Ladies and gentlemen, thank you for standing by, and welcome to the COMPASS Pathways third quarter 2021 investor call. At this time, all participants are in listen only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone keypad. To withdraw your question, press the hash key. If you require technical support at any time, please press star zero. I would now like to hand the conference over to your speaker today, Steve Schultz. Please go ahead, Steve.
Thank you, operator. Welcome all of you, and thank you for joining us today for our conference call today, which will combine both the third quarter 2021 results and the much anticipated COMP360 phase IIb top line results. We're able to combine these two events as they coincided from a timing standpoint. Again, my name is Steve Schultz. I'm the Senior Vice President of Investor Relations at COMPASS Pathways, and today I'm joined by George Goldsmith, Chairman and Chief Executive Officer, Dr. Guy Goodwin, our Chief Medical Officer, and Piers Morgan, our Chief Financial Officer. The call is being recorded, and it will be available on the COMPASS Pathways investor relations website shortly after the conclusion of the call. We hope you've had a chance to view the two press releases issued earlier today.
One on the phase IIb clinical results and the other covering our third quarter results. We've also posted a pre-presentation to the investor section of our website in the events section that supports the top line phase IIb data presented in this webcast, so you can follow along. There's also an excellent COMP001 phase IIb hub on our website in the clinical section, and I encourage you to check that out as well. Before we begin, let me remind everyone that during the call today, the team will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as amended. You should not place undue reliance on these forward-looking statements.
Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those risks and uncertainties described under the heading Risk Factors in our annual report on Form 20-F, filed with the U.S. Securities and Exchange Commission earlier today and in the subsequent filings made by Compass with the SEC. Additionally, these forward-looking statements represent our views only as of today and should not be relied upon as representing our views at any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statement. With that, I'll now hand the call over to our Chairman and CEO, George Goldsmith.
Thank you, Steve, and welcome everyone. I'm pleased to be here today to present both the top-line results of our phase IIb clinical trial of investigational COMP360 psilocybin therapy and our third quarter results in one webcast, which I hope makes it more convenient for all of you. Before going into the phase IIb result, which I know is the star of the show today, let me first begin today's call with a business update on our recent progress. I will then ask Guy Goodwin, our Chief Medical Officer, to discuss the top-line results of the COMP360 trial, and Piers Morgan, our Chief Financial Officer, to provide a financial review. We will then open the call to questions. This has been an exciting quarter as we've made great progress on numerous fronts.
Last month, we presented positive data from an open label investigator sponsored study from the American, Maryland Oncology Hematology at the Aquilino Cancer Center in Rockville, Maryland. In this study, the team also pioneered simultaneous group administration, with two to four participants being given psilocybin at the same time with one-to-one therapist support. This tested the value of group support for cancer patients with moderate major depressive disorder, as well as the potential for increased scalability in providing psilocybin therapy in real-world settings. Most importantly, some participants benefited from this study whilst expanding our knowledge on how to improve future research for this population of special interest in MDD. In our goal to continue to expand our development pipeline, last week we announced the launch of a study in post-traumatic stress disorder or PTSD.
This will be a COMPASS-sponsored phase II program and should begin in the next month or so. Over 350 million people worldwide suffer with PTSD with an individual lifetime prevalence of 7.3%. In addition to the COMP360 development programs that include our academic programs, we continue to expand our leadership in preclinical research, exploring new psychedelic compounds through the COMPASS Discovery Center, a network of leading scientists from the University of the Sciences in Philadelphia, UC San Diego School of Medicine, and the Medical College of Wisconsin. Notably, we have engaged Hamilton Morris, the research scientist and filmmaker, as a full-time consultant who will be working primarily at the COMPASS Discovery Center. Hamilton will be advising COMPASS on research related to new psychedelic compounds that could be developed into therapies in areas of unmet mental health need.
This early-stage work will enable us to broaden our portfolio beyond COMP360 psilocybin therapy. In September, we announced the acquisition of an intellectual property portfolio, including patent applications covering a variety of psychedelic and pathogenic substances, some of which are prodrugs, pharmacologically inactive compounds which are metabolized inside the body to produce an active drug. The IP was developed together with inventor Dr. Matthias Grill, who will be working with Compass on an exclusive research project to develop new product candidates. We plan to move some of these compounds into clinical development within the next two years, further expanding our leadership in this area of science. We also continue to grow our capabilities in digital and clinical innovation. Our digital team now comprises over 20 data scientists, engineers, developers, and designers.
They are working on developing tools to improve the patient experience, train and support therapists, and explore digital behavioral markers. Some of these tools will be incorporated into future clinical trials. Our clinical innovation team is also growing to refine our psychological support model across indications and prepare for the increased therapist training requirements across our expanding portfolio of studies. Before I hand the call to Guy to talk about our phase IIb data, let me say on behalf of the COMPASS Pathways founders, Ekaterina Malievskaia, Lars Wilde, and myself, we applaud the extended team of so many people who worked on this trial, including clinicians, COMPASS employees, and our clinical research organization partner, Worldwide Clinical Trials. Most importantly, we want to thank the patients who participated in the trial, enabling us to advance the understanding of how we can help others.
