Rising High: Exclusive talk with biotech company Tryp Therapeutics

In this edition of “Rising High,” The Fly conducted an exclusive interview with Jim Gilligan, CSO and interim chief executive officer of Tryp Therapeutics (TRYPF), a clinical-stage biotech company focused on developing intravenous-infused psilocin for diseases with unmet medical needs. Here are some highlights:

PSILOCYBIN-BASED TREATMENTS: Tryp Therapeutics aims to develop proprietary, novel formulations for the administration of psilocin in combination with psychotherapy to treat diseases. The company’s lead program, TRP-8803, is a proprietary formulation of IV-infused psilocin designed to alleviate the shortcomings of oral psilocybin. Tryp is conducting a Phase 2a clinical trial for the treatment of Binge Eating Disorder at the University of Florida as well as preparing for Phase 2a clinical trials with the University of Michigan for the treatment of fibromyalgia and with Mass General Hospital for the treatment of abdominal pain related to irritable bowel syndrome. Each of these studies are utilizing TRP-8802, a synthetic, oral psilocybin, to demonstrate efficacy. These studies help to fortify our IP position as well as provide data that will allow us to refine future clinical studies with TRP-8803 in these respective patient populations. “We have two major initiatives that distinguish us from others in the sector,” Gilligan said. “The first is we’re pursuing unique indications, while most of the other companies are in either treatment-resistant depression, anxiety or things like that. We’re looking at overeating, in particular binge eating, and then chronic pain.”

He added Tryp is looking at a specific type of pain called nociplastic pain, which originates in the brain. “The best example I can use is phantom limb,” the CSO said. “It could be a service member or someone in a car accident that loses a limb but then has pain in the limb that no longer exists. Clearly that pain signal originates in the brain.” However, the most important differentiator for Tryp is the company’s proprietary formulation for the IV infusion of psilocin, TRP-8803, he said. “Psilocybin, which is present in mushrooms and the capsules that people have taken in clinical studies, needs to be converted to psilocin in your body,” Gilligan said. “That’s the molecule that enters into the brain and induces a psychedelic state. We elected not to give the prodrug, but rather just the active molecule itself by an IV infusion. Those two approaches distinguish us from most competition.”

PHASE 2A IBS TRIAL: In July, Tryp received confirmation from the Food and Drug Administration to proceed with a Phase 2a trial of psilocybin-assisted psychotherapy in IBS at Massachusetts General Hospital. The planned study will evaluate the effect of psilocybin-assisted psychotherapy in patients with treatment-resistant IBS who experience chronic abdominal pain and other debilitating gastrointestinal symptoms. The primary efficacy endpoint of the study will be improvement in abdominal pain. “The primary efficacy endpoint is to look at abdominal pain and tenderness,” the CSO said. “One of the characteristics of patients with chronic refractory IBS is abdominal pain.”

He noted the indication is similar to other pain indications Tryp is exploring and 35% of people with IBS also have fibromyalgia. “There’s some commonality between these patient populations,” Gilligan said. “We’re looking to hopefully achieve a reduction in abdominal pain in the patients with IBS because there are medications available for other symptoms like diarrhea and constipation for people with IBS, but there’s nothing to really deal with the chronic pain.”

While the company has received allowance to proceed with the trial from the FDA, MGH is still awaiting Drug Enforcement Administration approval, he said. “For all studies here in the U.S., you need to get both national and regional DEA approval,” the CSO said. “You need to have both Ethics approval and the FDA notice to proceed in order to apply for the DEA license. That must be done at both the national and the state level. Once the DEA license is received that is when the study can commence because prior to that, you can’t actually ship the drug to the hospital.”

The company also announced in April that it had complete psychotherapy training for the trial in partnership with Fluence. “This is the third study that we worked on with Fluence,” Gilligan said. “The core of the training on administration of psychedelics is consistent in all the studies, but for each of the patient populations we modify it to a certain extent. To Fluence’s credit, what they do is meet with principal investigators and experts in the field, learn about the patient population that is the target and work to amend the training materials to reflect that population. The feedback from every site has been incredibly positive on how well the training went and how much they learned.”

PHASE 2A BED TRIAL: In January, Tryp announced interim results for the first five patients dosed in its Phase II STOP trial. In collaboration with the University of Florida, the STOP trial evaluated TRP-8802 in patients with binge eating disorder. The results demonstrated a significant reduction in the frequency of binge eating behavior for each patient as measured in multiple assessments of efficacy. Across all patients, daily binge eating episodes were reduced by an average of 80.4% from baseline during the four-week post-dosing measurement period, with all patients reporting a daily reduction in binge eating episodes of at least 60% from baseline. Four out of five patients reported at least a 75% reduction in daily binge eating episodes from baseline during the four-week post-dosing measurement period. The number of daily instances of patients feeling that they had lost control over their eating were reduced by an average of 81.6% during the four-week post-dosing measurement period, with four of five patients reporting a reduction of greater than 70%. In addition, analysis of the Hospital Anxiety and Depression Scale anxiety and depression scores demonstrated improving trends related to patients’ levels of anxiety and depression.

