Great. Thank you guys for joining us, Terry, Lori, and Steve. Let's start with your recent Phase III data, which has been the point of significant investor conversation. Most recent being the top line 6-week data from the repeat dose 006 study and full 26-week data with that duration, 26-week duration from the placebo-controlled 005, which top lined last year. Can you review the key highlights from both studies before we start drilling down into the individual data points in their meaning?
Yeah, I'll start. I mean, first, just a review of the designs of the two trials for those who aren't fully familiar. 005 is our placebo-controlled study, 25 milligrams of COMP360 versus placebo with a 6-week primary endpoint of change in MADRS from baseline monotherapy single administration. 006, 3 arms, 10 and 25 milligrams of psilocybin mirroring what we did in phase IIb, our large phase IIb. With 2 initial administrations, 3 weeks apart, still with a 6-week primary endpoint, otherwise similar inclusion, exclusion criteria. What we released recently was the full Part A of 005. Previously back in June, we released just the difference between the 25 milligram and placebo arms. This was all time points from day 2, which was the day following administration.
Week one, week three, week six, the primary endpoint. That was a difference of 3.6 on the MADRS, highly statistically significant at every time point, most notably including the 24 hours after that single administration. We saw an immediate effect, sustained, clinically significant, statistically significant out through the primary endpoint. We also had Part B from that study, which runs through week 26 and included up to a single retreatment, on still a blinded basis. If you had 25, you would get 25. Placebo, you'd get placebo. Very excitingly, this showed that for a subset of patients who had a clinically meaningful benefit with one or two treatments that continued out through at least 6 months, which is the latest we've measured at this point.
Very notably, those who had a clinically meaningful benefit, meaning at least a 25% reduction in the MADRS. Those who got a second administration, 40% of them then went into remission at that point. In the 006 study, we released Part A, which is the primary endpoint, and also shows statistically significant separation at every time point, starting at the day following administration out through the primary at week 6, where we saw a 3.8 point difference between 25 milligrams and the 1 milligram active comparator.
Some investors hypothesize that a straightforward additive MADRS benefit from the second dose. It looks like based on that, especially the 26-week, 005 curve, that the second dose, the PD, the pharmacodynamics of the second dose may be more nuanced. Based on the totality of the data so far, do you think the incremental benefit from a second, possibly even third dose, manifests more through higher remission rates and like sort of a responder-based benefit versus sort of like a mean population MADRS separation?
Without having the patient-level data from either of these studies at this point, we can't at this point differentiate whether the impact of that second dose that we're seeing, is a just a deepening of response for those who've already benefited or eliciting additional responders. We'll know that in time. What we can say is that whether it's on that fixed interval at three weeks after the first administration, as we saw in 006, or on a more variable interval between weeks 10 and 14, as we see in Part B of 005, there clearly is a benefit of that second administration. What's really notable about the effect of that second fixed interval administration in 006 is we showed a slide overlaying the first six weeks of both studies.
What you can see is a remarkably consistent curve in that 25 milligram group from baseline through week three. Then when they get the second administration at week three in 006, you see a further benefit. Again, whether that's within the patients who've already responded or new responders, we'll need to see. But it shows the very clear contribution of that second dose.
So-
Just to add to that, just really quickly. One of the other data points which may highlight that it could be both a deepening and a broadening is that the percentage of patients who where we saw a clinically meaningful reduction in MADRS, which we had said greater than 25%, which is commercially relevant. In the 005 trial, it was roughly 25% of patients. In the 006 trial, that jumped to almost 40% of patients. Not only were we seeing a lower low on the MADRS from that second dose, we are seeing, at least at the, at the data that we have so far, a significant increase in the percentage of patients that are getting a response. It may be both.
Got it. Well, the obvious follow-up question is, do you think that the 26-week, the Part B... curves will similarly have the same shape or overlap once we unblind COMP006?