I want to especially recognize Sue Stansfield, Compass's SVP of Clinical Operations, for her incredible contribution. This was a complicated and novel trial, and it was expertly managed in the midst of a global pandemic across 22 sites, 10 countries, and 7 languages. It's an extraordinary accomplishment and creates a foundation for expansion of our clinical development program across indications of significant unmet need. Thank you, Sue. This achievement would not have been possible had it not been for those who were exploring psilocybin therapy before Compass, and we want to recognize those researchers on whose shoulders we stand today. These include Robin Carhart-Harris, David Nutt, Roland Griffiths, George Greer, Charles Grob, and Dave Nichols, among others. I also want to personally recognize Katya for her leadership in the design of our program and training protocol. Without her insight and determination, Compass would not be here today.
With that, let me now hand over to Guy, who will provide a more detailed view of these results. Guy?
Thank you, George. It's a pleasure to speak to everyone today and review the positive data generated from the COMP360 phase IIb clinical trial, COMP001. I was referring to the slide on our website that Steve referred to earlier, and slide two is where I start our COMP360 psilocybin therapy. Our COMP360 psilocybin therapy consists of two components. The first is the investigational drug itself, which is presented in oral capsules, and the second is the psychological support, which consists of the preparation phase, support during psilocybin administration, and the subsequent integration. This in total is the psilocybin therapy that is being tested in this study. It is important to point out that this approach is developed as an integrated therapy, and the results from this trial can only be interpreted in this context.
Other forms of psilocybin on their own or with some alternative support therapy protocol are unlikely to be comparable. Slide three is COMP001 study design and endpoints. Looking at the trial design and endpoints, you will see that all patients were screened and subsequently entered into the study within 3-6 weeks. This preparatory period was to allow the managed withdrawal of antidepressants which the patients may have been taking. Bear in mind that these patients were all resistant to treatment with previously administered antidepressants and therefore had to be washed out before COMP360 could be administered. The randomization was to 1 of 3 doses, which were either 1 mg, 10 mg, or 25 mg of COMP360 and were administered, as you can see here, on day one.
The effects of the treatment intervention were measured on day two, at week two, week three, week six, week nine, and week 12. The primary endpoint was designated the change in the MADRS score, the gold standard rating scale for depression at week three, with a further important outcome at week 12 for the same measure to assess durability of effect. Randomization was equal to three arms of the study. Importantly, the MADRS score was assessed by independent raters who were remote from the trial site and blind to intervention and study design, effectively creating a triple blind. Slide four shows participant disposition and demographics. In all, 233 patients were randomized, and they were allocated to the three arms of the study, as shown on the slide.
The numbers in each arm were as follows: for the high dose 25 milligrams, 79 patients; for the intermediate dose 10 milligrams, 75 patients; and for the low dose 1 milligram, 79 patients. Of these patients, the majority completed the study. A few discontinued in each of the arms. Five in the 25 milligram arm, nine in the 10 milligram arm, and ten in the 1 milligram arm. We know that there were more withdrawals in the arms with lower dose treatment, and the reasons for the withdrawals are shown on the slide. In all, there were 131 patients from Europe and 102 from North America. We were delighted to see that 94% of the patients had no prior psilocybin experience, so this confirms a generally psilocybin-naive patient population. This is a percentage which reflects community surveys in Western countries.
The participant demographics, that is age, gender, race, weight, and baseline depression severity, were all well-balanced across the three groups. Patients were moderately or severely depressed and of course, met criteria for treatment-resistant depression. Slide five shows the primary endpoint change from baseline in MADRS total score. The primary endpoint in this trial is the change from baseline in the MADRS total score at three weeks. We are pleased to report a statistically significant primary endpoint at three weeks. That is the comparison 25 mg with 1 mg has a magnitude of 6.6 points in the MADRS and a P value of less than 0.001.
Additionally, there was a rapid onset of action seen as early as day two, and the effects were sustained with statistically significant treatment differences between the 25- and the 1 milligram group apparent from day two through to six weeks. In contrast, the 10 milligram dose showed an intermediate response of 2.5 points on the MADRS and was not statistically distinguishable from 1 milligram dose at three weeks or subsequently. Slide six shows the key secondary endpoint, MADRS responders. Looking at the key secondary endpoints, the first shows MADRS responders. MADRS responders were defined as patients that experience a 50% or more reduction in symptoms at any particular time point. You can see the results presented for day two, week 1, week 3, week 6, week 9, and week 12 across this graph.
In every case, the color code remains the same, with 25 milligram dose showing as the blue columns, 10 milligram as the green, 1 milligram as the gray. It will be evident from this plot that there is an important numerical difference between the 25 and the 10 and 1 milligram doses at all time points. The most important being at week three, where 36.7%, that is 29 of 79 patients, had shown a response at that time point in the 25 milligram group. This compares with about half the response rate in the other two groups. At week 12, there were 26 of 79 patients, or 32.9% of the 25 milligram group, that continued to show a response at this time point. Again, this was twice the number shown for the patients in the 10 milligram and 1 milligram groups.