“We’re performing these studies to determine if psychedelic-assisted therapy will be a benefit to these patient populations,” the CEO said. “Once we establish that it is a viable target, we will then pivot and all future studies will use TRYP-8003. We use the currently available oral psilocybin as a tool to explore the clinical utility of psychedelic-assisted therapy.”

PHASE 2A FIBROMYALGIA STUDY: In December, Tryp noted it was preparing for a Phase 2a trial using TRP-8802 to evaluate psilocybin-assisted therapy among patients with fibromyalgia, in partnership with the University of Michigan. The Phase 2a open label clinical trial is expected to enroll 20 fibromyalgia patients and includes a variety of exploratory endpoints given the high prevalence of co-morbidities such as poor sleep quality, depression, anxiety, and other conditions. “We received the allowance to proceed from the FDA over a year ago,” Gilligan said. “The process to get both national and state approval from the DEA took over 13 months. It significantly delays the program and we’re hoping that that will change as we go forward.”

Tryp’s colleagues at the University of Michigan have now received the clinical trial material, he said, and expect to commence that study soon. “But that’s an issue that most companies have to deal with because it’s not only the national DEA but on a state-by-state basis,” the CSO said. “You need to get approval for shipping clinical trial materials.” He noted while DEA approvals went particularly fast in Florida, they were delayed in Michigan, but now the trial is ready to go. “Given the results we have from preclinical models and anecdotal information, we expect to see a reduction in pain,” Gilligan said. “We’re also monitoring sleep disturbance as we believe these patients should benefit from improved sleep, as well as anxiety and depression scores.”

TRP-8803: TRP-8803 is the company’s proprietary formulation of IV-infused psilocin designed to overcome the limitations of orally administered psilocybin, including high patient variability in terms of drug blood levels and long duration of treatment. Tryp is hoping to develop TRP-8803 to offer clinicians greater control and more compelling economics, while providing patients with better acceptance. “Certainly oral administration of a capsule is convenient and we envision that all initial treatments will be done in association with therapists at a clinic,” the CSO said. “When you take a capsule of psilocybin, it needs to be converted to psilocin. It can take one to two hours from the time the patient takes the capsule until they enter the psychedelic state. Then that can last another six to eight hours, so you have two therapists and the patient in a room for what could be eight to ten hours. It’s a significant burden to both the patients and the therapists.”

As clinics try to scale and treat as many patients as possible, ten-hour sessions with two therapists for one patient per day will make having a commercially feasible environment too cumbersome, he said. “We wanted to have a model where the patient comes in and they receive an IV infusion over 15 to 20 minutes to get them into the psychedelic state,” Gilligan said. “You maintain that infusion for an hour and if necessary, we could extend that for another hour. You have total control over the administration of the drug.”

He added there is also significant variability of drug blood levels with orally administered psilocybin as the conversion effect varies for each patient. “It negatively impacts efficacy and safety because when you’re looking at clinical results, you need to ask are they due to the fact that the drug may or may not be working?,” the CEO said. “Or the fact that they may be underdosed or overdosed? If people can convert different amounts that leads to variability.”

The other confounding factor in oral administration is that the blood from the stomach and intestines passes through the liver first. “It’s called first-pass metabolism,” Gilligan said. “For individuals that may have a more active liver or less, it contributes to variability in blood levels. The last thing that we’re very interested in is nobody really understands or has been able to demonstrate what the optimal blood levels are for an optimal psychedelic experience.” Tryp will have the ability to do that by infusing to a target blood level and measuring the psychedelic effect, through methods like neuroimaging and EEG, he said. “In our studies, we’re targeting three different blood levels and we’ll look at maintaining those blood levels for up to two hours,” the CSO said. “We’ll be in a really good position to correlate blood levels with quality of the psychedelic experience and changes in EEG patterns.”

SCHEDULING: Several psychedelics are listed as Schedule I drugs under the Controlled Substances Act, including MDMA and psilocybin, however Gilligan said he believes the molecules will have to be rescheduled. “The definition of a Schedule I drug means it has no clinical utility and certainly psilocybin-derived molecules have shown clinical potential,” he said. “As of July 1 in Australia, limited psychiatrists can now prescribe psilocybin for treatment-resistant depression so clearly there’s a clinical benefit.”

Scheduling is a pivotal problem that needs to be addressed, the CSO said, as companies want to do top clinical research under Good Clinical Practice conditions. “This barrier of waiting months and months for local DEA approval just really makes things difficult,” he said. “And as you do larger studies, where you’re going to have multiple sites and multiple regions, the complexity of awaiting local DEA approval increases. We have a number of people now recognizing the benefit derived from psychedelics and there really needs to be a concerted effort to get these drugs off the schedule because it really does limit the ability to do clinical research.”

FDA DRAFT GUIDANCE: The FDA recently published its first draft guidance on clinical trials with psychedelic drugs highlighting fundamental considerations for researchers investigating the use of these drugs for potential treatment of medical conditions, including psychiatric or substance use disorders. “The guidance signals that the FDA is aware that they need to reconsider the approaches,” Gilligan said. “One of the biggest issues is double blind placebo-controlled studies. You have two therapists in a room with the patient, and they’re given a sugar pill and they’re in the room for eight or ten hours, where it is pretty abundantly clear that they haven’t received the drug.”

