Tryp Therapeutics recently announced interim results from its Phase II trial with psilocybin in the treatment of binge eating disorder, with daily binge eating episodes reduced by an average of 80%.
To discuss the study and the company’s drug development programmes, PSYCH spoke with Tryp’s CEO and Chief Scientific Officer Jim Gilligan.
‘We teed up several clinical studies with oral psilocybin while we’re developing TRP-8803, our proprietary product which is an IV infusion of psilocin,’ explained Gilligan. ‘These studies are in eating disorders and nociplastic pain, to confirm that we will see a clinical benefit that we can accelerate.
‘We have the binge eating programme at the University of Florida, the fibromyalgia programme at University of Michigan and recently announced a new initiative with MGH Harvard for IBS. The Florida study, in addition to generating great data, validates our model of doing small studies to establish a patent position. We have put in provisional patents for intravenous psilocin across the board and we have the data to support and enable the patent, which gives us a strong position in a field where getting IP is difficult.
From a corporate perspective, having a first-mover advantage and showing that we have data in the areas that we’ve selected – eating disorders, nociplastic pain and IBS – puts us in a good position and sets the stage for moving TRP-8803 into those programmes.’
PSYCH spoke with Tryp in September 2021 and briefly discussed preclinical studies with the company’s intravenous psilocin formulation TRP-8803. We asked CEO Jim Gilligan for an update.
‘We are keenly interested in advancing TRP-8803, but the FDA felt it was unique enough that we had to do a fair amount of preclinical work. Our rationale was that since psilocybin is converted to psilocin, we could leverage our psilocybin data, but the FDA said we could use some of it, but not all, and would need to generate data with intravenous psilocin too.
‘We have been doing this for the past nine months and have spent nearly US$1 million doing the research the FDA felt would be necessary to advance TRP-8803 into a healthy volunteer study. As predicted, it wasn’t toxic and is perfectly safe. We are now looking at ways to accelerate trials with TRP-8803 by performing studies in either the UK, Australia and Canada, as we have clinical trial sites there that are already set up.
‘We originally expected that the first trials we would initiate would be in the treatment of fibromyalgia, but just last week we heard that after ten months the University of Michigan just received state approval from the DEA to receive capsules containing psilocybin. That is one of the confounding issues we are facing in the states right now, on a state-by-state basis. But, I have to say, the federal DEA has become more accustomed to facilitating these approvals.
‘In the United States, we want to work with as many eligible clinical sites as possible so have pulled together a questionnaire to ascertain if they have a DEA license, an approved therapist and everything required for the study. Oral psilocybin administration is convenient and relatively non-invasive: patients go in and swallow the capsule. However, there are issues with this. It takes one or two hours before they enter a psychedelic state, which could last for another six hours or more. To have therapists in a room for eight, perhaps ten, hours is burdensome for the patient and physician. From a commercial perspective, it is difficult to see how this can be rolled out.’
Dr Robin Carhart-Harris, Head of the Centre for Psychedelic Research at Imperial College London sits on Tryp’s Scientific Advisory Board and provides counsel across the company’s drug development pipeline.
‘In discussions with Robin Carhart-Harris, blood levels of psilocin achieved through oral psilocybin administration are very variable,’ explained Gilligan. ‘Some patients are under-dosed, so they never really achieve the full psychedelic experience, while others have blood levels that could be ~ four times higher.
‘If we look at the COMPASS trials and the variability in their results, I don’t think it is the drug – I think it is the variability in blood levels. Some patients had a better psychedelic experience with 10mg of psilocybin than with 25mg. However, it could be that they had higher psilocin blood levels. It is not that 10mg is better; it just comes down to blood levels.
‘To accelerate the TRP-8803 programme, we are looking to perform normal healthy volunteer studies aimed at optimising IV infusion rates and dose.. We are working on a preliminary dose, what you might call a loading dose to achieve the psychedelic state, and then finding what infusion rate is needed to maintain that state.
‘With intravenous psilocin, we will have a very predictable timeframe, which could be one hour or maybe two hours, but could be tightly controlled. This will give therapists the flexibility to continue the infusion if someone is having a profound experience, or turn it off, giving the clinician complete control and the ability to modulate the treatment for individual patients.’
Psilocin binds to 5HT2A and 5HT2C receptors, with 5-HT2C receptor agonists found to suppress appetite in a manner consistent with an enhancement of satiety, which subsequently reduces caloric intake.
PSYCH was interested to learn whether the intravenous psilocin formulation had been dialed to increase activity at the receptor, or if a non-psychoactive drug binding to the receptor could have the same effect.
‘That is a great question and part of what we are learning is that a number of these issues are speculative,’ recognised Gilligan. ‘As an acute effect, psilocybin inhibits appetite and it also has an analgesic effect. So, you could see an acute effect from a drug that just binds to these receptors, and what we have seen as well as others examining psilocybin in the clinic is what we call the durability of response.
‘We saw a reduction in binge eating frequency that lasted out to 60 days, which was the last time-point we looked at, so it speaks to something more than just receptor occupancy during the time of drug administration.
‘We have seen a fundamental change and a reset in those neural networks. Robin Carhart-Harris is a firm believer that the psychedelic experience, the journey, is important to achieve that reset. That is solely his opinion but, in the absence of other data, that is the premise that we will pursue.
