Psychedelics sans side effects: neuroplastogens gain ground

Neuroplastogens are substances that boost neuroplasticity and have the potential to treat conditions that affect the nervous system. The past year has seen plenty of developments occurring in the field, with the most recent being Elkedonia’s funding to design neuroplastogens that can address depression and other neuropsychiatric disorders.

Elkedonia secures €11 million to boost neuroplastogen program

Elkedonia raised €11 million ($12.68 million) in a seed funding round to propel the development of its neuroplastogen program this year. Although it officially launched this month, researchers at the French biotech have been immersed in the field for quite some time, two and a half decades to be exact. 

Back in 2000, the biotech’s co-founder Jocelyne Caboche uncovered the role of the protein ELK-1 in memory and its implication in neurodegenerative diseases like Alzheimer’s, which affects around 24 million people worldwide. Since then, the team has been busy trying to come up with a way to block the protein in key brain circuits and target neuroplasticity, which is essentially the brain’s ability to form new neural connections. The solution: neuroplastogens.

“Academic research, upon which Elkedonia was founded, suggests that Elk1 inhibition is a therapeutic lever in depression, with rapid efficacy, and devoid of sedation, dependence, hallucinations, or other side effects commonly associated with existing antidepressant treatments,” said Caboche.

Those substances that induce hallucinations when treating neurodegenerative and mood disorders, psychedelics, belong to a class of drugs called psychoplastogens. They stimulate neuroplasticity and put people through mental states, such as dissociation or hallucinations via their effects on certain receptors at the synapse – the junction between two nerve cells – explained Caboche.

Non-hallucinogenic psychedelics: a reality

The use of psychedelics is shrouded in taboo. They have come under fire as experts have said these drugs have a higher risk of triggering a psychotic or manic episode in people who have a personal or family history of schizophrenia or bipolar disorder. For treating neurodegenerative disorders and conditions like depression and post-traumatic stress disorder (PTSD), psychedelics like psilocybin and MDMA (3,4-Methylenedioxymethamphetamine) have been trialed. 

However, due to their hallucinogenic effect, they have been dismissed by regulators. Last year, after a long-awaited call for the approval of MDMA to treat PTSD, the U.S. Food and Drug Administration (FDA) dropped the idea, citing a need for further safety and efficacy data.

Neuroplastogens, on the other hand, are essentially non-hallucinogenic psychoplastogens. This means that they do not come with unpredictable side effects. According to Caboche, they are a novel class of therapeutic agents that “promote rapid and long-lasting neuroplastic benefits without inducing subjective states.”

This move towards neuroplastogens to address brain and mood disorders is a reaction to uncertainty around the stability and potential approval of psychedelics. Elkedonia’s main focus is on treating depression with the help of non-addictive, non-hallucinogenic molecules at the moment. 

“Profound modifications of neuronal properties and circuits occur in neuropsychiatric disorders, and in major depressive disorders in particular. These include alteration of synaptic neurotransmission and morphology, which are called synaptic plasticity. Neuroplastogens restore this plasticity,” said Caboche.

Preclinical and clinical studies have found that the small molecules that are being developed at Elkedonia to act against Elk-1 have been pivotal in rewiring the brain when treating depression.

Delphine Charvin, co-founder and chief executive officer (CEO) of Elkedonia, said: “Elkedonia’s neuroplastogen program is completely novel as we believe it addresses the basic molecular process at the origin of neuroplasticity, specifically, regulation of the transcription factor Elk-1 within neuronal cells.”

Neuroplastogen spin out Transneural Therapeutics to treat depression and PTSD

The past year has seen growing interest in neuroplastogens. Emerging from stealth in April, Transneural Therapeutics was spun out of psychedelic drug developer CaaMTech with the sole purpose of designing neuroplastogens. At the helm of its launch is CEO Charmaine Lykins’ decades of research in neuropsychiatry. 

With its lead candidate in the Investigational New Drug (IND)-enabling stage, the Washington-based startup hopes to head to the clinic to treat depression and PTSD soon. As about 30% to 50% of people with depression inadequately respond to available treatments and 33% of those with PTSD are treatment resistant, there is a need for new therapies, explained Lykins. 

“There remains a high level of unmet need for patients suffering from depression and PTSD,” said Lykins in a press release. “Treatment options for these patients are burdened with safety issues and intolerable side effects. We have pulled together a team of scientific and strategic experts in neuropsychiatry to take on the challenge of transforming outcomes for patients and families. I am encouraged by the potential of our lead asset, TN-001, and look forward to wrapping up our preclinical efforts and progressing into clinical trials.”

