By their CEO, Kabir, their Chief Financial Officer, Teri, and their Chief Patient Officer, Steve. Thanks to all for being here.
Thanks for inviting us.
Maybe we'll just jump right in. I mean, data from COMP005 is imminent. Can you walk us through the trial design, what you're seeing with respect to the type of patients you've enrolled, and I guess how confident you are that you can get the right patients to reproduce the phase two data?
Yeah. As a reminder, the design is a single dose of 25 milligrams of COMP360 against a true placebo. The primary endpoint that we'll be declaring next month is at six weeks. The IE criteria are very, very consistent with the Phase 2b. This is really very consistent in terms of patient population. The only difference that we've made really is in the Phase 2b, we had capped prior experience with psychedelics at 10%, and we actually had around 6% with prior experience. In the Phase 3 across both trials, we've increased that to 15%. We will have a handful more patients likely with prior psychedelic experience. In terms, as I say, in terms of the IE criteria, it is very similar.
We obviously are on a blinded basis just tracking EPI at the moment, but there's no reason to suppose that we have anything different by way of.
The only thing I'd add is that in screening and the qualification of the population for these studies, consistent with Phase 2b, we are getting medical and pharmacy records to confirm that these patients have had adequate trials. These are truly treatment-resistant depression.
Now, one of the aspects that investors have talked a lot about is how long it's taken to enroll. On one hand, that speaks to the diligence in enrolling the right kind of patient. Can you speak a little bit more about some of the challenges and maybe why those have been overcome, how those have been overcome, and whether there's any risk that patients who may have been enrolled at the start of the trial are different than the ones that you're enrolling now?
Yeah, I can speak to that, and then I'll steer the comment on why that doesn't translate into broader concerns.
Yeah, I mean, to Steve's point, we require this is a very strict regulatory definition of treatment-resistant depression, which requires that subjects have failed at least two and not more than four courses of a specific medicine for a specific duration with documentation that they have failed to respond. That requires not only prescribing records, dispensing records, and so on. In the U.S. system, those are hard to get. What we actually discovered was actually putting all those together was taking us a very long time. What we put in place was traditional third-party vendors who, with the patient consent, actually go and gather all those records for you. That was the key thing that enabled us to significantly shorten that time.
As a reminder, the Phase 2b was 50% ex-U.S., 50% U.S. Though we'd had some of the same issues, this by being a 100% U.S. study, that really compounded it. Just as a note on that, as we 006, the other study, goes extensively into Europe, we are again discovering, as we did in the past, that it's much easier in those payer systems and those government-run systems to actually get all that data. It was really old-fashioned legwork in terms of actually making sure that we got all those records.
Do I think that has made any difference to the nature of the patient?
No. What it enabled us to do was just accelerate recruitment over time.
Yeah. And so then the second part about whether there's any read-through, any implications of the challenges of gathering those records in the U.S. in a commercial environment post-approval?
No. Necessarily in our trials, we need to be extremely rigorous about enrolling the right patients. That means gathering all of these records. In the real world, that's not what is typically done. It is a clinical decision as to whether this is an appropriate patient. Typically, it's not required to gather those records. And so along with some of the other relaxations of the standardizations in our trials, which are necessary to have reproducibility across all of our sites, in the real world, it is much more relaxed.
On the efficacy profile of COMP360, what you're looking for from COMP005, can you talk about what your expectations are?
I think we hear from physicians, from other investors, the range on moderates to anything from four to six points for what people might think is meaningful over standard of care. In this patient population, it is much lower than that. What do you think you need to show to be exciting?
Yeah. So I mean, just as a reminder, this is the treatment-resistant depression population. This is chronic refractory depression. So this is not MDD. So we see a difference of 3 at 6 weeks would be clinically meaningful, and we would be happy to get into that 4-6 weeks.
If you look at other analogs out there, of course, there's only one currently marketed pharmacologic drug for treatment-resistant depression, esketamine. Across their studies, it was anywhere from two to five. To Kabir's point, showing a three-point difference in the population would correlate with a highly clinically meaningful change.
Got it. The other aspect is, of course, the safety profile. Can you talk about anything that's come out of recent DSMB meetings since you've had the last ones in February? Maybe we can dive into some of the more specific AEs that people have questions.