We believe this is evidence for durability of response to the 25 mg dose of COMP360 psilocybin therapy. Slide seven shows the key secondary endpoint as MADRS remitters. Looking at MADRS remitters, these were defined as patients that at any particular visit shows a MADRS score of 10 or less. This is of particular clinical interest because it is evidence of beneficial reduction of symptoms to normal levels. You can see here with the same color coding for the results from different days that the rate for remission in the 25 mg group at three weeks was 29.1%. At 12 weeks, the rate was 26.6%. Bear in mind this represents in 23 and 21 patients respectively, who remained without additional treatment and were in remission at weeks 3 and 12. By contrast, the numbers in the other treatment groups are lower.
Slide eight, titled MADRS Sustained Responders. A further way of evaluating durability of response is to look at patients who individually met response criteria at a minimum of three visits, both week three and week 12 together with at least one other visit at week six or week nine. When you select that patient group, they represent 24.1% or 19 of the 79 patients entering the treatment arm with 25 milligrams, and as you can see, less than half that number in the 10 milligram and 1 milligram arms. Slide nine shows safety. These are treatment emergent adverse events. Looking at the safety profile and the treatment emergent adverse events recorded in the study, which in over 90% of cases were of mild or moderate severity.
The patients reporting a serious treatment emergent adverse event were five patients in the 25 mg, 6 in the 10 mg, and 1 in the 1 mg arm. As expected, the total number of adverse events was slightly higher in the 25 mg group than either of the other groups. Further analysis on the onset and duration of the treatment emergent adverse event is underway. Of particular interest will of course be the onset and duration because we are showing here treatment emergent events over the whole duration of the study at 12 weeks. This total includes all events that are likely to be related to the psychedelic experience on the dosing day. We know from our healthy volunteer studies and from the literature that we should expect adverse events on that day. That has to be taken into consideration in evaluating the results of this trial.
Slide ten shows the most frequent treatment emergent adverse events ordered by the 25 milligram arm. Those are at least 5% in any treatment group. The most frequent adverse effects are shown here ordered by the 25 milligram arm. We're showing all those adverse events that were shown by at least 5% in any treatment group. The most prevalent are headache, nausea, and fatigue, together with insomnia, and then a variety of other adverse effects which may well be related to mood. These are regularly observed in many clinical trials in depression. Next slide, Slide 11, shows treatment emergent serious adverse events ordered by 25 milligram arm. When looking at treatment emergent serious adverse events, this is ordered again by the 25 milligram arm. There were relatively few events reported.
As you can see, a number of them relate to suicidal behavior, suicidal ideation, drug withdrawal, and self-injury. These can all be common in patients with treatment-resistant depression. The number of events includes some cases in an individual patient and essentially part of the same episode, which are nevertheless classified as separate events for complete clarity. The conclusion is shown on slide 12. In conclusion, this is the largest randomized controlled double-blind psilocybin therapy trial ever conducted, and it showed rapid and sustained response for the 25 milligram dose level of COMP360 psilocybin therapy. It's also worth noting that it is a multi-center study. It involved multiple patient populations recruited through conventional medical care systems, and very few of the patients had prior psilocybin experience, in contrast to previous investor-initiated studies. We expect the top-line data with secondary analysis will provide the springboard for phase III development.
The study achieved its primary endpoint, with 25 milligrams achieving a significant treatment difference of -6.6 on change of baseline from MADRS scores when compared with the 1 milligram dose at week three. The P value for this effect was less than 0.001. The 10 milligram, interestingly, did not show a statistically significant difference at week three compared with the 1 milligram dose. The numerical difference being -2.5 points. The 25 milligram group demonstrated significant decrease from baseline in the MADRS total score the day after COMP360 administration. At week 3, the 25 milligram group showed a 12-point reduction from baseline in the MADRS total score.
Secondary endpoints suggested that at least double the number of MADRS responders and sustained responders were seen with the 25 mg dose compared with the 1 mg, and there was a rapid development of remission from day two to week three. The number of patients who showed a response was 29 of 79 patients in the 25 mg arm, and 23 of 79 patients were still in remission at week three. Nineteen patients of the 79 patients from the 25 mg group were sustained responders at week 12. Regarding safety, COMP360 is generally well-tolerated, and the majority of the treatment-emergent adverse events were mild to moderate in severity. We are particularly interested in understanding the reports of suicidality and suicidal behavior in treatment groups. Finally, let me echo George's thanks to the team, our clinicians, and especially our patients who were involved in this trial.
With this result, we are one very important step closer to our goal of providing TRD patients with a novel and potentially life-changing option for many individuals who currently have very few options. Thank you, and let me now hand over the call to Piers for the financial review. Piers?
Thank you, Guy. The company continues to maintain a strong financial position with cash and cash equivalents of $294 million at September 30, 2021, compared with $190.3 million at December 31, 2020. This is expected to fund our operations into 2024. I will now recap our financial results for the three and nine months ended September 30, 2021. The loss from operations for the three months ended September 30, 2021, amounted to $21.8 million, compared with $13.5 million for the prior year period. The loss from operations includes non-cash share-based compensation expense of $2.3 million for the three months ended September 30, 2021, compared with five point two million dollars non-cash share-based compensation in the prior period.
