” In other words, if you know the genetics of the patient, it doesn’t mean you can’t include them in the study. But you might now know whether you should increase or decrease the dose for that patient and still obtain the desired effect.

“I know several pharmaceutical companies that say patient pharmacogenomic stratification is a very real goal for their CNS products,” he says. “It’s hard for me to talk to most pharma companies nowadays without having this topic come up during the course of the conversation.”

Can You Be An Industry Leader Without The Right Testing?

In conclusion, Altar believes that clinical professionals will need to consider combinatorial pharmacogenomics as a means of selecting the appropriate medication for each patient. Anyone who wants to be a clinical leader will demand to have pharmacogenomic information because it is a good predictor of what medications work for each patient. With many drugs, their action can now be selected in or out based upon a person’s genetics. Altar notes that published clinical studies of patients with major depression whose clinicians prescribe medications guided by the test are 2.3 times more likely to show an improvement in their symptoms than patients who receive the standard empiric approach to selecting medications.

“I think we’re going to keep learning more about patients and their reactions to various drugs,” he says. “This is just a matter of conducting the research in a way that relates back to the drug mechanisms of action. We are seeing more and more genetic studies at therapeutic professional meetings, including CNS, oncology, and cardiovascular.

The trend has certainly been good for Assurex Health. When Altar joined the company just over two years ago, he was employee number 25. The company now has over 175 employees. He has seen growth not just in the internal employee numbers, but in the number of patients being serviced on a daily basis. Assurex has now tested over 70,000 patients. Altar notes that “It’s really quite gratifying to wake up each day knowing you are going to help clinicians determine the appropriate drug for hundreds of patients.”