COMPASS Pathways plc (CMPS) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to this COMPASS Pathways update webinar. [Operator Instructions] As a reminder, this call is being recorded. I would now like to introduce your host for today's call, Stephen Schultz, you may begin.

Welcome, all of you, and thank you for joining us today for this webcast. Again, my name is Steve Schultz, Senior Vice President of Investor Relations for COMPASS Pathways. Before we begin, let me remind everyone that during the call today, we will be making statements about our future plans and prospects that constitute forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement, including those risks and uncertainties described under the heading Risk Factors in our most recent filings with the U.S. Securities and Exchange Commission. These forward-looking statements represent our views only as of today, and we specifically disclaim any obligation to update or revise any forward-looking statements even if our estimates or assumptions change. The call is being recorded and will be available on the COMPASS Pathways' Investor Relations website shortly after the conclusion of the call and will be available for a period of 30 days. Today, I'm joined by Kabir Nath, COMPASS' Chief Executive Officer; Dr. Guy Goodwin, Chief Medical Officer; and Lori Engelbert, our Chief Commercial Officer; Dr. Steve Levine, Chief Patient Officer; and Teri Loxam, our Chief Financial Officer, will also be available for the Q&A portion of the call. I'll now hand the call to Kabir Nath.

Thank you, Steve, and thank you all for joining us. I'm very pleased today for us to be presenting these important results from the COMP360 Phase III 005 and 006 pivotal trials. I hope you've all had the opportunity to review our press release issued earlier today with these positive results. Let me start by setting the stage. There is tremendous unmet need in treatment-resistant depression or TRD. It's estimated that over 4 million adults in the U.S. live with TRD each year. This is a chronic condition. With a significantly greater burden of disease than MDD. Over the years, many products that have tried to demonstrate efficacy in a TRD patient population have failed so much so that currently there is only one marketed medicine approved for use. In comparison, COMPASS has now met its primary endpoint with high statistical significance in three consecutive trials. We believe that the safety and efficacy profile that's emerging for COMP360 through our Phase III trials is highly differentiated and the COMP360 can be an important novel first-in-class treatment option for patients with TRD. These positive results we're sharing today mean that with two Phase III trials in our large Phase IIb trial together in over 1,000 participants, we are three for three in achieving the primary endpoints with high statistical significance. The key takeaways are the COMP360 is safe to try and that if you respond on average, you do so on day 1. And if you have a clinically meaningful reduction in MADRS, the treatment effect is durable. In 005, 25% of patients achieved a clinically meaningful reduction in symptoms by week 6, and that response was sustained through 26 weeks. In 006, that figure increased to 39% of patients. Taking all these results together, the emerging profile for COMP360 is redefining rapidity and durability for TRD patients. To see patients respond so quickly and to have responses that are so durable is remarkable in this condition that's chronic, extremely refractory with very few options. The only drug that's currently indicated for TRD and actually used is Spravato which is now nearing $2 billion in annual revenue. Importantly, patients need 10 Spravato treatments by week 6 to achieve a similar effect to what we're seeing with COMP360 at week 6 with one or two treatments. There are no approved drugs for depression, including Spravato that offer rapid onset, clinically meaningful effect and durable outcomes from just one or two treatments. This supports a compelling novel paradigm for patients and providers where effectiveness can be determined almost immediately after a single treatment. This is incredibly exciting news for those living with TRD. We've submitted this data to the FDA and have requested a meeting with them to further discuss our NDA filing strategy and the potential for a rolling submission and review. With breakthrough designation, we will also request an expedited review, which we believe is likely to be granted. With these accelerated regulatory options, we will be prepared to launch by the end of this year. Lori will discuss our commercial strategy and the work we've already been doing to be prepared for launch. First, let me hand the call to Guy, who will take you through the data in detail.

