Clinical interest in psychedelic chemicals—classic hallucinogens like LSD (D-lysergic acid diethylamide) and dissociative drugs like ketamine—is becoming increasingly mainstream. In 2019, the U.S. Food and Drug Administration (FDA) approved a nasal spray called esketamine (Spravato) containing a ketamine-like compound for treatment-resistant depression.
Although ketamine and now esketamine are available in clinics, most psychedelic compounds remain illegal. Psilocybin, the “magic” ingredient in psychedelic mushrooms, is farthest down the path to FDA approval. Just a few weeks ago, researchers at NYU Grossman School of Medicine showed that two doses of psilocybin, a compound found in psychedelic mushrooms, reduce heavy drinking by 83 percent on average among heavy drinkers when combined with psychotherapy.
Besides the issue of legality, taking psychedelic compounds has risks. In addition to poisoning, there are long-term side effects that include memory loss, seizures, and anxiety. Also, the eponymous side effects of psychedelic compounds—hallucinations (seeing the world turn into fractals, hearing voices, or tasting colors) and dissolution (feeling out of control or disconnected from their body and environment)—pose a risk to serious harm because of the profound alteration of perception and mood. While not inherently dangerous, consumption of psychedelics has led people to harm themselves and others while having a mind-altering experience, with tales of people becoming suicidal and violent.
To harness the clinical power of psychedelics, the mechanism of action underlying the antidepressant and anxiolytic effects need to be separated from hallucinatory and dissolutive. Research has shown that result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. Isolating the chemical structures driving the rapid and long-lasting antidepressant and anxiolytic effects of psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.
Delix Therapeutics is a neuroscience company focused on harnessing the power of isolating psychoplastogens—novel neuroplasticity-promoting therapeutics—to better treat mental health disorders at scale. Based in Boston, Massachusetts, the company’s compounds, which do cause not cause hallucinatory or dissociative side effects, are easily manufactured small molecules capable of rapidly inducing structural and functional neural changes in targeted brain areas. Many of these molecules are inspired by psychedelic compounds and preserve their efficacy-promoting mechanisms while avoiding their hallucinogenic properties and other safety liabilities.
GEN Edge has taken a look into the motivation and structure of Delix’s R&D pipeline with CEO Mark Rus, a veteran industry executive. He joined Atlas Venture after previously leading Shire Pharmaceuticals’ Global Neuroscience Business.
GEN Edge: What motivated the founding of Delix Therapeutics?
Rus: Neuropsychiatry and neurodegeneration have had a shortage of innovation for the past few decades. We’re still using a similar selective serotonin reuptake inhibitor (SSRI). You can’t even find meaningful advances on the neurodegenerative side. Pick your access —moral, strategic, or financial. All roads lead to the need for better mental health treatments. The treatments do not match the unmet need in the space.
Through that motivation, Delix co-founder David Olson was working on ketamine at the Broad Institute on why these rapid structural and functional changes, called neuroplasticity, occur in the PFC. We know the intangible benefits associated with like ketamine or true psychedelics like psilocybin. Perceived dissolution of ego and the unique intrinsic experiences that one can have are very powerful. Who am I to say that those can’t be the most transformative experiences for someone in their lives?
But I’m a neuro drug developer, and I’m more interested to know what’s happening at the synapse or circuit-based level. It was inconceivable to me that structural and functional neuroplasticity did not play a role. That ultimately led to the foundation of Delix.
GEN Edge: How do psychoplastogens work?
Rus: If you think of a neuron as a tree’s trunk, the dendrite is the branch coming off that tree and the synapses or the leaves on the edge of the branches. A well-functioning circuit connective circuit of pre-frontal cortex (PFC) to other brain parts is like a rich forest, where the neurons are all connected. But then, in a scenario where there’s trauma, whether genetic or external, in both cases, those leaves start falling off, the dendrite branches retract, and the synaptic connectivity in the circuit is essentially lost or suboptimal.
To me, that’s a fascinating nexus that sits at the heart of a range of neuropsychiatric and neurodegenerative conditions. So, why do psychedelics seem to help so quickly and so robustly? It’s an indisputable fact that there is a massive and significant growth in the dendritic spine density process called synaptogenesis. David and I felt it was worth pursuing and drawing that lineup further. There are great companies, people, and funding behind hallucinatory-based approaches. But what if you could do it without the hallucinatory-based approach and some other aspects that may be suboptimal for some of these compounds—side effects, like HERG inhibition, other than removing the hallucinations?
For any brand, product, or therapeutic, I ask: What does it mean to a patient? Is it going to help? Will it make a difference in motivating them to want to take it? What does it mean for a payer and the prescriber? Is it sufficiently simple or motivating enough to change an ingrained habit that physicians may have in treating a particular condition? What does it mean for pharmacists, psychologists, and others in terms of ease of use? What does it mean for policymakers?
What motivated the Delix story was whether we could pursue the neuroplasticity-focused element, tease that out, and subtly tweak known hallucinatory compounds to generate our own novel IP. These eventually become very different compounds that, inspired by the hallucinatory ones, become more tolerable and orally bioavailable. You can take them home and thus be scalable to fit the current care frameworks and speak to the scalability of manufacturing, commercial, and patient access.
