Precision psychiatry: transforming therapeutics for CNS disorders

Neurons in the brain

Mike McCully, CEO of Gate Neurosciences, speaks to DDW’s Diana Spencer about the company’s pipeline of next-generation antidepressants and why this could be the most exciting time in the history of psychiatry.

DS: How has our understanding of the brain developed in the last 70 years? 

MM: Although our understanding of the brain is still very limited, we believe that this is the most exciting scientific time in the history of psychiatry. There is a growing appreciation and understanding around the ‘hallmark’ disease biology behind many neuropsychiatric disorders. The key factors underlying these diseases are higher-order levels of dysfunction of synaptic connections in the brain and the neural circuits involved in regulating cognition and mood. This is quite a difference from the simplified ‘chemical imbalance’ story that’s been told for many decades. 

A majority of the past 70 years has been dominated by antidepressant therapies which alter neurotransmitters implicated in depression, but not the core disease pathophysiology. These therapies take weeks to see an effect, only work in 30-40% of patients, and have many prohibitive side effects. Only in the past 10-15 years have we made strides with newer therapeutic approaches that focus on key neural pathways that enhance synaptic plasticity, or the ability of neural connections in the brain to grow, change, and adapt. This shift was largely driven by the discovery at Yale Psychiatry that ketamine, an NMDA receptor antagonist, achieves rapid (within 24 hours) and long-lasting (one to two weeks) antidepressant effects after a single dose through mechanisms of enhancing synaptic plasticity. 

Now, many next-generation CNS companies are developing therapeutics that focus on pathways similar to ketamine to enhance synaptic plasticity and restore higher-order levels of brain function and signaling. These approaches are particularly exciting because patients are consistently seeing rapid and long-lasting responses after a single dose and offer better potential for achieving remission. In the case of Gate Neurosciences, we are focused on novel mechanisms that rapidly, durably – and in contrast to ketamine – safely restore healthy neuronal signaling to treat mood and cognitive disorders.

DS: Why do you feel current antidepressants are not fully adequate therapies? 

MM: Currently, it is estimated that 30% of patients with major depressive disorder (MDD) do not respond to standard of care antidepressants, such as SSRIs and SNRIs. In the cases where treatment is effective, it may take weeks, or even months, before there is a noticeable effect. The combination of ineffective treatments and delay of effectiveness makes it really challenging to identify a treatment path right for patients, many of whom have to cycle through multiple treatments before they find something that works for them. Additionally, many treatments have seriously prohibitive side effects, like weight gain and sexual dysfunction, that discourage continuation. 

While emerging rapid-acting antidepressant drugs, such as ketamine, represent much-needed improvements over SSRIs and SNRIs, they have the potential to be abused, and their dissociative effects (out-of-body experiences) limit their accessibility because patients must be supervised in a clinic during administration.

DS: Why is major depressive disorder so challenging to treat? 

MM: The CNS is a very complex part of the body, and though we have made much progress in understanding it, there is still much to be learned. This complexity is partly why the standard of care for these diseases is very poor. It is also why the CNS is often seen as risky for drug developers. Multiple confounding factors such as complicated clinical study designs, outsized placebo responses, heterogeneous patient populations, or limited translational data supporting dose levels and intervals can capsize the prospects of the most promising therapeutics.

In the planned clinical trials for our two next-generation antidepressants (Zelquistinel and Apimostinel), Gate will be using insights from over 2000 patients dosed with our class of molecules to apply translational data and evidence-driven approaches to trial design to optimise our drug-to-placebo signal. Based on our team’s past experience, and on the large data packages the company had acquired, we are able to stratify patients and enact other patient enrichment strategies to pinpoint the exact subpopulation who would respond well to the therapy. We know from our experience that certain study designs do not effectively control for the placebo effect – which is why for our upcoming trials, we are opting for a simple 1:1 randomisation between the therapeutic and placebo arms in a standard parallel six-week study design, while also minimising clinician-patient interactions to prevent any bias from confounding the results.

DS: What does Gate Neurosciences hope to achieve? 

MM: CNS patients have been underserved for far too long. And especially after the Covid-19 pandemic, the need for better mental health treatments has never been greater. Our end-goal is to transform the treatment landscape in neuropsychiatry by offering effective, rapid-acting, and long-lasting treatments that can be safely taken at home, or administered in a physician office. Our path to get there involves taking the challenges of psychiatry drug development head-on, by leveraging insights from thousands of patients with our molecules and applying ‘precision medicine’ approaches to advance them towards approval. 

