Tuning (Back) into Psychedelics

The market for antidepressants, expected to reach $19 billion by 2023, is still dominated by selective serotonin reuptake inhibitors (SSRI), which first received FDA approval back in 1987. However, an estimated 30 percent of patients are not effectively treated with SSRIs. In March 2019, the depression market saw its first major advance in a generation, when FDA approved Janssen Pharmaceuticals’ Spravato (esketamine) nasal spray for patients with treatment-resistant depression. This first-in-class therapy, the first new antidepressant to be approved in 20 years, helped to spark renewed in psychedelics, such as psilocybin (“magic mushrooms”), among the academic, regulatory, and investment communities. While not a psychedelic, esketamine can have dissociative effects, and Spravato’s approval followed on the heels of FDA granting Breakthrough Threapy designation to 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin for treating major depressive disorder, post-traumatic stress disorder and treatment resistant depression over other available therapies.

With more pharma activity now focused on the therapeutic potential of psychedelic substances on a range of mental health problems. Pharm Exec spoke to three companies at the forefront of this research to discuss their psychedelic pipelines.

Cybin

Toronto-headquartered Cybin Corp. is a company focused on psychedelic drug development, unique delivery mechanisms, improved novel compounds and protocols that target psychiatric and neurological conditions. It aims to become one of the first life sciences companies to launch a fully approved psilocybin product targeting depression.“Based on studies performed at John Hopkins University, New York University, The Toronto Centre for Psychedelic Science, and Multidisciplinary Association for Psychedelic Studies (MAPS),” Cybin CEO Doug Drysdale told Pharm Exec, “psilocybin can potentially dramatically change how we treat mental health disorders such as depression, anxiety, PTSD, and addiction. Some patients were free of their depression or addiction to tobacco after just one treatment session in some of those studies. If we can repeat those results in the clinic, we can genuinely transform the treatment of mental health disorders.” Psilocybin is likely to be the first molecule to be approved for marketing, “but even this beneficial treatment has room for improvement, potentially with a 4-to-6-hour treatment session,” explains Drysdale. “Our early-stage development programs are focused on improving that patient experience and bringing psychedelic treatments to market that are scalable and broadly accessible.” Cybin’s priority is to optimize the patient experience. “Our sublingual film formulation is designed to avoid first-pass metabolism by the liver, which typically removes around 50%-60% of the active drug. The sublingual film should be able to provide a dose with a lesser quantity of psilocybin, while still providing therapeutic benefits. The sublingual route should also offer a more expedient onset of action, which is crucial for depressed or anxious patients who would prefer not to wait an hour or so for their treatment session to begin.”

Doug Drysdale

Cybin recently closed USD $45m financing, Canada’s largest go-public funding round in the psychedelic sector. “The incredibly strong support in this financing round from smart, US blue-chip Biotech funds is humbling,” says Drysdale. “Being well-capitalized enables us to progress our lead clinical program and accelerate our earlier stage novel programs.” The company plans to start dosing patients in a Phase II study in early 2021 and expects to be in a position to apply for a marketing application outside the US in early 2022, with an application to FDA expected around early 2023 for major depressive disorder.

Jaguar Health/Napo Pharmaceuticals

San Francisco-based Jaguar Health is focused on identifying opportunities to develop and commercialize first-in-class, plant-based prescription medicines that leverage its extensive botanical library. Its subsidiary, Napo Pharmaceuticals develops and commercializes proprietary plant-based human gastrointestinal pharmaceuticals from plants harvested from rainforest areas. Napo’s Mytesi® — whose active ingredient, crofelemer is a plant-based, non-opioid drug extracted from the purified red bark sap of the medicinal Croton lechleri tree in the Amazon Rainforest — is FDA-approved for the symptomatic relief of noninfectious diarrhea in adults living with HIV/AIDS on antiretroviral therapy (ART). Napo’s library of approximately 2,300 medicinal plants from tropical regions was assembled by ethnobotanist physician teams who conducted primary, first-hand field investigations and plant identification work in rainforest regions.