Thank you, Kabir. Let me begin by saying simply that the COMP360 clinical program, I believe, sets the international standard for psychedelic medicine. It is robust, it's creative, and it cuts no corners. The program has generated the most robust and consistent evidence to demonstrate the pharmacological efficacy of psilocybin for treatment-resistant depression. I want to thank the team that made this happen. They brought their experience and commitment to the single goal of developing a drug to change the course of treatment for patients with intractable depression. The team, which includes patients, caregivers, clinicians and the COMPASS team have our sincere gratitude. First, let me review the design of the COMP360 Phase III clinical program in treatment-resistant depression. In our trials, TRD was defined as having failed two to four previous treatments in the current episode. The MADRS total score was required to be greater than 20 at both screening and at baseline so moderate to severe current symptoms. Participants were also required to come off any existing antidepressant medication that they were taking. All 005 patients were from the U.S. about half of the patients entering 006 were from Europe and the other half were from the U.S. and Canada. COMP005 compares a single treatment with 25 milligrams of COMP360 to placebo, and primary endpoint at 6 weeks is the change in MADRS total score from baseline. The MADRS was administered remotely by blinded raters throughout our clinical program. After the 6-week point in Part B, patients were eligible for retreatment, if their symptoms had failed to remit. Patients had the option between blinded retreatment with the original dose of COMP360 or placebo or they could elect to go on to one of the predefined list of antidepressants. Today's data goes up to the end of Part B for 005. This was a blinded portion of the trial, which continues to 26 weeks and is now complete. Part C continues out to week 52. The second trial, COMP006 compared three doses of COMP360, 25 milligrams, 10 milligrams and 1 milligram delivered twice at a 3-week interval. Today, we are presenting data up to the 6 week primary end point and beyond to 9 weeks, which is the end of Part A in this trial. It is an ongoing study so patients are continuing in Part B, which remains blinded. The criteria for retreatment are as in 005. Approximately 80% of patients have now completed Part B in 006. Note that in 006, the comparator is 1 milligram COMP360 delivered twice. It is an active, not an inert placebo. The advantage of this are that it reduces unblinding leaving patients uncertain of which dose they're likely to have received. Therefore, it adds validity to any claim about a pharmacological effect at 25 milligrams and also effectively parallels the design of our Phase II study, COMP001. The primary endpoint for 006, like 005 was changing the MADRS total score from baseline at week 6 comparing 25 milligrams and 1 milligram and there were additional secondary end points, which are not all available at this time. Looking now at the demographics 005 and 006, the blinded randomized allocation of the patients between the arms successfully generated very similar treatment groups. Over 800 patients entered the two studies, there were 171 randomized to receive 25 milligrams of COMP360 and 87 to receive placebo in 005 and 296 to 25 milligrams, 142 to 10 milligrams and 143 to the 1-milligram group in 006. Study discontinuation rates were low and well within the assumptions that we made in creating the power calculations and the model for analyzing this data. Prior psychedelic use was again well below the 15% threshold set for the studies so an overwhelmingly psychedelic-naive population. Next slide shows the treatment history of the current episode. This and the MADRS baseline of 32 confirms that this was a highly symptomatic treatment-resistant population. Bear in mind that these treatments were required to have lasted 8 to 10 weeks at adequate dose and with proven medical records, which was a very exacting criterion for study entry. The number of patients required to withdraw from antidepressants in the trials was about 70%. Everything, again, was very consistent across study arms in both trials. Finally, in both trials, we see a consistent depression history. The mean length of the current episode was over 3 years and the number of lifetime episodes again, relatively high in all groups, illustrating the persistent and recurrent nature of the disorder. So to summarize, this represents a patient population who had recurrent depressive illness and a current episode that was well documented, chronic and proved very difficult to treat, a very different population from MDD trials, which we are much more used to seeing in the literature. We have successful recruitment, even patient distribution successful randomization to the different treatments and the high patient numbers required for a high-quality, well-powered clinical study. Let us now look at the results of the 005 trial, starting with Part A. Last year, we announced just the primary endpoint of this study at 6 weeks, the difference between 25 milligrams and placebo. Here, you can see that the 25-milligram dose produced or a bigger effect than placebo at every time point with high statistical significance. Moreover, the effect of the treatment is immediate and so observed, in fact, the day following drug administration, an extremely rapid onset of action. Next slide, please. The data from Part B provide the key finding from COMP005 that we present today for the first time. It is a remarkable graph because it demonstrates the persistence of a treatment effect of one or two 25-milligram doses of COMP360 psilocybin over the full 26 weeks of a double-blinded study in treatment-resistant depression. You can see numerical separation at all time points up to 26 weeks. Recall that after 6 weeks or Part A, eligible patients have the option for a second administration of COMP360. About 70% of the patients in the 25-milligram arm and 50% of the patients in the placebo arm received a second administration in Part B. So our second dose of 25 milligrams for the 25-milligram randomized patients and a second placebo for the placebo allocated patients. Most of these treatments occurred between 10 and 14 weeks. Some will alternatively have started antidepressants, but we do not have these numbers at this time. There are also patients who withdrew from the study in both treatment groups at approximately equal rates. Accordingly, further analysis is needed for a complete