The identification of multiple genomic markers that are linked to specific mental health diseases is beginning to improve treatments and enable precision psychiatry.
HMNC Brain Health has developed both a therapeutic and a blood test companion diagnostic to identify which patients are most likely to benefit from its therapy for major depressive disorder (MDD). It also is developing this artificial intelligence-enabled precision medicine approach for other mental health disorders to better tailor treatments to improve outcomes.
Three drugs are in HMNC’s therapeutic pipeline, addressing MDD and treatment-resistant depression.
Nelivabon, the furthest along, is being studied for MDD. It addresses dysfunction in the HPA axis (the body’s stress system) by blocking hyperactive vasopressin systems in patients. Because vasopressin, a neuropeptide, manages hormonal and behavioral reactions to stress, blocking that system when it becomes hyperactive decreases the symptoms of depression. It could potentially be used to treat about 30% of the depressed patient population.
When the drug was originally developed by big pharma, there was no easy way to identify patients for whom it could be effective, so Nelivabon failed to meet the endpoints of one of two clinical trials, but showed some efficacy in the other. Subsequent genomic analyses conducted by the Max Planck Institute in Germany found a common genetic signature involving a number of single nucleotide polymorphisms (SNPs). “This signature is our genetic test,” Hans Eriksson, M.D., Ph.D., chief clinical development officer at HMNC, told BioSpace.
That experience shows a clear, unmet need for precision therapeutics in psychiatry both for patients and for drug developers. “We are planning two studies to test the companion diagnostic and to get better efficacy, and then to run the diagnostic test in an enriched population against randomized, active patients and placebo controls,” Eriksson said.
“Take depression, for example. You can have a diagnosis of MDD (the most common type of depression) and a combination of symptoms that make patients dissimilar despite having the same diagnosis. One patient may sleep a lot and gain weight, while the other may be unable to sleep and will lose weight. There are different biologies in play that may contribute to depression,” Eriksson, a psychiatrist, said. Despite those differences, interventions are prescribed the same way, by trial and error, with no good guidance for prescribing.
The identification of multiple genomic markers that are linked to specific mental health diseases is beginning to improve treatments and enable precision psychiatry.
“Genetic analyses are cheaper and easier to conduct, so scientists can analyze larger patient sample sizes than ever before, and the data can be interrogated by artificial intelligence (AI) and machine learning (ML) algorithms to an extent not possible previously,” Eriksson said. “It’s possible to look at a genetic data set – or, in principle, any characteristic of a patient, such as levels of certain proteins or neuroimaging findings – and feed information into the AI/ML system.” AI/ML then can identify commonalities – in this case, common genetic signatures among individuals with a specific condition. In mental health, that includes biological disturbances linked to depression.
HMNC’s lead compound is Ketabon, an oral, prolonged release form of ketamine for treatment-resistant depression. It was developed with Swiss-based Develco Pharma. “Ketamine is a dissociative anesthetic that’s been around since about 1970 and has had a renaissance as an antidepressant at low doses,” Eriksson said. “There’s no doubt of its efficacy, but (current formulations) come with unpleasant psychological experiences and they increase patients’ blood pressure, so they must be given under direct medical supervision.”
Administering ketamine orally appears to avoid its dissociative effects while maintaining efficacy. Additionally, he explained, “with Ketabon’s slow-release formulation, we get a gentle increase in concentration that avoids the high peaks generated by intranasal or intravenous formulations. Because our medication is oral, it is taken up by the gut and metabolized, so we get a slightly different mix of the parent compound and metabolites.
“We’re seeing good tolerability,” Eriksson continued. “Our target is to have no, or almost no, hallucinogenic side effects.”
Ketabon is in an investigator-initiated Phase II study at the University Hospital Zurich in Switzerland. A readout is expected soon. Eriksson said he expects a larger Phase II trial to start later in 2022.
HMNC’s third compound is called Cortibon. “Similar to Nelivabon, this inhibits a small peptide hormone in the brain. It is involved in the regulation of stress and affects the same system as vasopressin, but in a different way,” Eriksson said.
“Cortibon blocks the effects of corticotropin-releasing factor (CRF) – also known as corticotropin-releasing hormone (CRH). None of the CRF compounds developed historically made it to regulatory approval because they were tested in broad populations, where CRF antagonists had little efficacy,” he explained. A genetic test was developed at Max Planck Institute of Psychiatry to identify individuals who responded to the CRF antagonists. HMNC plans to test Cortibon in that population. “This is still in preclinical development.”
Looking forward, Eriksson said, “We plan to put all our efforts into conducting the necessary studies diligently and in the most expeditious way to get the data out as soon as possible, and to move Cortibon into full clinical development. We want to refine our predictive tests, which is the core of what we are doing as a company.