“Our team’s ethnobotanists would go out to parts of the Amazon, East Africa, and Papua New Guinea and talk to traditional healers about how they use plants for specific health conditions, such as infectious disease, diabetes, CNS disorders, fungal infections, etc.,” Jaguar’s Chief Sustainable Supply, Ethnobotanical Research & IP Officer, Steven King, PhD, told Pharm Exec. “In the course of those expeditions, we would learn about plants that had some side effects, such as hallucinations or psychoactivity, associated with their use for other conditions.” When Jaguar was conducting this work, there wasn't much appetite in the pharmaceutical industry or the FDA for psychoactive plants for the treatment of mental illness, depression, PTSD, etc. So we kind of put those to the side.”

Lisa Conte

Jaguar’s founder and CEO Lisa Conte told Pharm Exec, “Here we were working away on potential crofelemer follow-on indications, and we saw what was going on with compounds like psilocybin, MDMA, and ketamine. Until then, Jaguar had purposely de-prioritized anything in its library that might have a psychoactive or psychedelic effect.” Adds King, “So, we recently asked ourselves, ‘What if we went back and looked at those things that we had de-prioritized?’ That’s what started our current journey.”

Steven King, PhD

In September 2020, Jaguar announced the launch of its mental health Entheogen Therapeutics Initiative (ETI), which aims to discover and develop novel, natural medicines derived from psychoactive plants for treatment of mood disorders, neuro-degenerative diseases, addiction, and other mental health disorders. The company is now in the process of working with an experienced scientific strategy team, that includes ethnobotanists, physicians, pharmacologists, chemists, and experts in neuropharmacology, with expertise in psychoactive plants from around the world, and intends to seek corporate partnerships with companies with skillsets in the clinical development of psychoactive therapies.

Jaguar Health's ethnobotanists talked to traditional healers about how they use plants for specific health conditions.

“We have identified one compound used by a traditional healer in West Africa to treat a variety of psychoses. That particular plant has yielded a pure compound that looks to have promise for the treatment of schizophrenia with some novel mechanism of action, as well as fewer side effects,” says King. “And we're looking at other plants within our database. Our team has done field research for over two decades in 25 countries, working in tropical areas where information is not well-documented. We collected the plants, we have the experts, we have the data. So, we're going back into that stream of information to identify compounds with unique mechanisms of action that may have a distinct impact on various parts of the brain.”

Small Pharma

Small Pharma (London, UK) was founded in 2015 by Peter Rand, formerly of Teva, who wanted to position the company “somewhere between generics and completely new drugs.” That is, explains Carol Routledge, “to take known active pharmaceutical ingredients/known molecules and develop them into novel medicines. Not repurposing them exactly, but working to give them a distinct advantage, for example more efficacy or a greater safety profile.” While it wasn’t Small Pharma’s original intent to move into the psychedelic space, with growing research in the psychedelic field presenting convincing evidence of the therapeutic potential of the dissociative/ psychedelic effects of these drugs, the company started looking at tryptamines. They “saw that they could really optimize the psychedelic and treatment experience and deliver therapeutic benefit across a number of disorders.” It is now developing N,N-dimethyltryptamine (DMT) and a pipeline of novel patent-protected deuterium-enriched tryptamine compounds for psychedelic-assisted psychotherapy as a rapid onset, sustained treatment for mental health disorders. “Regarding our initial approach of DMT we aim to secure a patent position on this molecule,” Routledge told Pharm Exec. “We also have a number of proprietary molecules behind that, which we've modified to optimize that psychedelic experience, and based on this, the therapeutic benefit, we'd also like to bring an oral formulation forward.”

