Investigational Drug Could Provide At-Home Treatment-Resistant Depression Care
Dual NMDA modulation could provide an oral, at-home therapeutic option for treatment-resistant depression.
Treatment-resistant depression (TRD) is defined by non-response to at least two antidepressant treatments.
Persistent gaps in the management of TRD continue to challenge patients living with the condition and the clinicians treating them. While rapid‑acting TRD therapies have improved onset of action for individuals who have not responded to first- and second-line antidepressants, they also introduce trade-offs in tolerability and monitoring burden, which can be a barrier to uptake. Researchers are increasingly investigating treatment options that move beyond the scope of traditional antidepressants, which primarily act by increasing the availability of specific neurotransmitters, such as serotonin, to promote beneficial neural adaptations.
As a trained psychiatrist with over 25 years of experience in drug development, Dr. Hans Eriksson, chief medical officer of Fundamental Pharma, is well-positioned to draw on both clinical and industry perspectives in TRD. Technology Networks spoke with Eriksson to explore the practical challenges of developing drugs for TRD, and how dual‑acting N-methyl-D-aspartate (NMDA) receptor modulation may help address current treatment gaps.
How has your experience across late-stage depression programs shaped your approach to developing therapies for TRD?
Hans Eriksson, MD, PhD (HE):
We understand the operational challenges in developing therapies for TRD. Since TRD is defined by a failure to respond to two antidepressant treatments during the current depressive episode, the approach has generally been to add new therapies alongside existing ones. We believe that this is the most pragmatic design.
Several of the compounds in development for TRD have a rapid onset of action, and it is key to use a trial design that captures early improvement. It is also important to recognize the fact that TRD is not a diagnosis, but a classification of patients diagnosed with major depressive disorder (MDD). Therefore, many of the building blocks of MDD programs can also be used for TRD, like outcome measures and safety approaches.
IH:
What are the challenges in developing treatments for TRD?
HE:
Most compounds in development or approved for TRD have the advantage of an early onset of action, but in many cases, they also have significant immediate tolerability issues that make medical oversight during and after administration necessary (e.g., intranasal esketamine and psilocybin).
Demonstration of the durability of effect is typically required by regulators and payers for rapid-acting treatments for TRD. For compounds that are dosed more regularly, e.g., daily like conventional antidepressants, this is often less of an issue, but for treatments that are based on a few doses or less frequent administrations, a strategy has to be in place for how to best demonstrate efficacy over time.
Finally, since TRD is defined by non-response to antidepressants, it may be less likely that a compound developed for TRD that has a similar mechanism of action as the drugs the patients failed on will become successful. Therefore, sponsors generally need to explore alternative mechanisms in TRD programs.
IH:
How does FMP374’s dual-acting NMDA receptor modulation work, and how does this inform its potential clinical profile?
HE:
Dual-acting NMDA receptor modulation refers to the molecule’s unique ability to disrupt a complex formed by the NMDA receptor and the sodium channel termed TRPM4, while acting as a conventional antagonist of the NMDA receptor channel.
NMDA receptor antagonists, TRPM4, and depression
NMDA receptors in the brain are essential for learning, memory formation, and neural plasticity. But excessive activation can trigger harmful signaling pathways, in part mediated by a complex formed by the association of NMDA receptors with TRPM4. Sustained, excessive NMDA receptor excitation has been identified as a key pathological mechanism in depression.
Classical NMDA receptor antagonists worked by broadly blocking receptor activity and required a high degree of NMDA receptor channel blockade for efficacy. While this could produce antidepressant effects, it also disrupted essential brain signaling, leading to adverse events such as dissociation and sedation.
FMP374 prevents the binding of NMDA receptors to TRPM4 while acting as a blocker of NMDA receptor activity. Due to its dual-acting properties, the level of NMDA receptor blockade required for antidepressant efficacy is lower than that of classical NMDA receptor antagonists. Therefore, FMP374 could retain more of the receptor's physiological function at the synapse and potentially avoid adverse effects, including dissociation.
Hence, our molecules constitute a novel pharmacological class with a mechanism that is highly differentiated from prototypical NMDA receptor blockers, including esketamine.
The two distinct pharmacological effects appear to be at least additive, if not even synergistic, in depression models. This substantially reduces the channel block that is causing the unwanted pharmacology seen in standard NMDA blockers.
FMP374 has demonstrated rapid and sustained antidepressant effects in gold-standard depression models at low nanomolar unbound central nervous system (CNS) drug concentrations, with exceptional ≥10–20x pharmacological margins over side effects associated with NMDA receptor inhibition*.
"Most importantly, FMP374 has shown no evidence of dissociation‑like or sedation-associated behaviours in preclinical studies at efficacious exposures. Therefore, it is predicted to be non-dissociative/non-sedative in humans and is being developed as an oral at-home treatment for TRD." — Dr. Hans Eriksson.
IH:
How might these preclinical observations translate into first-in-human studies, and what uncertainties remain?
HE:
The preclinical data for Spravato® (esketamine), the current pharmacological standard of care for TRD, were highly informative of the effects seen in the studies in humans.
In preclinical models, the efficacious exposure of esketamine (or the racemic mixture ketamine) overlapped with the exposure that caused side effects, such as dissociation. A similar pattern has been observed in TRD patients. Accordingly, extensive monitoring is a must.
In contrast, our preclinical data demonstrate a robust dose and concentration separation between established indicators of antidepressant efficacy and signals of adverse effects*. We intend to carefully monitor for any signals of dissociation/sedation in our clinical program, but based on our preclinical work, we do not expect to see this around the target concentrations for clinical efficacy.
"Based on the pharmacokinetic properties of FMP374 we also expect that the CNS drug concentrations predicted to be efficacious in patients to be achievable via oral dosing." — Dr. Hans Eriksson.
Overall, the key advantage of the FMP374 clinical program is that the company will gain a general understanding of the propensity for tolerability issues that have impacted the adoption and extensive monitoring requirements of eketamine already in healthy volunteers.
IH:
What unmet needs remain in TRD, and what timelines are realistic for addressing these gaps?
HE:
Even drugs that have shown efficacy in TRD do not help all patients, so there is a remaining efficacy need. If different classes of antidepressants with novel mechanisms of action are being developed for TRD, it is possible that this gap can be diminished, based on the hypothesis that there are several biological disturbances that contribute to depression. The more tools that become available to overcome these disturbances, the better the overall outcome.
We should not underestimate the profound side effects of several compounds under development, like dissociative or psychedelic experiences. Though possibly beneficial for the treatment outcome, especially for psychedelic experiences, they are perceived as unpleasant by many patients, and require costly and complex oversight programs. This would compromise scalability and impact the availability of these treatments.
"Given the number of TRD programs approaching late-phase development, it is likely that there will be tangible impact on how depression is treated within the next 10 years." — Dr. Hans Eriksson.
However, the uptake of novel treatment modalities has historically been relatively slow in psychiatry, and the important factors of treatment convenience and access should not be neglected. If a novel, efficacious treatment for TRD with a safety profile that would permit at-home use were approved, the change in the practice of psychiatric medicine may come faster.
*This article is based on research findings that are yet to be peer-reviewed. Results are therefore regarded as preliminary and should be interpreted as such. Find out about the role of the peer review process in research here. For further information, please contact the cited source.
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