The future of mental health treatment: Zelquistinel’s role

Neuropsychiatric treatment is on the verge of a major transformation. Neuropsychiatric disorders, affecting millions worldwide, disrupt the brain’s intricate processes of mood regulation, cognition and behaviour. Historically, treatment options have been limited, with patients relying on daily medications that have minimal efficacy and troublesome side effects. However, a deeper understanding of brain function – particularly the role of synaptic plasticity – is now opening the door to innovative therapies.

In this interview, Dr John Donello, a leading expert in translational neuroscience and chief scientific officer (CSO) at Gate Neurosciences, discusses the potential of groundbreaking treatments like zelquistinel and the future of this transformative field.

Advancing drug candidates across key therapeutic areas

Dr John Donello brings over 25 years of experience in pharmaceutical drug discovery, development and collaborations. He has contributed to more than 130 granted patents and advanced over 12 clinical drug candidates across various therapeutic areas, including cognition, depression, pain and other disorders. Previously, he served as VP of Science & External Innovation at Allergan, where he played a pivotal role in the global development of zelquistinel, a third-generation oral N-methyl-D-aspartate (NMDA) receptor modulator. An NMDA receptor modulator is a drug that targets the NMDA receptor in the brain, which is crucial for processes like synaptic plasticity, learning and memory. By adjusting the activity of this receptor, these drugs can influence brain functions associated with mood, cognition and pain, positioning them as potential treatments for conditions like depression, cognitive disorders and neurological diseases.

Now in Phase II development at Gate for depression and other synaptopathies, zelquistinel represents a key part of his current work. “A major focus of my work at Gate is better characterising the underlying synapse pharmacology of zelquistinel and other molecules that enhance synaptic function,” explains Donello.

Event-driven pharmacology

Donello highlights the growing recognition of synaptic plasticity’s crucial role in the biology of depression. He explains that several protein receptors, including NMDA, 5-hydroxytryptamine receptor 2 (5HT2) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), are involved in these processes and are attracting significant interest from the biotech and pharmaceutical industries. This has sparked the development of a new approach to treating neuropsychiatric disorders.

“The classic paradigm with today’s psychiatry drugs involves patients chronically taking a daily medication,” says Donello. This is based on the traditional model of ‘occupancy-driven pharmacology’, where a drug’s therapeutic effects are directly related to the time it occupies its target. The drug’s pharmacokinetics (PK) and pharmacodynamics (PD) are closely linked. This means that how the drug moves through the body (PK) is directly related to its effects on the body (PD).

However, the emergence of plasticity-enhancing drugs necessitates a re-evaluation of how we maximise drug efficacy. “A single dose of a plasticity-enhancing drug can trigger a cascade of long-lasting effects on synapse structure, function and protein composition that can be sustained beyond one week,” Donello explains. This means the PD effects of synapse-targeted drugs can significantly outlast their PK. “We call this phenomenon ‘event-driven pharmacology’.” This distinction is crucial for dosing strategies. “We have found that it’s critical to characterise dosing dynamics (dose level and dose interval) that can maintain therapeutic effects with repeated sub-chronic dosing,” says Donello. He cites the example of once-weekly ketamine dosing, which has proven sufficient for maintaining antidepressant effects and strengthening synapses over time.

This concept is crucial in early drug discovery because it challenges traditional methods of drug development, where the focus is often on the PK. In contrast, the idea of event-driven pharmacology suggests that the lasting effects of a drug, particularly those enhancing synaptic plasticity, can persist long after the drug is metabolised. This shifts the focus to understanding the long-term impact of a single dose on brain function, potentially allowing for more efficient treatments with fewer doses. It activates new possibilities for developing drugs that can produce enduring therapeutic effects, reducing the need for continuous dosing while improving efficacy in the treatment of disorders like depression, cognition-related diseases and neurological conditions.

The impact of dosing frequency on synaptic plasticity

Donello explores the fundamental biology of synaptic plasticity, which involves processes of long-term potentiation (LTP) and long-term depression (LTD). “Drugs that enhance synaptic plasticity should be dosed just enough to maintain LTP and the strengthening of synapses, without causing compensatory LTD,” he advises.

He stresses that each drug type and synaptic target strengthens synapses differently, making it essential to characterise the impact of each drug based on dose and frequency. The ultimate goal, he says, is “to achieve a dosing regimen that maximises and maintains enhanced synaptic LTP, while minimising compensatory changes such as LTD.”

Zelquistinel’s unique mechanism of action

Zelquistinel’s mechanism of action sets it apart from other neuropsychiatric treatments. “Zelquistinel is a positive modulator of NMDA receptors,” Donello explains. “Essentially, it activates the NMDA receptor to drive the enhancement of synaptic plasticity, structure and function in the brain, which is impaired in many neuropsychiatric and cognitive disorders.” He highlights the rapid antidepressant effects observed with drugs targeting NMDA receptors, often within days of a single dose. This contrasts sharply with standard antidepressants like Prozac or Zoloft, which work on neurotransmitter levels and can take six to eight weeks to produce a therapeutic response, often accompanied by challenging side effects.

Gate’s zelquistinel uniquely targets NMDA receptors, aiming to minimise severe side effects while maintaining strong antidepressant effects. Clinical studies so far have demonstrated zelquistinel’s safety and good tolerability, which is a significant benefit in psychiatry. Donello also believes that zelquistinel’s mechanism of action holds promise for treatment beyond that of depression, with potential to address the underlying biology of other brain disorders, including schizophrenia, Alzheimer’s disease, anxiety disorders and autism.

Hopes for the Phase IIb trial

Donello discusses the key outcomes he hopes to see in the Phase IIb VITALIZE study of zelquistinel for major depressive disorder (MDD). “For the VITALIZE Phase II study, we hope to better understand the safety and tolerability profile of zelquistinel and demonstrate a clinically meaningful improvement in depression symptoms versus placebo after six weeks of once-weekly dosing,” he states.

This is crucial in early-stage drug discovery because the VITALIZE Phase IIb study plays a key role in evaluating the safety, tolerability and efficacy of zelquistinel for MDD. Gaining insights into these factors early helps determine if the drug is suitable for further development. By focusing on outcomes like meaningful improvements in depression symptoms with once-weekly dosing, the study aims to validate the promising results seen in earlier Phase IIa trials.

The future of antidepressant treatment

Donello envisions a brighter future for those living with depression. “We envision a future in which patients can be free from the daily struggle of depression and no longer have to constantly manage medications with challenging side effects.”

We envision a future in which patients can be free from the daily struggle of depression and no longer have to constantly manage medications with challenging side effects.

He expresses hope for a future where patients can access a new type of treatment offering rapid and enduring symptom relief with limited side effects. “This can be a truly liberating way of life for people with depression,” he concludes.