Carol Routledge

The company will start clinical trials of DMT in January 2021. At the end of this study, towards the end of 2022, “we should have proof of concept in people with major depressive disorder,” says Routledge. Her “optimistic view” is that, in the long run “this would be a first-line treatment, based on the efficacy. It’s an alternative treatment t currently marketed treatments, and there is no reason why it shouldn’t be first-line, based on the expected safety and efficacy of this approach.” Routledge says one in-clinic treatment of DMT, administered in combination with a program of wraparound therapy. Some patients may need a second and third treatment with therapy alone. “The benefit of this approach is that it will work almost immediately” says Routledge. “And should be sufficient to provide significant benefit to patients that’s got to be significantly beneficial over some of the other medications.” While SSRIs work by regulating the levels of neurochemicals like serotonin which regulate mood and anxiety and can do this well in a number of people, “they don't really get to the root cause of the depression, whereas this treatment does,” says Routledge. “This treatment resets the mindset, helps to break those ingrained, ruminative thoughts and helps the brain to develop new neuronal connections.”

Psychedelic renaissance

During the 1940s and 1950s, before their association with the “tune in, turn on, drop out” movement of the late-1960s, psychedelic drugs and their effects were the subject of legitimate medical inquiry in the west. But their link to the radicalism and subversiveness of hippie era proved hard to break. Even by the 1990s, you could not bring psychoactive or psychedelic agents through the FDA,” says Jaguar’s Lisa Conte. “The legitimate research that had been going on before the 1960s had stopped dead in its tracks.” The hippie-era connotations of psychedelic drugs served to negate the robust research that had earlier explored their application to a variety of psychological conditions, notes Jaguar’s Steven King. “We're talking about hundreds of scientific articles, documenting the efficacy of, for instance, LSD therapy for people with alcoholism, as well as other disorders.” But in the last few years, he says, the “stigma” around these treatments has been evaporating.” At universities, FDA, and pharma companies, the mindset towards psychedelics has been shifting. And the investment community “now seems to be intrigued and excited about this frontier,” adds King. “The fact that a lot of SSRIs and other things used to treat depression and mental illnesses are not particularly effective in certain populations and also have some side effects, I think, has helped to overcome some of the negative baggage associated with the words ‘psychoactive hallucinogen’.”

Cybin’s Doug Drysdale also observes that there has been “an incredible renaissance of psychedelic science in recent years, with much public and media interest.” It seems now that there is a willingness to investigate the medical benefits of these treatments to help patients with mental illness, he adds. “In my view, science needs to lead the way. By pursuing a science-based pharmaceutical development pathway, we finally — after 50 years — have the potential to bring an approvable (and importantly, reimbursable) psychedelic-based medication to patients.”

Small Pharma’s Routledge says she understands why there has been a lot of legislation around the recreational use of psychedelic drugs. But over the past few years, “the research has started to push through.” She adds, “I think lots of people are starting to change their minds. Psilocybin, for example, is now in Phase IIB clinical trials for the treatment of treatment-resistant depression and has been given Breakthrough Therapy designation by FDA. So the regulators can see the benefit of these medicines as long as they are approved and administered appropriately and correctly.”

Whilst one train of thought focuses on the psychedelic effects experienced by subjects taking this medication, Routledge stresses that the “effects” of psychedelics “are not side effects, they're a result of the pharmacology of the medication.” She explains, “You have to go through the psychedelic effect to get the therapeutic benefit. In addition, a key message is that you cannot just take the medicine on its own, because it needs to be taken in combination with wraparound psychotherapy. So it will always be an in-clinic treatment. But if it lasts, from a commercial point of view, it will be absolutely worth doing the in-clinic treatment.” While Routledge believes SSRIs and SNRIs “will absolutely stay and have a place in the market and in the treatment paradigm,” psychedelics “could help those people who cannot get benefit from SSRIs, and that’s a significant proportion of people.” Not everybody will want to go through a psychedelic experience to get the therapeutic benefit, but those that do will be taken through very it carefully. Routledge concludes, “I think, psychedelic medicines, once approved and on the market, will revolutionize the treatment of mental health disorders.”