‘It could turn out that people have molecules where you don’t have a psychedelic experience but still derive a clinical benefit, but those studies remain to be seen. A reduction in binge eating frequency was one of the efficacy endpoints the FDA wanted us to look at and we saw an 80% reduction in binge eating episodes, which is very exciting.
‘The other thing we found was that the number of days people felt they had lost control over eating was reduced by 84. In addition, and what we were hoping for, is that scores for both anxiety and depression were reduced, so we saw a holistic change and have this effect on neural networks that is more profound than simply stopping binge eating.
‘We looked at other satiety peptides and things like that, but I don’t think patients care so much about that – they just want their eating behaviour to change – and we are incredibly encouraged by the outcomes we have been able to achieve. Given where we are right now, binge eating disorder could be our first target for TRP-8803 because of the robustness and consistency of data we have in hand.’
In the press release detailing the positive interim data from its Phase II clinical trial in the treatment of binge eating disorder, Tryp provided data at four weeks following the oral psilocybin administration. As the clinical biotechnology company collected data at 60 days following drug administration, PSYCH asked for further information on the treatment’s durability of response.
‘We wanted to have two drug administrations in our study, the second dose being administered three weeks after the first, but the FDA felt that for a first trial a single administration would be better from a safety standpoint,’ explained the CEO. ‘For a single administration, four weeks was the primary endpoint because we felt that if we didn’t see anything within the first four weeks, we wouldn’t see anything and why continue.
‘We wanted to look at durability, and four out of five saw a durability of response. The one individual that did have a durable response was over 300 pounds and did not have a full psychedelic experience, so perhaps could have benefited from a second intervention. The patients that did achieve a fuller psychedelic experience achieved durability out to 60 days, which is pretty consistent with studies performed in treatment-resistant depression.
‘Our fibromyalgia studies will have two administrations, and as we proceed into Phase IIb and Phase III studies, where we are looking at longer-term results, we might need another intervention at three or six months.’
As Tryp looks towards Phase IIb and Phase III studies, which are more extensive and therefore more expensive to conduct, PSYCH asked Gilligan if the drug developer would need to embark on another round of fundraising.
‘I will give you the answer I gave our board. I have been doing drug development for a long, long time and my recommendation is that we do a healthy volunteer study first, to get the ability to achieve different blood levels of psilocin which we can maintain for up to two hours.
‘What I’d like to do then is another exploratory study with maybe 10 or 12 patients to confirm that the dose and blood levels we have chosen from the literature are actually correct. Target blood levels for psilocin have been published, but nobody has been able to confirm these numbers as they have been unable to correlate blood levels of psilocin with the ideal psychedelic state nor have they been able to control the duration of the experience.
‘The factors that drive the number of patients in pivotal clinical trials is related to the effect size achieved and the variability of the response. The standard deviation associated with the response impacts the power analysis on how many patients will be required to achieve statistical significance; the higher the variability the more patients needed in the study.
‘The expectation is that with TRP-8803 we will have tighter data because all patients are receiving the correct exposure, so the size of Phase IIb studies should be relatively small. Given several of the indications we are pursuing do not have suitable current treatments we could pursue an adaptive design clinical program to potentially limit the size of the pivotal Phase 3 studies.
‘I’ve conducted global studies and the last trial had sites in the UK, Bulgaria, Poland and South Africa US etc. To harmonise the studies, you go to different regulatory bodies ahead of time to see if the data and protocol is sufficient to meet their regulatory requirements for registration.
‘Sometimes you have to go back between the US and Europe to make sure that you check all the boxes, and at the appropriate time that is certainly what we will do. We would want to make certain that, whatever we do, we have satisfied the requirements for the EU And US. This is not my first rodeo, and we would make certain we have all those meetings and all those boxes checked before we get into larger studies, so you can be confident that the money you spend in subsequent studies is money well spent.
‘There have been many drugs that never reach the market because people hastily did not select the right dose or the right regimen. I can assure you that we will not make that mistake.
‘Big pharma could be interested when we have significantly reduced the development risk and shown that our treatment paradigm works – at that point it just comes down to execution. We just need to show how much money it will take to perform the trials and successful commercial launch.’
Reading between the lines, PSYCH asked whether the company was positioning its drug development programmes for acquisition by a larger pharmaceutical company, one with the resources to take TRP-880 through the final stages of drug development.
‘At a certain point, given what the licensing or acquisition looks like out licensing is certainly an option. Hypothetically, there could be a company that is very interested in nociplastic pain that would look to acquire the rights to that programme, and we could look at eating disorders or IBS instead. Those opportunities exist and there are also opportunities for regional deals.
‘Data is king, as it reduces risk and positions Tryp for potential deals with other organisations. I have experience with licensing deals with major pharma companies like GSK and Novartis as well as other pharmaceutical companies in the past, for the most part they are happy to wait until they see enough strength in the data to say “okay, we will take it on.”’
With this in mind, PSYCH asked Tryp’s CEO whether he had any final messages for shareholders and potential investors. Gilligan deferred the question to Peter Molloy, the company’s Chief Business Officer.
‘We have identified at least one indication and possibly others that are going to work, but the most important thing is that with TRP-8803 we have a commercial pathway forwards,’ explained Molloy. ‘We have got something that works for the clinic with the clinicians, and more importantly for the patients. We have something scalable with IP and that is the most important thing for investors.’