The net loss was $15.8 million or $0.38 loss per share for the three months ended September 30, 2021, compared with a net loss of $16.7 million or $1.30 loss per share during the same period in 2020. The loss from operations for the nine months ended September 30, 2021, amounted to $54.9 million, compared with $39.9 million for the prior year period. The loss from operations included non-cash share-based compensation expense of $5.9 million for the nine months ended September 30, 2021, compared with $16.6 million non-cash share-based compensation in the prior period.
The research and development expenses for the nine months ended September 30, 2021, amounted to $30.4 million, an increase of $11.6 million compared with the nine months ended September 30, 2020. This increase in research and development expenses compared with the prior year period was primarily attributable to an increase in development, personnel and consulting expenses as the company continues to expand its activities, including launching a new trial in PTSD, preparing for phase III trials in TRD, and expanding our digital activities. General and administrative expenses were $24.5 million for the nine months ended September 30, 2021, compared with $21.1 million for the same period in 2020.
The increase of $3.4 million in general and administrative expenses compared to the prior year period was primarily attributable to increases in personnel costs to support our growth initiatives, including our transition to a public company, increased insurance and other costs of operating as a listed company, partially offset by a decrease in non-cash share-based payments. The net loss was $46.1 million or $1.17 loss per share for the nine months ended September 30, 2021, compared with a net loss of $41.5 million or $3.90 loss per share during the corresponding period in 2020. Thank you. I'll now hand the call back to George.
Thank you, Both. We're now working to schedule an end-of-phase II meeting with the FDA as quickly as possible. I remind you that we have Breakthrough Therapy designation, which can provide us with a more rapid and open dialogue with the FDA. Our immediate goal is to present these data to the FDA and gain agreement on a phase III program design. We will report on our progress in future communications. In addition, we expect the SSRI drug-drug interaction study to be completed by the end of this year, which will provide important information about the potential influence of concomitant SSRI use with our COMP360 psilocybin therapy. You will recall that our phase IIb study did wean patients off of their SSRI therapy prior to the COMP360 psilocybin administration session.
Overall, this trial's result is consistent with the data we saw coming from the Imperial College London study in April and the recent Aquilino Cancer Center data, which is to say the patients saw a rapid and sustained effect with a generally well-tolerated safety profile. We believe this consistently supports our assertion that COMP360 therapy can potentially bring a new approach on how we may be able to treat patients for whom few options exist today. Today's result continues to bolster our leadership in this field. To be clear, all of our efforts are aligned with our commitment to think differently about mental health and to follow up those thoughts with well-executed actions. The need is great. Patients are suffering. We have to provide them with the new tools in the most responsible way.
That means we must understand who can benefit from our work and who cannot at this point. We are working day and night to ensure we expand our understanding. Thank you for your time today. We will now open the line for questions. Operator.
Thank you, ladies and gentlemen. We will now begin the question and answer session. As a reminder, if you wish to ask a question, please press star one on your telephone keypad. We'll pause for just a moment to compile the Q&A roster. Your first question comes from Ritu Baral from Cowen. Your line is open.
Hi, Ritu.
Good morning. Hi. Good morning. Congratulations on the entire data set, not just the top line, but especially that remitters analysis. I have my first question, and I'll keep the second one really tight. My first question is slide 11, the TAEs, the vendor preferred terms. Can you go into a little more detail about what was seen around the individual behaviors, like when did they occur? Were these patients responders or remitters? And were they on rescue meds? Especially-
Oh, that's something I can-
Suicidal behavior, self-injury, and ideation, I think are the most concerning to investors.
Great. Guy?
The suicidal behaviors were really reported at least one month after the administration of treatment, and they occurred in patients who were essentially non-responding. The suicidal ideation was a little different. That was, at least in one case, quite early on in the treatment process. Of course, these numbers are very small and our plan is to look at them in as much detail as we can. In addition, in the secondary analysis, to look at the Columbia suicide scales that were collected on every patient at every visit, that will give us, I think, a much more accurate understanding of the relationship between treatment and suicidal ideation and suicidal action.
The intentional self-injury is that, I guess an aspect that is overlapping with the suicidal behavior and suicidal ideation?
We actually don't believe it does. It, it's classified in that way, but it represents really quite trivial self-harm. It means scratching or banging the head or very simple things that really don't carry any suicidal threat or intent. They are quite common in depressive populations. They're well-described, and I'm afraid they're just part of the picture for these patients and part of their suffering.
Got it. A very quick follow-up. George and Guy, do you have your dose now? Do you think that a phase III with the dose or powering a phase III for durability, whether it's week eight or week 12, would make sense for phase III from a reimbursement perspective?
Yes, we think we conclusively have our dose. In speaking with payers and others, we have included even in our phase IIb trial, health economic related measures, quality of life measures. We'll be discussing all of this as we go into our phase III design, with those who advise us on payer metrics, et cetera. We've been working with payers and health technology assessors here in Europe, since 2016. We're well aware of their requirements, and we expect to be able to address that in a well-powered study. Obviously, our phase III program will have to be agreed and discussed, which we've been discussing already with regulators on both sides of the Atlantic. We'll look forward now to bringing these data, to then agree that program and swiftly move into its execution.