Yeah. I mean, the good news is nothing has come out of the DSMB to date other than proceed as planned. There have been no specific concerns or no recommendations to change protocol or change course. The DSMB sees SAE data on a regular rolling basis unblinded. At any point, they've seen up to the last month's data. Again, nothing has come out at this point that suggests that they are seeing any imbalance or that there's any recommendation level for us to change trial combat.
Yeah, I think worth noting that the DSMB is across both 005 and 006. They are seeing the full spectrum of data, which is quite a large number of patients at this point.
Got it. That's helpful. I think one aspect of the safety profile that people are most interested in is the suicidality. There's a number of reasons that there may have been some elevation in the phase two. On the other hand, effective antidepressants tend to lower the risk of suicidality. Can you maybe talk about what happened in the phase two and sort of what your expectations are for risk of suicidality in 005 and then ultimately what's acceptable in the real world given the treatment population.
Let's start with that last point. As a reminder, this is a treatment population that sadly is at high risk of suicidal behavior. As a reminder, in the Phase 2b, 70% had lifetime history of suicidality, either suicidal ideation or suicidal behavior. In the Phase 2b, in the context of the safety events reported on the day of dosing and subsequently, we saw a low rate of suicidal ideation that was consistent across the arm. What we did see was more than a month after dosing, three non-responders in the 25 mg arm with signs of suicidal behavior. Non-responders, as I say, and in our view, that was largely a random event. They happened to be in that. That's the view that the agency has taken as well.
They had no concerns about that in terms of how we designed and executed phase three. They had no concerns about how we're tracking this. Clearly, by studying close to 900 patients across two phase three studies, we'll actually see if there is any specific signal there. I think in our view, that was underlying disease reasserting itself. We do expect a black box warning for suicidality as every other antidepressant.
What related to that black box warning, I think it's an important distinction to draw to point out that that primarily relates to more traditional antidepressants that often have a significant delay to effect if they will ultimately be effective of several weeks. In the early period of having started that drug, there's often some activation that in some cases can enable somebody who was having those thoughts to act upon them. There are also a period of time where there can be some worsening of mood directly related to the daily administration of that drug.
That is very different than what we saw in phase two, where we have a drug that is very quickly cleared metabolically and where we saw a significant delay weeks beyond that period of time when we had those incidences of suicidality, all in non-responders, all with a history of suicidal ideation or behavior prior to the drug.
One other thing to note actually, one of those three patients has been written up as a significant case study that was published in the British Journal of Psychiatry earlier this year. This patient has been very public about her experience as well. While acknowledging that pattern of suicidal behavior after four weeks, at the end of a year, has changed her life around, is in a much better place mentally, and clearly states that she would do it again.
Yeah, that's really interesting. Another aspect of the COMP360 profile that warrants a lot of discussion is the durability. To that end, we recently published some follow-up data from the phase two. Can you highlight maybe the key takeaways on what that data means for durability? In addition, there was some dose ranging there, obviously, how that speaks to the appropriate doses that you brought forward.
Yeah. What we published was the data from 004, which was the follow-on study from 001, and indeed 003, which was a small 19-patient adjunct study that we did at the same time. What we published recently was when you look at that entire cohort of whom the majority terminated at the end of 001 or 003 at the end of 12 weeks, when you look at the entire cohort, including those who did go on to consent into the next study, we saw a time to depressive event for 25 milligrams of 92 days. A depressive event is a specific score on MADRS. It is a specific example of behavior. What we saw was that for the whole population. To be clear, most of that population is artificially sensitive at 12 weeks because most did not actually roll into the longer-term study.
Of those who did, and we were doing this during COVID, so we got a relatively low percentage who did, 58 patients. What we saw there was that those on 25 milligrams actually went 189 before a depressive event. However, we had to recognize there was some survival bias for those who actually did roll into that. I think the core data coming back to that 92 days, as I say, an artificially sensitive number because most patients stopped at 12 weeks, that suggests significant durability.
When you actually look then at the significant differences from 25 to either 1 or 10 in terms of MADRS effect, we're very confident that 25 milligrams is the appropriate dose to carry forward.
In 006, as you'll be well aware, we are still studying two tens as well. That was a number of investigators and others felt we should do that.
Plus, frankly, from a confounding expectancy and therefore maintaining blinding, having the 10 mg in as an intermediate dose is a very effective strategy for that. Our expectation is that 25 will clearly demonstrate superiority to 1 or.
