Circular Genomics has created the first ever circular RNA-based test to predict a patient’s response to selective serotonin-reuptake inhibitor antidepressant treatment.
- Circular Genomics
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Depression is a debilitating disorder. Globally, around 350 million patients worldwide live with depression, and this could increase to 400 million by 2029. The current standard-of-care is a trial-and-error approach, and as many as 60% of patients fail their first-line treatment with selective serotonin-reuptake inhibitors (SSRIs). The cycle of treat, wait and then treat with a different medication can mean that for some patients it takes over a year to find the right approach. Up to a third of patients have treatment-resistant depression and may have failed as many as four drugs, according to Paul Sargeant, president and CEO of Circular Genomics.
“Antidepressants can be highly effective in a subset of patients, but healthcare professionals and patients can struggle to find the right treatment,” said Sargeant.
Circular Genomics’ goal is to make fundamental improvements to the standard of care in depression and support physicians in choosing the most effective treatments more rapidly. The company launched its first product, MindLight, in September 2024. MindLight uses the company’s circular-RNA (circRNA) platform to predict the patients who are more likely to respond to the SSRI class of anti-depressants (Fig. 1).
Fig. 1 | Responses with and without MindLight. Clinical trial data showing the proportion of major depressive disorder patients achieving clinical response with or without circular RNA testing by MindLight. SSRI, selective serotonin-reuptake inhibitor.
“Our data-driven approach will help healthcare professionals select the right treatment for the right patient. By taking the guesswork out, it has potential to redefine the standard of care,” said Nikolaos Mellios, CSO and co-founder of Circular Genomics. “We are backed by a highly experienced team and a scientific advisory board of topline researchers and clinicians in psychiatric and neurological disorders.”
circRNA as a brain biomarker
Biomarkers play a vital role in precision medicine and have led to a major step-change in cancer care, but until now there hasn’t been a direct response biomarker for depression, according to Mellios.
When carrying out research at the University of New Mexico, Mellios observed higher levels of a specific circRNA in SSRI non-responders compared with those who did respond. As robust and dynamic molecules that are enriched in the brain, resistant to degradation and able to cross the blood–brain barrier (BBB) into the peripheral blood, circRNAs can be detected with a polymerase chain reaction (PCR) blood test, making them excellent biomarker candidates. Seeing the possibility that circRNA could bring precision prescribing to depression, Mellios and co-founders Kosmas Karadimitriou (advising CIO) and Alexander Hafez launched Circular Genomics in February 2021 and began the development of MindLight.
In MindLight clinical trials, 77% of the patients who were classified as having a high likelihood of responding reacted well to SSRI treatment. Results are available in three to five days, allowing physicians to make a quick treatment decision. Circular Genomics is seeking partners for MindLight outside of the US.
Stepping into a precision future
Circular Genomics is developing next-generation versions of MindLight: a multianalyte version with enhanced sensitivity; and a version tailored for adolescents with depression, a subgroup particularly affected by high rates. These will be followed by a multiclass antidepressant-response test that could simultaneously predict responses to SSRIs, selective noradrenaline-reuptake inhibitors (SNRIs) and atypical antidepressants. Patients who show low likelihood of response to all three classes can be defined as having treatment-resistant depression.
“It can take one or two years and failure of at least two classes of drugs to get to the diagnosis of treatment-resistant depression needed to access alternative approaches to treatment such as transcranial magnetic stimulation or ketamine. Our multiclass test, which we plan to make available in 2026, could reduce this to just a single test,” said Mellios.
Existing approaches to drug selection in depression include DNA-based pharmacogenomic (PGx) tests that focus on the genetic variations that affect how individuals metabolize drugs. These could advise on dosage and potential drug interactions, but do not directly predict response to treatment. The US Food and Drug Administration (FDA) has issued warnings that PGx assays lack clinical efficacy/utility for predicting response to antidepressant treatment, echoed by a systematic review of PGx-based clinical studies by the American Psychiatric Association. Because circRNA is a dynamic biomarker that reflects changes in status, circRNA-based tests could have potential to monitor treatment as well as predict response.
“MindLight determines the brain’s response to SSRIs, and the PGx tests assess the body’s ability to metabolize drugs. Because circRNA and PGx tests provide different perspectives, they could work together to provide a fuller picture for choosing the right antidepressant treatment,” said Sargeant.
A variety of circRNAs have been linked to psychiatric and neurodegenerative disorders, and Circular Genomics has a pipeline of tests in development. These include a differential diagnostic for depression/bipolar disorder, and disease-risk/diagnosis-response tests for Alzheimer’s disease and Parkinson’s disease. Its ongoing academic clinical study collaborations suggest that circRNAs can be robust biomarkers for predicting risk of developing Alzheimer’s disease in pre-symptomatic older individuals, significantly outperforming all existing protein-based biomarker assays. These could be developed in collaboration with biopharma companies that have a relevant therapeutics pipeline.
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