Great. Thanks. I'll hop back in queue.
Thank you.
Thank you so much. Next question from Josh Schimmer from Evercore ISI. Your line is open.
Great. Thanks so much for taking the question. How are you thinking about ways to preserve effect beyond the first few weeks, either with use of adjuvant therapies or patient selection to optimize for durable effect? Thank you.
Josh, I'll start the answer and hand off to Guy. I think it's a really important question. When we started this whole program, our whole goal was to identify who responds and who doesn't, and who responds longer and who needs additional support. To that end, what we've done is actually recorded every therapy interaction. We have machine learning now looking at transcripts across the trial of participants, really starting to understand the deeper level of patterns, including changes to patient narrative, therapist actions that are then correlated with particular outcomes. This is unprecedented data, and we'll be digging deep into that to look at how we can in fact optimize therapy and develop, as we've said from the beginning, a more precise and predictive model of care with psilocybin therapy. We're looking deeply at these data.
Keep in mind, we just received the data about 48 hours ago. There's a lot of work to do. We're just reporting top line today. Guy, do you have anything else to add?
I think I'd just underline that, the way in which this study was designed is that the psychological support is essentially safety around the administration of the medication. So this is a test of the medication in isolation. It's pretty remarkable that we get these effects after a single dose up to 12 weeks. Clearly, if we are working with colleagues within the company, to look at digital support mechanisms and monitoring, which may very well carry the promise that we can improve outcomes through that sort of approach. We'll certainly be considering that in the future.
I should just also say that, you know, this is the data set that we developed in close collaboration with payers and regulators, again, on both sides of the Atlantic and over 10 countries to answer the fundamental questions. We couldn't do that unless we really looked at the dose finding and a single dose and its durability. Only then can we look at how we can identify the patients who have different experiences and look at how to optimize that experience to maximize the outcome and the duration.
Got it. When do you expect to have some of the additional analysis completed in full data presentation?
We'll be working on that hard and doing it as soon as possible. We don't have a date, but you know us, we're going to be at it with intensity and vigor.
Super. Thanks so much.
Thank you so much.
Any other-
Next question. Next question from Charles Duncan. Your line is open.
Okay. Super. Thank you, George and team. Congratulations on a rigorously conducted trial. It's clearly a seminal event for the field. Thanks for taking the question. My first question is regarding next steps on sizing and timing, and I know you need to discuss this with the agency. Could you imagine being able to outline a protocol or even operationalize a next step, maybe a phase III by roughly mid-2022?
We can certainly imagine many things, and that's one we're focused on imagining, to use your term. We are very heavily recruiting sites and looking at preparing our phase III infrastructure to build on our really robust phase II infrastructure. That all work is in process, but again, we can't anticipate what the agency, the FDA and the EMA and MHRA will say as we review these data. We are ready to hit the go fast button as we do whenever we get the word from the agencies. We will be reviewing these very rapidly with them.
Okay. That's good, George. Second question is regarding any phenotypic factors. I understand that this is fresh data, so probably haven't done the analysis. But is there anything that you're in particular interested in, such as prior lines or time since diagnosis that may have drove responses in terms of either the primary endpoint or durability? Anything that you're particularly interested in looking at or you've seen.
Again, I will start that and then hand off to Guy. I think a few things were really important to us. One was that this study actually used patients who were referred based on medical records. We have a validated background, and that background information will be used in future analyses, obviously. One of the things that was really important to us was to be able to demonstrate that these benefits could happen to people who had no prior experience, or 94% of our sample had no prior psilocybin experience, quite at odds with the prior studies. The majority of our therapists in all of our centers also had no prior psychedelic experience.
This was so important for us to generalize to all of the population, which is approximately the same in our study, about 90%+, who haven't had these experiences. To be able to demonstrate that this works in that environment is really important for scalability and more importantly, to help the most patients possible. Guy?
Yeah. Just to say that obviously we're aware of existing data that suggests that one can, to a limited extent, predict treatment response from baseline measures, and we have those baseline measures. There is also, of course, emerging interest in biomarkers, and we'll be looking at the measures that we have in that category as well. As you rightly said at the beginning, we're not yet in a position to comment on that. We're just gonna be very excited to follow up and look at those questions and answer them for you.
Okay, last quick question, then I'll hop back in the queue. Referring to slide six and seven, in terms of remitters or responders and remitters, it looks like weeks nine or six and nine numerically are a little bit less than week 12. I guess I'm wondering if you think that's an artifact of the remote visit or if there's something else going on there with the drug. It's hard to imagine what that might be, but tell us about that and tell us how you would use those learnings in future trial designs.
Well, I think in general, we feel that the data from 6 to 12 weeks gets slightly more difficult to interpret because there is additional treatment going on in the three treatment arms with some of the patients. That's a factor that we've had to consider and we're gonna have to analyze more closely. I think we feel very confident about the statistical differences up to six weeks. After that, we're encouraged by the group who received no treatment, but we need to understand the whole data set. We're gonna have to take into account the fact that antidepressants were available for use and in some cases were used in all three arms of the study.