Yeah, based on what we've seen in 005 26-week data so far, where we showed the subgroups based on those who were in remission at week 6, those who had either a partial or full response, and then the non-responders. The effect out to weeks of 26 for the remitters and those who had a clinically meaningful response are pretty consistent all the way out. Yeah, I think we would expect in 006 to see something similar, that with the two initial doses-
Mm
... or for those who got a third administration during the Part B period, we would expect to see a similar durability of response out to that six-month time point.
And-
And it's als-
Oh, go ahead.
No, I was just gonna say, it's also worth noting that we're just seeing out to 26 weeks, right?
Mm-hmm.
We may see actually even further than that once we get the 52 week data, Part C.
Particularly since in O05 Part B for the remitters, only three of them actually needed a second treatment. The rest continued to have stable response out to that time point.
Okay.
It's, you know, who knows how long they may go out for.
Just to add to the consistency aspect of this, so we've shown now consistency on primary endpoints across three trials.
Mm-hmm.
On that long tail, the long-term follow-up from our phase IIb, while it was a smaller data set, for responders, we're seeing that same consistent response out to six months. This 005 is replicating that in a much larger patient population. We're seeing this consistency of results.
Mm-hmm
which I think is important and bodes well for O06.
Terry, to your point on the clinical meaningfulness of that 25% reduction, just given that these TRD patients are starting from this very high baseline of 30 points, you know, what does that 8 point-ish translate to into a TRD patient's daily function? Like, if you could drill down on the clinical meaningfulness.
We'll let the psychiatrist answer that.
Yeah.
Yeah. I mean, having sat across from people living with treatment-resistant depression, thousands of them over a long career at this point, it is, you know, really remarkable the differences you can see in people's quality of life and their level of function with even relatively modest improvements on a measured scale. You know, the choice of identifying a group that had a clinically meaningful benefit of at least a 25% reduction in MADRS, that wasn't random. That is based on scholarly work that's been validated in a esketamine SPRAVATO data set, where there were some crosswalks done between MADRS, CGI-S, Clinical Global Inventory of Severity of Symptoms, PHQ9, the Sheehan Disability Scale. What it showed is that a what is a generally accepted reduction in CGI-S, which is one point, correlates to about a six-point reduction on the MADRS.
If we look at our baseline MADRS scores, which were on average about 32.
Mm-hmm
... 6 out of 32 is about 19%, so 25% is comfortably above that.
Yeah.
That generally would be considered a change in the patient's status that would really have an outsized effect on the quality of life.
Notable to the clinician, treater, and investigator per the CGI. Yeah. Okay.
patient, most importantly.
Yeah. Okay.
Yeah. I'll just chime in just 'cause I can't help myself. It's very hard to contain the excitement around how to promote this data.
Yeah.
I mean, I, like Steve, I am also long in my career and have been promoting products for a very long time. This data set, what the reactions that we will see in how we determine physicians that we're going to, showing that graph alone will be.
Mm-hmm
... unlike anything they've ever seen. It is almost mind-blowing how remarkable that drop-off is for those who have that clinical meaning response within 24 hours, and how long it is sustained.
Mm-hmm.
There's nothing out there like it.
We're already hearing that response. Okay. Drilling down on that profile a little more, first question, the 10 milligram. We had a KOL call a couple... Your mic's not working, Lori, sorry. We had a KOL call last week, then we had our panel yesterday morning, the doctors uniformly would love the option of that 10 milligram, which behaved completely different in COMP006 than it did in the Phase II. Phase II was like placebo. This was almost like 25. What is your strategy for that 10 milligram, given that doctors say Phase III is probably more real life than Phase II?
Yeah, I'll take.
That's what they said anyway, so. Now that's not working.
Is it working now?
Yeah. Now that's working. Okay.
I'm just speaking into this.
Yeah.
Is it working now? What do you need?
I think the mic is working. Yep.
The mic is working?
No. Is there a light?
All right. What about now?
Yes.
Yeah? Okay.
Okay.
Oh, give me a better one.
Chief Commercial Officer and soon to be IT.
I know.
There we go.
oh, I do sound loud.
You sound great.
Louder. Sound louder.
Yes.
No one likes the sound of their own voice. With the 10 mg, yes, of course. Psychiatrists are notorious for wanting options for their patients. The interesting thing for the 10 mg is that we only saw the statistical significance in one of the three trials, very robust trials that we had. Actually two that we ran-.