GEN Edge: What advantages do psychoplastogens have over hallucinogenic psychedelics?
Rus: I saw an inherent scalability issue regarding first- or second-generation hallucinatory psychedelics. It’s not a reason not to do it. People can and will be helped by those experiences, but spending eight hours in an inpatient treatment clinic with multiple therapists surrounding you to support you and to walk you through that mission is one of the reasons why Spravato—which a lot of people were excited by, the first ketamine derivative that was approved launched by Janssen and justifiably created a lot of motivation for our space and approved by the FDA—hasn’t been a huge success. It’s tough to get high throughput payers to pay for it, and people that want to come back to take it with that high degree of complexity. Now, many people have been and will be helped with it.
There is a wide proportion of patients with comorbidities who will never even be candidates for hallucinatory psychedelic therapy. For someone with bipolar, schizophrenia, or a history of psychosis, it’s not the first, second, or third thing you’d want to take to risk exacerbating that condition. When you start moving in that neurodegenerative direction and particularly individuals who are perhaps older or later in life, the ability to build rapport with therapists is plausible for some, and for others, it isn’t. I’m not sure how one discerns that early on.
So, the need for more options is there. There’s a mix of scalability, comorbidity, and other related reasons. That makes a lot of sense for more treatments in our approach. And that’s what the Delix approach was all about. We wanted to take this non-hallucinatory approach to validate it preclinically. I’ve been searching for the right scalable approach in this space because I see the promise that rapid structural and functional neuroplasticity changes may bring.
Delix is a psychoplastogen platform company. We now have thousands of compounds at this stage at various stages of characterization. We have two candidates that we nominated last year and moved into IND-enabling studies. We are in the process of completing those now. We’ll be in phase one early next year to show the translatability of this non-hallucinatory reality in man, efficacy, and safety with our approach while continuing to characterize, develop, and nominate subsequent candidates. We have a pipeline that we can produce from our platform as we drive forward the Structure-Activity Relationships (SAR) and the related screening discovery full of the scheme.
GEN Edge: What is the Delix R&D pipeline scheme?
Rus: We’re certainly inspired by the fact that this work has been going on for a long time. We’re standing on the shoulders of a lot of great work that has been going on for decades in the hallucinatory psychedelic space. But all our novel chemical and composition matter-supported compounds are synthesized and built in-house and are inspired by predicate compounds.
We have a phenotypic-driven drug discovery engine. Each one of these lens tests produces compounds that fit the Delix narrative for what an eventual clinical candidate would be. The first thing we do is assess for psychoplastogenic properties—if something is a compound generating robust neurite outgrowth. We look at targeted binding and functional assays that one would typically use and the classic battery of safety profiles you do in neuro-drug discovery, such as ADME and PK. Then, we quickly test for the likelihood of hallucinogenic properties and an efficacy profile. So, we’ve got a range of multiple assays we assess so that as early as possible in the process, we can take some compounds off the assembly line that we feel are likely to display hallucinogenic properties and separate them from the non-hallucinogenic ones.
We don’t allocate resources, time, or effort to the early-stage compounds we’ve developed and synthesized that have robust IP but are likely to be hallucinogenic. Over time, I feel those could be good candidates for other companies who are better natural owners and stewards of the hallucinatory approach. That’s not our lane, but we have identified and can build compounds that perhaps have an optimized hallucinatory profile.
The preclinical to clinical translatability is not great for hallucinatory properties. Some pretty good models like head twitch and related rodent models also have a pretty good R-square value for not being hallucinatory in man. We test efficacy through assays such as the non-forced four swim test, where we do the highest possible bar and most possible assays to demonstrate effectiveness in early-stage rodent models.
We also directly compare the compounds that we find most attractive against positive and negative controls. How are they doing against ketamine for being rapid-acting and long-lasting? We also don’t want to develop another SSRI or something you must take daily. We want to be a once a month, twice a month, once every two months therapy, not once a day. Finally, we look at safety, toxicology, and dosing models that inform eventual clinical candidate selection and then patient subtypes.
GEN Edge: What is Delix’s approach to funding?
Rus: The syndicate you build is essential, not just from the capital perspective. It’s important to build with investors who truly understand neuro-drug development and are interested in building a leading neuroscience company, not short-term investors. And we’re fortunate to have that syndicate, having raised about a hundred million last year through our Series A and convertible note round. We have great teammates from ARTIS Ventures, RA Capital Management, founding investor OMX Ventures, and others.
GEN Edge: What’s on the horizon for Delix?
Rus: We want to get into the clinic to demonstrate human translatability for a Delix compound ASAP next year and continue to advance our pipeline candidates out of our platform, ready to move into IND-enabling studies adjacent to those clinical studies from phase one. We feel that being the leading non-hallucinatory, psychoplastogen company globally is a step towards being a leading neuroscience company by 2030.
We’re building out our headquarters, and we’ll be moving in next year here in Massachusetts in Q1. We couldn’t be more thrilled to have a shot at making a big meaningful difference in something that all of us face one way or the other—either with ourselves, loved ones, or friends—with the suboptimal standard of care in mental health.