The only thing I'll add is that although it is in parts B and C of these trials, both 005 and 006, that we are examining longer-term durability as well as the effective retreatment, even with our primary endpoint at week six following single administration in 005, two in 006, the demonstration of response out to week six in either of these trials would already be highly differentiated from any option available today, incredibly meaningful, we believe, to both patients and.
I think maybe another point of debate, there's a lot of them in the psychedelic fields, has been how to prevent unblinding and the functional unblinding. You guys have been very strict about making sure that you keep the blind. Can you talk about what's been driving that? Has that been internal? Has it come from the FDA?
As we sit in a regulatory landscape that's evolving, do you think that ultimately there may be some flexibility around that back towards the leucine?
Yeah. I mean, I think first just on that point, we pioneered that design of three separate doses in our Phase 2b. We continue to believe that particularly with the 10 and the fairly overlapping distribution of responses to the 10 and the 25, that is a very effective strategy, as I say, for confounding expectation and maintaining blinding. That is why 006, the bigger trial in Phase 3, maintains that same strategy.
Obviously, 005 is against true placebo. We recognize that the vast majority of patients will therefore know which arm they're on. As a reminder, we're doing that study at the behest of the agency to get a true safety baseline. It's not necessarily a study we would have chosen to do ourselves.
With that said, clearly around the Lycos Advisory Committee, there was a lot of discussion both there and subsequently as to what impact this may or may not have on the agency's interpretation. In many ways, it's absurd because all psychiatry trials, including specifically esketamine, have been unblinded until now. But let's recognize that for psychedelics, this has become a major issue. With that in mind, we had always intended for 005 to disclose six-week data, but we've been very clear that it is going to be a very limited release. It is just going to be the primary efficacy endpoint and a single statement from the DSMB to preserve the integrity for the 26 weeks as much as possible. For 006, we did make the decision to actually disclose only after 26 weeks. So we had originally said again we would disclose the primary endpoint at six weeks.
We made the decision to hold that all the way through the 26 weeks. I don't think we know enough yet to know how the agency may be evolving their thinking around unblinding specifically. I think obviously there are straws in the wind out there that suggest this new administration is thinking about how could we potentially get these drugs to patients more quickly. That is something we're very keen to capitalize on. I don't think we can say yet we have a sense of how that thing is different. One final thing to say, in Phase 2b, we did not ask patients ahead what they expected. In Phase 3, we have. We are asking patients what they expect ahead of the actual approach.
Now that 005 is almost done recruiting, we've been talking a lot about, I guess it is done recruiting.
It is done recruiting.
Can you talk about what your expectations are for how quickly we can get 006 recruited, especially you talked about more EU patients and maybe learnings and being able to pull through patients faster? What can we expect from that?
Yeah, so for now, we're very confident to reconfirm the guidance that we will see 26-week data in the second half of next year. Clearly, it is our intent to tighten up that guidance. Indeed, we've also said we will definitely disclose when we have completed improvement in 006. Just to build on that, we are now in 14 countries. We have a very significant number of sites open, essentially what we always committed to if you look at our investor deck in terms of number of sites for 006. As we've said, some of the better performing 005 sites from the U.S. are moving into 006 as well. That process is well underway. Not fully complete yet because 005 has only just finished up. We are very confident in that guidance at the moment. 006 is recruiting well.
I think one factor is it does indeed have three doses of psilocybin. It is an easier trial to recruit into than a placebo-controlled trial.
I know it's still early days, but you guys must be thinking about the commercial model. I'm curious, just at a high level, how do you stage an initial launch of the drug with a profile like this? I guess, how do you see that working in the real world with a psychiatrist, clinic where patients will get the therapy?
Yeah, you know, without significantly investing in this area, we've been able to do a lot of work already. Still early days, but some things to highlight. We've made a number of announcements of strategic collaborations, which are with live sites of mental health care delivery that span the gamut of where mental health care services are delivered today from hospital systems, integrated delivery networks, decentralized models. Importantly, the interventional psychiatry infrastructure. Our most recent announcement was with a CCBHC, Certified Community Behavioral Health Clinic, to specifically address where those who are underserved receive their care.