Yeah
... with the 10. The 10, the important thing to note is that it actually didn't meet that clinical relevance at six weeks.
Okay
... which is typically three and below, or three and above, in terms of MADRS deltas.
You know, for us, especially given the inconsistency of the two, given the Phase IIb was not statistically significant, from an FDA filing standpoint, the 25 mig is still our standard what we will launch with.
Mm-hmm.
We are exploring the 10 mig in the PTSD trial.
Mm-hmm
... as well. Which I feel better about from a commercialization standpoint, making sure that that clinical experience, not only for the patient, but also for the physician, is that they have the best shot of achieving-
Mm-hmm
you know, clinical meaningfulness.
Once the trials are presented 005 and 006, will you have as part of the future data set, quality of life outcomes like the CGI that you mentioned, and like the MADRS anhedonia subscale, like work subscales, et cetera?
Anna can start just real quick at the high level. For this data set, given that the O06 enrollment last year had come in quickly and put O06 and O05 timelines on top of each other, we prioritized the set of data for the CRO to be able to deliver to us.
Mm-hmm
... that was... The prioritization was really driven by what information would be needed by the FDA to be able to facilitate that ongoing discussion.
Mm-hmm.
To your point, we didn't get all the data from 005 yet because we are prioritizing which data sets. I'll turn it to Steve because we've got a whole slew of secondary metrics.
Mm-hmm
that can help us from a commercial standpoint.
Right. Short answer, yes. You know we of course have many secondary scales across PROs, quality of life measures, level of function, et cetera. We have a lot of work ahead of us in terms of multiple analyses of all these other endpoints that we haven't been able to analyze or report yet. They will come out, you know, probably across a variety of ways of disseminating this. We're, you know, putting together a conference strategy for the fall. We have, you know, I've already said that we will have data in early Q3, which is the part B of 006.
Mm-hmm.
Some of this may potentially come at that time as well. Suffice just to say, we will have a much richer set of data in terms of complementary scales.
To go to the FDA with.
Yeah.
Well, not only the FDA, these are very important for physician decision-making process.
Okay.
You know, obviously I will, at the risk of, you know, hurting egos of psychiatrists in the room, no one knows what a MADRS is, and you typically don't understand what MADRS is, and you don't really know how to translate that to a patient. If you tell them in these patient, you know, reported outcome scales what they might expect, it becomes a much easier conversation.
Mm-hmm.
I will not speak for the psychiatrist, but this is generally speaking, the Patient-Reported Outcomes are much more important than MADRS delta is.
Can you speak to your current relationship with the FDA? I mean, there was a lot of controversy about you guys applying for the Commissioner's voucher, not getting it, but then everybody's like wondering what the Commissioner's vouchers mean to begin with. There's that whole thing. Maybe, you know, stepping up a couple levels, can you speak to how FDA is approaching this package?
I'll start, and you guys can chime in. We have had a very long-standing, very good relationship with the Division of Psychiatry at the FDA. It's the same review team that we've had over the course of our entire development. They have been very committed to us and to this program because of how robustly we are developing COMP360. We are not taking any shortcuts, as you can see from both the size and design of our 2 Phase III trials, the complementary Phase IIb trial, which was very robust. We've got over 1,000 patients now that have been treated with COMP360 in these trials. In addition to that, we have a whole surround sound of, you know, preclinical toxicology, safety, you know, CMC.
We are not cutting any corners, and we have from the beginning said that because we are first in this class, we need to do everything right, and we have been doing that hard work to do it all right. Yes, we had applied for the Commissioner's voucher last July. When it first came out, no one really knew what it was all gonna be about. Us and.
Still don't.
thousands of others, you know, applied. it very quickly became evident that it was highly politicized. it's still unclear exactly what the process is, what the benefits are. We're actually quite happy right now in the position that we're in because we've now submitted the data set that we announced. That was already submitted to the FDA, requested a meeting, granted a meeting, so we'll be reviewing all of that data with the FDA. We've had really positive, collaborative, ongoing dialogue with them. We've seen both from the psych division comments as well as from, you know, all the way up to the FDA Commissioner, HHS, a lot of openness to psychedelics.