The candidate for major depressive disorder, TN-001, is a dual 5-HT2A partial agonist and 5-HT2B antagonist that engages with the serotonergic receptor – a protein receptor that binds to the neurotransmitter serotonin. The company says that it has been tailored to “deliver rapid and enduring antidepressant efficacy rivaling psychedelic treatment, but without hallucinations or dissociative effects.”

Enveric and Delix devote pipelines to the neuroplastogen field

Like TN-001, Enveric Biosciences’ EB-003 also targets the serotonergic receptors to induce neuroplasticity, and is in the IND-enabling phase. Moreover, the Florida-based biotech, which took part in the BIO International Convention last week, was recently issued a ‘Notice of Allowance’ for its new class of neuroplastogens called aminated tryptamine derivatives by the United States Patent and Trademark Office (USPTO). 

This marks the approval of its patent application for these drugs that represent an alternative approach to non-hallucinogenic psychedelic-inspired therapeutics. Preclinically, they demonstrated low hallucinogenic effects, including minimal head twitch response (HTR) and reduced 5-HT2A receptor activation – both of which are established measures of hallucinogenic activity in rodents.

“The allowance of this application adds a new tier of patent-protected innovation to our pipeline of non-hallucinogenic neuroplastogens,” said Joseph Tucker, CEO of Enveric, in a press release. “Unlike traditional psychedelics that require intensive clinical monitoring due to their hallucinogenic effects, our molecules are designed for frequent, flexible, outpatient dosing, which we expect will be better aligned with patient lifestyles, clinics workflows, and payers established models.”

Meanwhile, in the clinic, Massachusetts-based Delix Therapeutics’ DLX-001 is being assessed to treat depression. In the ongoing phase 1 study, DLX-001 demonstrated a favorable safety and tolerability profile, where the therapeutic candidate showed robust signs of central nervous system (CNS) engagement. Preclinical data demonstrated that DLX-001 increased dendritic spine density in the neurons in the prefrontal cortex, the region located at the front of the frontal lobe of the brain – an important sign of neuroplasticity. 

Neuroplastogens are not conventional treatments, says Anavex CEO

Similarly, Anavex has been developing its small molecule blarcamesine to treat Alzheimer’s disease. Although not a traditional neuroplastogen, blarcamesine works by targeting and activating sigma-1 and muscarinic receptors to boost neuroplasticity. Anavex’s CEO Christopher U. Missling explained that this kind of therapy could play a significant role in stalling neurodegeneration.

“Neuroplastogens differ from conventional symptomatic treatments because they work to restore neuronal plasticity while boosting autophagy and maintaining cellular homeostasis, which is essential for neurodegenerative diseases including Alzheimer’s and Parkinson’s,” said Missling. 

In a phase 2b/3 trial, early and late start treatment groups were compared. Those who were on blarcamesine earlier in their disease progression had better cognitive function compared to those who did not receive the treatment until a year after. 

As the Alzheimer’s therapeutics market is expected to boom, an analyst predicted that blarcamesine, along with other Alzheimer’s drugs in the clinic, are set to give Leqembi a run for its money in the coming years, according to a report in Fierce Biotech.

Another Massachusetts-based biotech has designed a neuroplastogen as part of its neuro-drug pipeline. Seaport Therapeutics set sail after the leadership from Karuna – acquired by Bristol Myers Squibb last year – took it upon themselves to develop antidepressants and other medicines to treat mental health disorders. Buoyed by years of research and expertise, Seaport’s SPT-348 is in early preclinical stages to take on mood and neuropsychiatric disorders.

New partnerships forged; AbbVie wants in 

While the field of neuroplastogens is still in its infancy, the challenge is to actually identify the best-suited target to enhance plasticity and resilience, Missling pointed out. Still, big pharmas like Ab­b­Vie want a piece of the action. The American giant joined hands with New York-based Gil­gamesh to design neuroplastogens to treat mental health disorders last year for $65 million upfront and $1.95 billion in milestone payments. 

More recently, another deal that was signed to drive neuroplastogen development was between neuro-drug developers, Florida-based Psilera and German atai Life Sciences. Psilera’s preclinical therapy born from its proprietary neuroplastogen platform, PSIL-006, is a non-hallucinogenic derivative of psilocybin poised to hit the clinic next year to address frontotemporal dementia, a progressive brain disease.

With many neuroplastogens still in preclinical stages, the future of the therapeutic field relies on how they fare from here on out. But Caboche is certain it is worth the wait. As Elkedonia sets out to conduct further clinical research on the back of its €11 million funding, Caboche said: “We believe neuroplastogens represent the future of antidepressants.”