DS: What does Gate’s pipeline of drugs offer to patients over existing therapies? 

MM: Our goal is to advance a pipeline of therapies that address underlying disease biology by enhancing synaptic plasticity and restoring healthy neuronal signaling. And we’ve found that our therapeutic candidates can do this more directly, quickly, and safely than the current standard of care. 

For our MDD candidates – Zelquistinel, our lead candidate, and Apimostinel – the goal is to enhance synaptic plasticity through positive modulation of the NMDA receptor (NMDAR) on the glutamatergic interneurons. We have found that this is a more direct mechanism to enhance synaptic plasticity and elicit rapid antidepressant effects compared with NMDAR antagonists (such as ketamine) which act on this system more indirectly and cause dissociative side effects, abuse liability, and many other safety and logistical concerns. We believe that our drug class offers a safer, more tolerable means to elicit antidepressant activity, and has applications in other areas besides MDD, such as anxiety disorders, schizophrenia, and cognitive disorders.

DS: What role can patients/clinicians have in the discovery of new therapies and the design of clinical trials?

MM: Incorporating a patient-centric approach has been widely discussed as a method for improving clinical trials. This is especially true for CNS disorders. 

Gate is currently working on two key trials – a Phase Ib confirmatory study for Apimostinel, which is starting this quarter, and a Phase IIb study for Zelquistinel. Gate has designed both trials in a way that selects for patients most likely to respond to treatment, minimises false efficacy signals from the placebo effect, and encourages patients to adhere to the protocol and stay in the trial by making the protocol easy to follow. Throughout this process, we will be working with the clinicians, at the trial sites, and patients to ensure that for the eventual pivotal trials, the protocol will be designed to maximise patient engagement.

DS: What would you say are currently the greatest unmet therapeutic needs of people living with psychiatric disorders? 

MM: There are two significant needs that we can identify: (1) viable biomarkers for patient selection and monitoring response, and (2) safe and effective medications that are tailored to patients’ specific manifestation of a disorder and any comorbidities.

Many of the issues we see in mental health therapeutics – low efficacy, poor safety profiles, etc. – can be traced back to the need for better informed treatment decisions. For example, antidepressants, such as SSRIs, are largely prescribed to all patients, oftentimes regardless of any other factors. Because of this, we see that current antidepressants are ineffective for 60-70% of patients.

Clinically relevant biomarkers could improve how well we identify who is likely to respond to therapy, and, therefore, improve its effectiveness.

This is the primary reason why Gate is focusing its efforts on precision psychiatry, which has the potential to improve the outcomes of patients with a psychiatric disorder, just as precision medicine and patient stratification have greatly improved treatment options in oncology. For our lead molecule, Zelquistinel, we found that patients presenting with anxiety and depression responded better to the drug. And so, we are focusing on this particular group in our upcoming clinical trial. 

DS: Where do you think the breakthroughs in the treatment of psychiatric disorders will come in the next five to ten years? 

MM: Treating CNS disorders has always been challenging. We understand some of the physiology, genetics and biochemistry – but not enough to have a big-picture view of how these intricate processes and chemicals interact together, and where the machinery is breaking down. Understanding and demystifying the CNS in general will be at the core of the biggest therapeutic breakthroughs.

With the momentum of new therapeutic options and precision techniques developed by biopharma, startups, and academia, we could very well see the standard of care for many disorders, including depression, improve over the next decade. At Gate, our hope is that our therapies successfully clear clinical trials and regulatory approval and become one of many options for treatment available to patients.


Mike McCullyMike McCully is the President and CEO of Gate Neurosciences. An experienced biopharma executive, investor, and entrepreneur, Mike has spent the past 20 years contributing to the development of dozens of successful biotech companies. During his time at Recombinant Capital and Deloitte, Mike held operating roles at several emerging and established biopharma companies, notably serving as Head of Business Development, BioNeurology at Elan Pharmaceuticals, Head of Financial Strategy at Coherus Biosciences (CHRS), and Chief Business Officer of the pain-focused specialty pharma Charleston Laboratories. Most recently, Mike was the Chief Executive Officer of Anagin, Inc.

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