Now with the data and package that we've got to support it, we think we're actually in the best possible position to be able to file this and get this approved without all of the noise around a Commissioner's voucher. Because of how fast we're doing all of this, and the FDA in early discussions with them had encouraged us to be submitting data on a rolling basis, we don't think that a Commissioner's voucher would actually give us a lot of increased benefit.
Mm-hmm
from a timeline perspective. We're already on a very fast timeline. We've got breakthrough designation. Last November, we announced that we had accelerated our filing timelines by 12 to 15 months, we're already really far along down that path and really close to that, you know, that end zone. We wanna do it the right way without taking any shortcuts, and we think that's what's best for Compass as well as for the entire class behind us. A long-winded answer.
Yeah
... to your short question.
It makes sense.
Do you guys wanna add anything else?
Within the discussion of, you know, the recent history of the Commissioner's vouchers, it seems like the divisional relationships are much more important to ultimate outcome than a Commissioner's.
Well, like Terry said, we're playing the long game here.
Yeah.
We don't wanna be seen as having political favors. We want to be seen as doing this the right way as any pharma, as any standard that the FDA sets, and that's what's important to us.
back to the response and remission analysis, another thing that the KOLs have said is that, like, you know. You, a clinician, know who a responder is the next day or the day after, by day 1 or day 2, of course, the question they were unable to answer on my panel was: how can you tell in advance who a responder is? They went with patients who were younger, maybe had less of a duration of disease, were less sort of entrenched in their depression as far as identifying potential responders or those that would have, like, a higher NNT. As you look at the data, is there a commercial profile of patient with an index of suspicion for a response, both from a commercial angle and a clinical angle?
You know, those characteristics of duration of illness or age, et cetera, as far as it relates to COMP360 at this point are speculative.
Mm-hmm.
It's generally true of the TRD population. We have not done the analysis yet to identify if there are any baseline patient characteristics that would be predictive of response, but the point of you will know by the day after administration, let's emphasize that 'cause that's a big, big deal.
Yeah.
Right? As a psychiatrist sitting with a patient with TRD, to be able to present them an option where they will know almost immediately if this helps them, and if it does, it's likely to in a highly durable way, I can't overstate how important that is and how potentially life-saving that is. That is something that gives people hope. That is something that is highly, highly differentiated from anything available for these patients today. Perhaps in due course, we may identify some characteristics that are more predictive, but even ahead of that, knowing that there's a significant subset of these patients who may get benefit that quickly and durably is game-changing.
The other thing I'll add is, a lot of that data can come through real-world evidence.
Mm-hmm.
once patients start getting
Not just the trial.
Not just the trial.
So it's-
Once the-
Yeah
... patients start actually getting treated, we'll be collecting a lot more data where we may be able to refine the profile to be a little bit more predictive or indicative of.
Is that something we'll see soon, that time to response or time to remission?
Well, it likely will depend on how many patients we can get dosed after approval, because that will be more after approval.
Mm-hmm
We're starting to collect data from those patients.
We won't get it from 005 or 006?
Mm-mm. No.
Okay.
It will only come after approval.
Just adding one important point to add to what Steve and Lori was saying. The data that we showed, importantly, the safety profile that is emerging for-
Yeah
COMP360 is such that it's a really low bar to trying it. Why wouldn't you, if you know you're gonna know pretty darn quick, and if it does work, it's durable, there's a very low bar to a patient wanting to try it because that safety profile was also very encouraging.
Right. If you have to put a fine point on it, if you look at the other two treatments that are being prescribed to patients with TRD today-
Mm-hmm
... SPRAVATO and TMS. With SPRAVATO, as we know, it is 8 treatments in the first month, that is considered induction. You are making the decision about response after those first 8 treatments at least. That's a month. Weekly in the second month, and then maintenance is often weekly, maybe every other week. You are having a conversation with a patient about a delay to determining response and then a commitment to many, many, many multi-hour treatments over the course of a year that their caregivers need to drive them to. With TMS, every day for 6 weeks, Monday through Friday for 6 weeks. Typically, response is evident 2 or 3 weeks at least into it.
