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Circular Genomics Readying to Launch Zoloft Response Diagnostic Based on Circular RNA Biomarker


NEW YORK – Molecular diagnostics startup Circular Genomics has identified a new biomarker that can predict which patients are likely to respond to Pfizer's antidepressant Zoloft (sertraline).

The biomarker, which researchers will disclose in a forthcoming scientific publication, is a brain-enriched circular RNA (circRNA) that differentiated responders from non-responders and correlated with long-term recovery from depression in the recently completed Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, sponsored by the University of Texas Southwestern Medical Center.

Circular Genomics, a University of New Mexico spinout, also conducted its own animal study to delve into the mechanisms that induce this same circRNA in neural tissue through the activation of well-known molecular pathways specifically linked to antidepressant response in the brain.

"We identified a robust blood circRNA biomarker associated with response and remission to [Zoloft] that in the brain can be activated by well-established molecular pathways of antidepressant response," said Circular Genomics Cofounder and CSO Nikolaos Mellios.

The Albuquerque-based company is currently preparing a manuscript to describe their EMBARC findings in greater detail and has begun collaborating with institutions in France to study biomarkers of response to depression therapies in the Biomarkers of ANTidepressant RESponse and Development Risk of Bipolar Disorder (ANTaRES) study.

Circular Genomics' goal is to identify and commercialize biomarkers predictive of therapy response to help streamline the treatment of psychiatric illnesses, which Mellios, who is also an associate professor of neuroscience at the University of New Mexico School Medicine and a medical doctor by training, says currently relies disproportionately on trial and error.

Mellios explained that prescriptions are often based heavily on whether patients are likely to experience side effects. "It's pretty much [decided] out of caution," he said.

Furthermore, existing pharmacogenetic assays largely focus on an individual's ability to metabolize a given drug. This is still very useful information, Mellios explained, as someone unlikely to be able to metabolize a drug will also not respond to it. The converse, however — that a good drug metabolizer is more likely to respond to that medication — does not always hold true.

"I can metabolize the drug properly, but that doesn't mean it will fix the mechanism in a pathway that [underlies] my depression," he said.

The double-blind and placebo-controlled EMBARC study evaluated changes in measures of depression among nearly 300 participants between 18 and 65 years old with recurrent major depressive disorder. Participants were given either Zoloft or a placebo and monitored over an eight-week period. Those who responded well to Zoloft remained on it, while non-responders were switched to bupropion, often sold under the brand name Wellbutrin, from Bausch Health Companies for another eight weeks. Similarly, participants who showed improvements while on placebo remained on the placebo, while non-responders from that group were switched to Zoloft.

The study found a subset of patients "optimally suited" for Zoloft treatment, who could be identified by the pre-treatment variables of higher depression severity and neuroticism, older age, greater cognitive control, and being employed. The study noted, however, that this model remains to be tested prospectively and that nonclinical factors such as molecular biomarkers are likely to improve predictions.

Although Circular Genomics also analyzed changes in circRNA related to Wellbutrin, Mellios said that "these findings were specific to [Zoloft] since no associations were found between this circRNA and response to placebo or [Wellbutrin] treatment."

While Mellios described Circular Genomics' findings from EMBARC as a "significant milestone," he noted that they require further validation to increase the company's confidence in the results, which is where the ANTaRES study comes into play.

This study is largely similar to EMBARC, but researchers are assessing patients' responses to four antidepressants — Zoloft, Prozac (fluoxetine) or Cymbalta (duloxetine), both from Eli Lilly, and Novartis' Ludiomil (maprotiline) — and tracking behavioral outcomes.

The study is being performed by a consortium consisting of the Centre National de la Recherche Cientifique (CNRS), France's national scientific research institute, and several hospitals throughout France; Circular Genomics is currently the only commercial partner involved in this project.

According to Eleni Tzavara, a senior scientist at France's National Institute for Health and Medical Research (INSERM) and the coordinator of the ANTaRES study, the researchers aim to recruit up to 250 people. The study comprises a clinical portion focused on detecting early biomarkers of response and an animal model portion, which will provide researchers insight into the mechanisms driving resistance and response.

"Initially, the study focused on coding RNA," Tzavara said. "But our hypothesis is that a combination of biomarkers may be more pertinent."

To that end, her team has expanded their search to biomarkers of inflammation and engaged Circular Genomics to analyze circRNA, a type of noncoding RNA.

Participants enter the study unmedicated (although having taken past medication does not disqualify them) and in a state of depression. After taking baseline measurements, patients will receive one of the four antidepressants with or without a class of anti-depression drugs called benzodiazepine for eight weeks, during which time researchers will take regular blood draws. At the end of that eight-week period, a physician will classify each participant as a responder or non-responder based on a clinical evaluation.

"We take blood measurements three days after [beginning] antidepressants, then at two weeks, and then at two months," Tzavara said.

Biomarkers for inflammation were included in the study because, Tzavara said, studies have shown connections between inflammation, depression, and drug response. "It has been shown," she said, "that low-grade inflammation could be a factor of resistance to treatment, but no clear biomarkers have been developed." 

Although the study is in early stages, Tzavara expects to be able to present interim data related to circular RNAs near the end of this year or in the first quarter of next year.

And while Circular Genomics is currently the consortium's only commercial partner, Tzavara said that the possibility of adding more "down the road" shouldn't be excluded.

One key data point that Circular Genomics will look for in the ANTaRES study is whether the identified biomarkers are specific to predicting response to Zoloft or can inform treatment with the broader class of selective serotonin reuptake inhibitors.

The company is hoping to launch a diagnostic product based on the Zoloft biomarker research next year, initially marketing it to concierge care and primary practices while the firm works on acquiring payor adoption for reimbursement. "But we're going to use the results from the ANTaRES study to expand our product options," Mellios said.