It's really allowing us, especially over the past year as we've dived deeper into this work, to get really important understandings of the TRD population, their experience, the patient care pathways.
We've been able to learn a lot from the sites that have implemented Spravato about the operational and administrative capabilities they've needed to build their early experience and how that's evolved over the past few years of delivering that treatment, the economics associated with delivering it. We've also focused on how these organizations currently manage training and continuing education for their workforce. On top of that, as we've announced long ago, we did work on reimbursement codes, CPT codes that are specific to psychedelic treatments. We've laid the groundwork for the reimbursement framework there. An area where we have made more investment is at the state level. As a reminder, as a Schedule I substance, after an FDA approval, federal DEA will have 90 days to reschedule a product, but it will then still need to move to the states.
About half of the states have so-called trigger laws where they would somewhat automatically follow federal guidance on their own rescheduling. The others require some administrative or legislative activity. We have started the work there to ensure that there is minimal gap in that in time of rescheduling in those states so they can very quickly shift to all 50 states.
Steve, it may be helpful just to expand on the fact that we think we can leverage the Spravato network that has been built.
Yeah, important point, Teri. When Spravato launched in 2019, there was essentially zero infrastructure to deliver interventional psychiatry. Today, Spravato is being delivered in about 5,500 interventional psychiatry centers, prescriptions written by 4,000 plus healthcare providers. Much of that concentrated in about 20% of those sites, with Spravato at a run right now of GBP 1.3 billion. There has been a rapid increase, rapid building because of the presence of Spravato in the market to deliver interventional psychiatry treatments. The trend is to grow further. That is a scaling sector of mental health care service delivery. The jump from no interventional psychiatry infrastructure and no capabilities to being able to deliver Spravato versus the very tiny incremental adjustments they may need to make to deliver COMP360 gives us a lot of confidence that there will be readiness at the time of launch to deliver.
I can just add one other point to scaling that I know investors sometimes focus on, which is the role of the person in the room because there is a view that needs to be a psychotherapist and there aren't enough of those to deliver subscale. A couple of points on that. First, with Psilocybin, the experience for the patient is a largely inner-directed, self-directed experience. We now have clear data that actually shows what we've always said. There is no active therapy happening. In fact, for a six-hour session, typically four to five hours of it are almost complete. There is no active therapy happening. Second, the agency, the FDA, is very clear that they do not wish to regulate therapy. They see what happens alongside the drug as a matter of clinical practice that is not in their purview to regulate.
In our discussions with them, as we think about label, REMS, and real practice, we believe as long as there is a licensed HCP in the room who is able to monitor for safety, that is where we will land. That clearly opens up the pool of people able to be in the room massively. The nurses, other workers, potentially licensed social workers, and so on. Again, very engaged dialogue around that and moving that beyond this notion that it needs to be a therapy.
Just to put a fine point on that and put some numbers to it, although there's a lot of talk about limitations of workforce to deliver care to people with mental health conditions, with what Kabir is describing, the expansion of the pool of healthcare providers who will be able to care for patients receiving COMP360, the expansion of that, that represents many hundreds of thousands of healthcare workers who could support.
Guests have shown promising data in PTSD as well. I wanted to touch on that in maybe the last 90 seconds that we have left. How are you thinking about the level of evidence for the drug's activity in PTSD? How are you thinking about next steps?
Yeah, so you're right. We had a 22-patient over-label study, which showed a very, very strong efficacy signal value. In fact, at 12 weeks, it showed a much stronger efficacy signal than MAPS was able to generate at 18 weeks or Transcend more recently in their study. We are very working assiduously on designing a robust late-stage study, which we should be able to talk about relatively soon, obviously once we're past 005 data, which is the primary focus. We believe that not only that signal of efficacy, but also in terms of how I was just describing a psilocybin experience, the experience for both therapist and patient is much easier than one, let's say, with MDMA. Therefore, we're excited to design a robust Phase 3 study. That's something we will be looking to move forward the latter part of the year.
Yeah, there's also high rates of comorbidities of PTSD and DD or TRD. In some ways, we think of this as a relatively similar population. Of course, should we have an approval in that indication as well, there's a high degree of synergy in terms of where these patients are treated.
I think we're basically up on time. Thank you all for being here. Thank you everyone in the audience for listening.
Yeah, thanks, Leon.
Thanks, Leon.