To Terry's point, with the safety profile we've seen so far, where this is generally safe and well-tolerated, and you're gonna know so quickly, and it's potentially such a low burden of treatments over the course of a year, why wouldn't you consider it first?
Lori and Steve, the other part you mentioned was the safety. Terry mentioned the safety. How do you expect that to reflect in another really big topic of conversation with investors, which is the required site-specific safety and monitoring, the personnel required, what that final REMS is gonna look like, how far it spans around day of treatment? You know, does it need to encompass some of these next-day events that are popping up, not just with 360, but with the class in general? There seems to be a next-day sort of bracket of some of the psychoactive SAEs. What are your thoughts right now ahead of O06 Part B, obviously?
Yeah. I mean, taking them in reverse order, you know, no psychiatry treatment is a one-night stand, and then you get ghosted. This is longitudinal care.
Sorry.
He does it every time.
I know.
There's a new one every time.
I don't know how, I don't know how they put up with me. I'm insufferable. No, seriously, you know, this is chronic disease management. These patients are in longitudinal care, whether it's medication management, therapy, et cetera. Certainly these patients should be followed up on for safety, but they're already being followed up on.
Mm-hmm.
That fits very much into the treatment models that already exist. As far as the REMS and the personnel required to monitor.
Mm-hmm
... support patients during these treatments, fortunately, much of it's already built. You know, with the 7,000 plus sites delivering SPRAVATO that are set up to deliver multi-hour treatments already today. A room that's used for COMP360 would be the room that's used for SPRAVATO.
Mm-hmm.
They'll probably use the same room within the same day for both of them, frankly.
Mm-hmm.
The personnel are the same. The, the workflows...
The staffing might have to go up, correct? Or no-
No, not really.
Well, if they wanted to keep doing ketamine as well, would they? No? No.
Not really, 'cause it's a team-based model of care delivery. It's typically a single prescriber who might be a psychiatrist-
Mm-hmm
... or even a nurse practitioner or physician's assistant, and then a mix of nurses, medical assistants, maybe there's a therapist on site.
Mm-hmm
... administrative staff. There are multiple rooms operating simultaneously, multiple patients having a range of treatments.
Mm-hmm.
This team is taking care of all of those patients simultaneously.
When the guidance says there needs to be somebody in the room with the patient during the treatment, does that mean-
That is not to say that
that was clinical trial protocol.
Mm-hmm
which is very different than commercial application.
What do you expect the final requirement will be for that person the practice is paying to be in the room during the 6 hour-ish?
I wouldn't think about it that way.
Uh-huh.
I would start with the REMS, and we have been directed by FDA to look at the SPRAVATO REMS.
Mm-hmm
what they prepared in their briefing materials for Lykos's AdCom, which is very comparable to-
Mm-hmm
... the SPRAVATO REMS-
Yeah
... in terms of their expectations for what ours might look like.
Okay
... we will ultimately negotiate with them. What you will see is language around a prescriber available, licensed healthcare provider on site.
Mm-hmm. Mm-hmm.
There isn't the granular detail like you would see on our clinical trials.
Mm-hmm
... as far as-
Staying in the room, single person.
Right. Even with SPRAVATO, though, in practice, somebody is in that room much more than they're not in the room.
Okay.
The nasal spray administrations take 20 to 30 minutes, and those need to be directly witnessed.
Mm-hmm.
There are required vital signs checks. They're otherwise in and out of those rooms checking on patients. They also have cameras in the room, CCTV, that they use to centrally monitor these patients. It is highly comparable to what will be required for COMP360.
Great. With that, we are over time. I have, like, 10 other questions. Thank you guys very much. This is really It's a story that's certainly coming together this year through the end of the year, look forward to more updates and data.
Yeah.
Thanks, everyone.
Thanks for having us.
Yeah.
Appreciate it.
Thank you.
Appreciate it. God, usually it's other way around.