Companies can try to conduct placebo-controlled studies, but blinding will be near impossible as part of the goal with current treatments is for the patient to have the psychedelic experience. “The other thing that will be interesting is in traditional drug development, you have a primary single endpoint,” the CEO said. “What we’re seeing so far with the data is these patients have a constellation of symptoms that are interconnected and that they derive a benefit. So from a drug perspective for package labeling, the Package insert, I think the FDA will have to start recognizing the additional benefits in the label for the products.” The FDA is starting to see good, solid data on psychedelics, he said, and therefore has started to reconsider the standard approach. “It’s a good first step and some recognition that these clinical studies are going to be different, and they need to be different,” Gilligan said. “These guidance are open for public comment, so hopefully they hear from the folks that are doing these studies and that will be reflected as the guidance proceeds.”

CHALLENGES: When asked about the largest hurdles facing the psychedelic space, the CEO pointed to the process for DEA approval as one of the biggest challenges. “I’m not picking on the DEA,” he said. “It’s just not what their expertise is in for their local ability to have to review clinical protocols and look at multiple clinical sites. It’s a mismatch.” Gilligan noted the FDA has become very good at reviewing investigational new drug applications, with several of Tryp’s INDs going through the 30-day review period. “They have shown a very good level of sophistication on understanding in what is being done,” he said. “I’m hoping that the Schedule I designation can be changed, and I think that will represent a major breakthrough in order for a lot of people to continue to do good quality research in the psychedelics sector.

OPPORTUNITIES: As the psychedelic industry develops and matures, the CEO pointed to the broad utility for the use of psychedelics as a huge opportunity in the sector. “We are certainly encouraged by our indication areas and now there’s positive data in anorexia nervosa,” he said. “Additionally, Imperial College has seen preliminary positive results in pain, so we’re starting to see that there is a broader applicability.”

Gilligan said Tryp is most excited about the development of TRP-8803, as the company believes it can be applied to any indication using oral psilocybin. “If we’re able to dial in the perfect dose to a patient, they can be in and out in an hour,” he said. “For a clinic, when there is a need to administer a maintenance dose, it can be a very short period. As people demonstrate other areas where psychedelic-assisted therapy works, 8003 would be a great tool for them to use for a better administration paradigm for their indication. Tryp will be very well-positioned in the field.”

CANNABIS/PSYCHEDELIC STOCKS: Publicly-traded companies in the space include Aleafia Health (ALEAF), Acreage (ACRHF), Atai Life Science (ATAI), Audacious (AUSAF), Aurora Cannabis (ACB), Avant Brands (AVTBF), Awakn Life Sciences (AWKNF), Ayr Wellness (AYRWF), Body and Mind (BMMJ), BZAM (BZAMF), Cannara Biotech (LOVFF), Canopy Growth (CGC), Chicago Atlantic (REFI), Clearmind (CMND), Clever Leaves (CLVR), CordovaCann (LVRLF), Cresco Labs (CRLBF), Cronos Group (CRON), Columbia Care (CCHWF), Compass Pathways (COMP), Curaleaf (CURLF), CURE Pharmaceutical (CURR), CV Sciences (CVSI), Cybin (CYBN), Delic Holdings (DELCF), Delta 9 (DLTNF), Entourage Health (ETRGF), Enveric Biosciences (ENVB), Fire & Flower (FFLWF), Flora Growth (FLGC), General Cannabis (CANN), Greenlane (GNLN), Green Thumb (GTBIF), GrowGeneration (GRWG), Goodness Growth (GDNSF), Hemp (HEMP), HEXO (HEXO), High Tide (HITI), India Globalization Capital (IGC), Indiva (NDVAF), Innovative Industrial Properties (IIPR), InterCure (INCR), IM Cannabis (IMCC), Wellbeing Digital (KONEF), Khiron Life Sciences (KHRNF), Lowell Farms (LOWLF), Lotus Ventures (LTTSF), MediPharm Labs (MEDIF), MedMen (MMNFF), MindMed (MNMD), NewLake Capital (NLCP), Numinus Wellness (NUMIF), Organigram (OGI), Planet 13 (PLNHF), Reunion Neuroscience (REUN), Revitalist (RVLWF), RIV Capital (CNPOF), Relmada (RLMD), RYAH Group (RYAHF), Safe Harbor (SHFS), Small Pharma (DMTTF), SNDL (SNDL), Sproutly (SRUTF), Skye Biosciences (SKYE), Stem Holdings (STMH), Sunniva (SNNVF), TerrAscend (TRSSF), Tetra Bio-Pharma (TBPMF), Tilray (TLRY), Trulieve (TCNNF), Tryp Therapeutics (TRYPF), Verano (VRNOF), Village Farms (VFF), Wesana Health (WSNAF), Zynerba (ZYNE) and 4Front Ventures (FFNTF).