I should also add that one other thing we need to look at. This study was conducted through the very depths of the pandemic with people being in lockdown. We'll be also looking at are there any effects of when the lockdown was occurring on patient populations, et cetera, because that's quite an unusual event. Clearly, it had many mental health sequelae for people. We are going to be looking at that. It's an unusual thing to have to consider in a trial, but it's a very meaningful one. Stand by, please.
Okay. Thanks, George. Thanks, Guy. Thanks for the clarity in presenting this data. Very nice.
Thank you, Charlie.
You're welcome.
Thank you so much. Next question from Esther Hong. Esther Hong, your line is open.
Hi. Congratulations on data. Really impressive. Wanted to ask about patients who had to discontinue antidepressants prior to the administration of COMP360. Any additional details on these patients and perhaps regarding washout periods and response rates and remitter rates? I've got a follow-up.
Yeah. Well, all the patients were washed out from antidepressants, and we will be giving further in details as to how long it took, and what the delays were between initiating that and the actual dosing day in due course. You ask a very interesting question, of course. There's a lot of interest in the effects of discontinuation. We think that discontinuing in patients who were highly symptomatic and treatment resistant proved to be relatively straightforward to generalize rather grossly, but nevertheless generally successful and acceptable to patients. As you can see, many of them stayed off for the next 12 weeks as well.
Right. Got it. Just quickly, can you remind us what biomarkers you're looking at? Thank you.
We have a polymorphism in the 5-HT2A receptor that may be of interest to the drug action. We're also interested in an inflammatory biomarker which will be informative as well.
Got it. Great. Thanks. Congratulations.
Thank you.
Thank you.
Thank you so much. Next question from Patrick Trucchio. Your line is open.
Thanks. Good morning and congrats on the data.
Hi, Patrick.
I have a follow-up question on the suicidal behaviors. I'm just wondering, what was the protocol definition in terms of how far out post the exploratory session could this be considered attributable to the treatment? Is there a limit to that? Is it within the 12 weeks? Is that something that's consistent across TRD studies or was this unique to phase IIb trial for COMP360?
I mean, at any time in the 12 weeks that there was a suicidal ideation or behavior, it was recorded, and the timing, of course, is recorded. In terms of frequency, although these very low numbers make the estimate very uncertain, but they are comparable with, in fact, the majority of studies ever conducted in depression. The recent meta-analysis which suggested that the average rate of suicidal events of various kinds was about 3% in actively treated patients. We seem to be aligned more or less with that kind of rate. Of course, this is a group where you would expect to see emergent suicidality as a risk because of their history and so on.
Got it. That's helpful. I'm just wondering if there was any learnings that emerged from this study or some of the others that have read out recently in terms of the feasibility of simultaneous treatment or therapy. I'm also wondering if you think you would need a separate phase II trial to assess the feasibility of simultaneous therapy or could this potentially be, you know, a separate treatment arm in the phase III program?
I don't think we're at a stage where we can answer that question. We will have experience of administering 25 milligrams of psilocybin therapy to patients who are still taking SSRIs in a small open label study, which we'll report relatively soon.
Okay.
We'll then be in a position to make an informed judgment about the rest of your question.
Yeah. No, makes sense. Just one last one if I may. Just in terms of the PTSD trial, if you can just discuss again there too any learnings you could take from this TRD phase IIb trial, the other trials for that program or even a program with MDMA and how you know how should we kind of expect the pace of enrollment in the PTSD trial to progress?
The learnings I think will relate to the therapy provision. We have an enormous amount of data that we will be able to analyze that can pick apart the interactions between the patients and the therapists in this study. Every single administration, in fact, all of the sessions with therapists were recorded, and we have really sophisticated approaches ongoing to analyze the interactions and the key themes that come out, and that's going to shape how we deliver our treatment program in the future. With the specific lessons for PTSD and the recruitment and so on, we're doing the study to find out about PTSD.
Great. Thank you very much.
Yeah.
May I just build on that? Yep, I'd just say that, you know, as we pursue areas of high unmet need in multiple indication areas, our focus is to be a learning organization and continue to apply learnings in real time so that we can actually progress all of our clinical studies and benefit patients as much as possible. We are very much looking at building these staircases with smaller studies into larger studies and drive learning.
Terrific. Thanks so much.
Thank you.
Thank you. Next question from Sumant Kulkarni. Your line is open.
Good morning. Thank you for taking my questions and for all the company's work on what must be an exciting day for patients who might see another treatment option for TRD. I have three questions. I'll ask them individually. First, based on what you now know with your phase IIb data in hand, are there any specific variables that you instantly see in terms of needing adjustment for your upcoming phase III program?
Guy Goodwin, do you wanna start with that?
I don't think instantly we see anything we need to adjust, but obviously we're reflecting on a whole series of issues that are raised, particularly when we look at the secondary analyses. What is your reaction, George? That's mine.
