Reformulating psychedelics for neurodegenerative diseases

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There is a clear demand for novel, neurological treatments. While it’s widely known psychedelics hold enormous therapeutic potential, there are a host of challenges, including dosing and potential side effects for the patient. Our guest this week is Dr Sam Clark, who founded Terran Biosciences to develop a safe, effective portfolio of therapeutics and technologies for patients with neurological and psychiatric diseases. 

Table of contents

    About Terran Biosciences

    The company has built a CNS-focused, tech-enabled drug development platform, and is advancing late-stage assets. These include a neuroimaging software platform (now FDA cleared), a late-stage therapeutic for schizophrenia, and a drug design engine that has generated first-in-class and best-in-class psychedelic-based therapeutics.

    Since 2017, Clark and the Terran Biosciences team have coinvented more than 200 patent applications and the world’s first new forms of psilocybin and MDMA.

    Since the company was founded, Clark said, it has brought on late-stage assets, partnered in exclusive licensing agreement assets with Sanofi, as well as with Pierre Fabre, for the drug idazoxan. 

    “That’s right now in a clinical study that’s ongoing and we think that could really revolutionize schizophrenia treatment,” Clark said.

    Terran Biosciences’ innovative approaches in psychedelic drug development

    Psychedelics may make a different, but they are highly regulated compounds. 

    Clark said Terran Biosciences is also improving some aspects of the drugs.

    “There are psychedelics that have long histories of human use. One of them is DMT and 5-methoxy-DMT (known as 5-MeO-DMT, or 5-methoxy-N,N-dimethyltryptamine or O-methyl-bufotenin). But these compounds aren’t orally active, meaning you can’t take them in a pill without combining them with other compounds because they break down. 

    “But when you combine them with other things, called a MAO inhibitor, it can lead to nausea, vomiting, and side effects. So, we took a unique approach, where you add a little extra side chain to the molecule that allows it to be absorbed through the stomach, but then the side chain ‘falls off,’ allowing just the normal molecule in the bloodstream to act on the brain without modification. That worked, we created the world’s first orally active DMT.”

    Clark said the company took the same approach to create the world’s first long-acting MDMA (3,4-Methyl​enedioxy​methamphetamine), which is also known as the drug ecstasy. 

    “This could be a potential take-home medication for depression, something that would allow the power of psychedelics to reach more people.”

    Sam Clark, CEO, Terran Biosciences

    “As MDMA right now in clinical studies has shown, you have to, in many cases, dose it twice because it wears off so quickly. So, we created a longer-acting form.”

    The company has also created new forms of LSD, improved forms of compounds like 2C-B and other empathogens similar to MDMA. 

    “We’ve improved compounds like methylone and MBDB. These are weaker empathogens but have a lot of potential for treating PTSD,” Clark explained.

    How do psychedelics work?

    Clark noted that psychedelics hit a lot of receptors in the brain.

    “But there’s actually only one receptor in the brain that’s responsible for the hallucinations, the trip caused by psychedelics. So, whereas the actual receptors involved in efficacy are still hotly debated in the literature, the trip is caused just through the serotonin 2A receptor. 

    “That discovery led to another big breakthrough that we’re working on. We know the 2A is the only one required for the trip. What if we were to take a psychedelic, combine it with a selective serotonin 2A blocker, a second compound that was so selective it only blocked the receptor responsible for the trip. Could we then allow the psychedelic to hit all those other receptors, maintain its efficacy, but have no hallucinations? 

    “If that were the case, this could be a potential take-home medication for depression, something that would allow the power of psychedelics to reach more people.”

    Clark said a trial in Europe showed the psychedelic with the blocker still maintains the same rewiring of the brain in the absence of a trip. 

    “Now Terran Biosciences is developing this into a medication where we believe this could potentially be a take-home medication where you can get the benefits of psychedelics to treat diseases like depression with a pill you can take at home where there is no trip.” 

    Why are psychedelics so useful?

    There are many companies tackling conditions such as mental illness, depression or schizophrenia. 

    Clark said psychedelics are a new mechanism to treat a variety of conditions. He noted that some treatments have a lot of side effects or can take many months to work. 

    “Psychedelics seem to be able to have longer lasting efficacy that is rapid acting. They’re not necessarily a cure where you just take it and you’re good for the rest of your life, but they do represent a class where the mechanism seems to have serious benefits in both safety and time to onset and efficacy. 

    “And that’s why people are so excited. Now they do come with a trip, which can present an obstacle for some people, but there are ways to remove that trip that we are pursuing. And then there are conditions where the trip may be useful, conditions that are based on life trauma, such as PTSD,” Clark explained. 

    Idazoxan’s journey from Parkinson’s to schizophrenia

    Idazoxan, which Terran Biosciences licensed from Pierre Fabre, was a drug that started out as a potential treatment for Parkinson’s disease. However, Clark pointed out that the National Institute of Mental Health in the US said it could be a very effective drug for schizophrenia. 

    “It’s a selective alpha-2 antagonist and by adding it to existing antipsychotic regimens, we’re able to boost the efficacy, and in many cases, double the efficacy of the baseline treatment. And what that means is that this could be an adjunctive treatment, something you add on top of existing therapy for another enormous benefit.” 

    Terran Biosciences has spent several years building a daily version of the drug, an extended release version of Idazoxan. 

    “Then we went to the FDA, we got the green light to put that into this phase 1 trial to show that pharmacokinetically, we could hit the right pharmacokinetic range that you could achieve to treat schizophrenia, and the drug has performed great in that trial. The goal is to take it into a schizophrenia trial next as an adjunctive treatment.”

    Eplivanserin and Volinanserin as hallucination blockers

    Eplivanserin and Volinanserin are selective serotonin 2A receptor blockers Terran Biosciences is using to remove hallucinations from psychedelics. This could lead to a take-home medication without the trip. 

    Terran Biosciences is also using them as standalone compounds to end trips early in situations where a physician is giving psychedelic-assisted psychotherapy.

    “That’s something we think will be needed by all psychedelic treatment centers in the future. Everyone is going to need a way to tailor the duration of their trips and to end bad trips. And with these compounds, we hope to provide that solution.” 

    The Terran Biosciences’ NM-101 platform

    Terran Biosciences isn’t limited to just producing drugs, however.

    The company has a software platform recently approved by the FDA. There is a biomarker for dopamine, neuromelanin, which is a good diagnostic and prognostic marker for Parkinson’s disease. 

    Clark explained it can be detected on a standard MRI without contrast. This compares favorably with current methods of detection, which often involve the use of a DAT scan.

    While there were recommendations that the MRI scan for neuromelanin should be adopted, it was not cleared by the FDA. This was because there was no way of standardizing and  automating the measurements, Clark explained.

    However, he said that algorithm breakthroughs at Columbia University and the University of Ottawa in Canada made that possible. Terran Biosciences then licensed the solutions and built a cloud-based deployable package. This can integrate with any hospital worldwide directly through their imaging system.

    “A doctor can just get an MRI, push a button, it sends it straight to Terran Biosciences, we analyze it and send back a result,” he said.

    “This is the first time in history that a software has been FDA cleared for the analysis of neuromelanin by MRI. And we’ve had 20 years of doctors calling for this to be included in the standard of care, and so we’re very excited to finally make that available.” 

    To learn more about this topic

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