Yeah, it's mine as well. Again, these are very fresh results. We have the largest data set ever created in this area. We have an incredible team of statisticians and data scientists, and we're really looking at all of that and taking that into discussions with regulators and devising the path forward.
Got it. My second question.
You-
Sorry, go ahead.
No, it's fine. No, I was just gonna say that, you know, you appreciate the top line results are all driven by a very, very strict and conservative analysis plan. You know, that's a sort of limitation on how far one can immediately react to differences.
Understood. Second question. Given your work with patients, physicians, payers, and other components of the supply chain so far, what do you think would be the sweet spot for durability and COMP360 therapy in the real world?
I think that, you know, everyone's dream is to actually look at how we can predict and prevent relapse. We're hard at work looking at new tools that might help with that and digital phenotyping. I think that people understand today that this is an incredibly difficult patient population to support and serve. With a single administration of a monotherapy, we see, you know, great promise at three weeks as well as 12 weeks considering the lives of these people. You know, we'll be in lots of discussions, and I think we'll come back to that question with more information in the not-too-distant future as we start finalizing our phase III plans.
My last question is, should we expect to see any difference in response to COMP360 based on the specific antidepressants used or failed by patients in the past?
We have no idea what to expect because it's an empirical question, and fortunately, we have data to be able to answer it.
Thank you.
Thank you. Let's continue. Your next question from Bert Hazlett. Your line is open.
Thank you, and my congratulations on a well-conducted study and an important one. Just one or two questions to try to better understand the patient characterization in the study. Would you be able to provide baseline MADRS rates for either the study as a whole or any of the particular groups?
Yeah.
Yeah.
I think it's on. Go ahead.
Yeah, it's on slide five if you want to-
Oh, forgive me.
It's written rather small. It's very easy to miss, but it's on all the data is on slide five that you requested there.
Okay. Thank you. Just with regard to geographical groups, are there any notable similarities or differences within the particular patient groups, either in North America or in the U.S.? Or excuse me, or in Europe?
We'll be looking at that with great interest. We have none yet.
Okay.
I think what's really go ahead.
Go ahead. Please go ahead.
I was just going to say, what's really remarkable about this is we've trained therapists in seven languages, ten countries, and demonstrated this result across the board. It's going to be fascinating to look at all sorts of cuts in terms of demographics, countries, et cetera. We were amazed, and I think also amazed at the level of recruiting and engagement we had in the Netherlands from our sites. I think that was also a very interesting characteristic given the availability of other substances there. This is clearly a high unmet need and a high level of interest in the trial.
then just thank you for that. just one more for me. with regard to the serious treatment-emergent adverse events, do you have any more information at all with regard to the time course of those events, just in general characterization? Were they closer to the administration and maybe waned further on or just again, any anecdotal characterization you might be able to make with regard to those?
It wasn't simple. Every patient tends to have their own complexity, as you probably appreciate. The suicidal behaviors all occurred at least a month after the drug administration. We can certainly say that from this data. Some of the ideation occurred closer, a couple of cases. I think I would emphasize again that we will get much finer grain data when we look at the ratings of suicidality that we will have in the secondary analysis, and we'll certainly let you have that information as soon as we have it.
Thank you very much for that, and congratulations again.
Thank you. Next question from François Brisebois from Oppenheimer. Your line is open.
Hi. Thanks for taking the question. Just wanted to ask, in terms of the placebo effect, was that based on, you know, literature and your expectations mostly in line, just based on the potential negative placebo effect here and the triple blind that you mentioned?
Well, you know, we had nothing really to go on. There had been other studies, but they'd usually been crossover studies. We had to really think this through from the start when we designed the study. All of the patients were obviously prepared in such a way that they their expectation was that they would have a psychedelic experience. Our assumption was that there would be an appreciable nocebo effect in the group who got one milligram. At the same time, we also knew that they were getting the wraparound psychological support that's, you know, extremely positive and could be regarded as placebo.
Well, the reason we do experiments is to find out what happened and, you know, this is what happened, and we will try and interpret it as best we can.
Thank you.
Thank you so much. Next question from Elemer Piros. Your line is open.
Yes. Good morning, Guy. Good morning, George. How are you?
Hi. Good to hear from you.
Yes, George. You mentioned that you think you have the right dose, the 25 milligram dose. Would you exclude maybe repeated dosing within the clinical trial?
Right now what we're doing is trying to understand, as we said, each patient's experience, and I think that will help inform thoughts along that line. I think what we really needed to do with this trial was to actually establish a level of understanding of durability up to three months of a single dose. That will help inform a tremendous amount of analytics moving forward. Then I think we'll step back and look at what's required. I do know that I think if we have in the 21st century the ability to predict relapse and to preempt it, that's really the goal for us. We're hard at work looking at those kinds of things, not rolling anything in around at this point. Obviously lots to do and lots to discuss with regulators.
Yes. The last question is, how many sessions of integration were there in this protocol, George?
There were two.
Two. Do you think that that number is sufficient?
Again, we have an amazing team working on all the transcripts, all the interactions, and creating an empirical response to that question. I think that one of the things that's really important is that we look at a very fine-grained precision approach to this, patient by patient, so that we can really develop a plan for everyone and anyone. I think this is really where we're headed. We're gonna again be doing all those analyses and sharing what we learn and informing our future plans.
Thank you so much, George, and congratulations.
Thank you.
Thank you so much. Next question from Neena Bitritto-Garg. Your line is open.
Hey, guys. Thanks for taking my question. I just wanted to ask about the use of rescue meds just in the follow-up period. I guess can you talk a little bit more about when patients were allowed to start taking rescue meds? Anything you can share at this point on the actual rates of use of rescue meds in the different arms, that'd be great. Thank you.
Sure. I just think that, Guy, when you talk, you should probably make a clarification or start with a clarification of rescue versus other medications.
By our understanding of rescue would be the use of medications on the day of the study, the day of the dosing. If my memory serves, I think there was only a single example where that was necessary. You know that means that we were successful at delivering the actual dosing day without having to rescue patients from the experience. We think that this therapist did a great job. The other sense in which there's rescue medications is that these patients had been withdrawn from antidepressants, so we had to accept in advance that there would be a pressure for them to go back onto antidepressants if they showed no response or limited response to our treatment. That would apply in all three arms of the study, of course.
However, we did encourage the clinicians entering the trial to give the treatments a fair trial up to three weeks as far as they could, and then after that, they were free to use medication if they felt it was clinically indicated. We've got a picture that we've not yet fully analyzed of a number of the patients returning to antidepressant treatment. When we fully understand the patterns, we'll publish them. I don't know whether you want to say any more about that, George, but.
No, I think that's sufficient.
Thank you.
Thank you so much. Your next question from Michael Okunewitch. Your line is open.
Hey, guys. Thanks for taking the question.
Sure.
I wanted to ask if you could put the data in a bit of context because it seems like the magnitude of the result is not as high as previous studies. Could this be somewhat owing to the fact that this is a single dose protocol? And considering that, you know, the patients and the clinicians were psychedelic naive, should this be viewed as a more conservative study to establish that, you know, a baseline for COMP360, which could be improved in a more optimized setting?
I think that's a really, really hard question to answer. First of all, I think that we simply did this study to address all of the regulatory and payer concerns about whether this was actually a generalizable model or not. I think we can feel confident in saying that this is a generalizable model, and in fact may be optimized in various ways that we're investigating. I do think that what really distinguished this study is that it was multicenter. It was done with a great deal of clinical and scientific equipoise, which you know is something we could do at this scale that's very difficult to do in single site study environments.
We used this triple-blinded model where we had an independent rater calling each patient in their native language, completely blinded to the study. This was the bit that said, we can really count on these results just because of the independent assessment, using the gold standard MADRS. We think that this is a great place to start from, and you bet we're interested in optimizing.
All right. Thank you. I wanted to ask about how clinically meaningful the absolute reductions in MADRS score, which were around, I think, -12 at week three, and that stayed around -10 at week 12. How does that compare to SSRIs? Guy, would you like to take that?
Yeah. Well, I mean, I think just what you make of the average change in the population is obviously very much to do with how you interpret clinical trials. The experience of individual patients is something that I suppose more concerns me. I think when you look at this data and see the high rates of remitters after 12 weeks, that's something that I take away as particularly clinically significant. The comparison between different deltas, as they're sometimes called, is quite interesting, but it's difficult when the trials aren't designed quite the same way. You'll appreciate that our effects are seen from day two. The effects of SSRIs are seen usually by week six. So in a sense, they only look at the interval over which we're showing statistically significant results.
You can probably see that just eyeballing the data on slide five, that the difference between 25 milligrams and 1 milligram at that point is still around five or something on the MADRS, five or six. The usual reported six weeks in SSRI trial on average is somewhere between two and three. I think in terms of comparison, as far as I'm prepared to make them, that would be the comparison I would make. But of course, we're looking at a TRD population. There are various caveats around that population not responding at all to SSRIs, but by definition have failed to respond to SSRIs. You know, this gets a little, it gets slightly academic after a while, those sorts of comparisons.
All right. Thank you. Just one more quick one. I'll jump in the queue. For the suicidality, considering that that was largely a month after, could that be related to a sense of hopelessness in patients that nothing worked for them so far, and now they've tried psilocybin, and they didn't respond to that either?
Well, I think that's a consideration we'll certainly be taking into our, you know, deep dive into the data in the future. It's an interesting possibility, we agree.
Thank you very much.
Yeah, I think we will have to look also at, you know, the level of expectation that is set in the general press. I think, you know, this is something really important to take responsibility for that there are no panaceas, and this study indicates that. Any other questions?
Thank you. Thank you so much. No further question at this time. Steve?
Sure. Let me hand it back to George for closing remarks, please. George?
I just wanna thank everyone for their interest, participation, and support. This is something that is going to be the start of, really developing what we view as a, way to transform the patient experience in mental health. We're on it. We're working at how we can help reduce suffering at scale and appreciate all of your interest and support. Thank you very much.
That does conclude our conference for today. Thank you for participating. You may all disconnect.