understanding of this data. Nevertheless, viewed as an intention to treat, it's very striking that the treatment difference is maintained over such a long double-blind follow-up. Furthermore, the relative nonresponse in the placebo group is prospected evidence to suggest that this patient population was indeed difficult to treat and further demonstrates the robust execution of this trial. We have also looked further as planned at the 25-milligram arm to clarify just how the average effect you see here can be understood as composed of patients showing good effects of treatment and those who are effectively nonresponders, something we had tentatively explored recently -- previously pardon me in our Phase II trial. This chart shows a breakdown of the patients receiving 25 milligrams COMP360 in 005 into three groups. The first group were defined as remitters and are shown in green. These were patients who showed a very rapid reduction of symptoms to levels below 12 on the MADRS. And you can see that the effect is well sustained out to 26 weeks. Only three of these 11 patients receive retreatment and only after week 12. So a sustained remission is possible out to 26 weeks after a single administration of drug. It represents a smaller group in this trial than we saw in our Phase II study. However, if you look at the portion of participants that achieved a clinically meaningful reduction in MADRS of more than 25% in the 005 trial at 6 weeks, which was 25%. Interestingly, this figure in the 006 trial increases to 39% with the second fixed dose. Responders and partial responders are shown in blue. The justification for taking an interest in partial responders or patients who had a reduction in symptoms of between 25% and 50% is that in TRD, even marginal changes in the intensity of severe symptoms is a significant benefit, both subjectively to patients and objectively in terms of the cost of their illness and the risks that are associated with being chronically depressed. The dotted red line on this graph provides a guide to what a 25% reduction of the average baseline score of 32 would look like. A 6-point change in the MADRS has been recommended previously as clinically meaningful in TRD after an in-depth analysis of data from the esketamine trials. This obviously corresponds to a less than 20% change from the mean of 32 in 005. Some of this group will have received a second treatment between 10 and 14 weeks but as a group, they show sustained benefits out to 26 weeks. Of those who did receive a second dose in this period, over 40% achieved remission after that second dose. And then finally, for comparison that there are the nonresponders, the gray line. This is a group who do not particularly benefit from COMP360 as a dose of 25 milligrams, and one knows that very quickly because they never show a sustained benefit. So to summarize, 25% of participants in the 25-milligram arm achieved a clinically meaningful reduction in MADRS at week 6, and that effect was maintained at least through week 26 with the majority of retreatment between 10 and 14 weeks. The magnitude of the MADRS improvement among responders is cost, consistent, it's durable and it's clinically meaningful, and Lori will talk more about how commercially meaningful it is as well. Now I will review the Phase III COMP006 trial data. The results of the primary endpoint from 006 at week 6, as shown on this slide. In orange, you can see the response has change in blinded MADRS ratings from baseline to 1 milligram repeated dose of 3 weeks. In green, the response to 10 milligrams repeated at 3 weeks. And finally, in blue, the 25-milligram dose repeated at 3 weeks. There is a statistically significant difference from the 1 milligram dose for 25 milligrams at every time point beyond baseline. In addition, you can see that at 1 week, 3 weeks and 6 weeks, there is a numerical dose response effect with 25 milligrams showing a bigger effect than 10 milligrams and a more markedly different effect from 1 milligram. The 10-milligram effect is bigger than we saw previously in our 001 study, which did not find 10 milligrams to be an effective dose. It is notable that the effect size at 6 weeks of minus 2.5 while statistically significant is below the level of 3 on the MADRS, which is often regarded as a threshold for clinical significance. In summary, we have a successful clinical trial demonstrating clinically meaningful and highly statistically significant effects of 25 milligrams COMP360 repeated after 3 weeks in patients with severe treatment-resistant depression. This is a remarkable finding given that we now have as Kabir has already said, three positive results in three similar trials for our preferred dose of 25 milligrams. For completeness, this slide shows the same data up to 9 weeks, the end of Part A. We do not see this data as fully interpretable without the longer-term 6-week data we will see later this year. To further understand the relationship between the two studies, 005 and 006, this slide compares the primary endpoint results from 005 overlaid with the results from 006 for 25 milligrams and their comparator. What you can see is the remarkable reducibility reproducibility of the treatment effect at day 2 and week 1 for the solid line 25-milligram dose and the secondary response to treatment with 25 milligrams at weeks 3, giving a deeper response at week 6 in blue than we saw in 005. Turning to the dotted lines, 1 milligram also shows a numerically greater response than inert placebo at all times from 1 week, suggesting that it is acting as planned as a low dose of active drug different from inert placebo. Obviously, the difference from this comparator is less than might have been seen had there been an inert placebo in 006. This, again, is a validation of our trial design a validation of what we thought was important in terms of providing an active comparator and clearly, validation of the idea that retreatment with this drug produces a significant reduction in symptoms. Moving now to safety. We will consider the two trials, 005 and 006 together. Just to give a high-level summary, we believe COMP360 has been demonstrated in both trials to be generally well tolerated with a safe profile and the majority of adverse events resolving on the day of treatment. Overall, the safety we have observed is consistent with the known profile of COMP360, and we had no new safety signals identified in this large database of now over 1,000 patients. For the data available to date across both trials, the rate for SAEs, Serious Adverse Events of suicidal ideation was less than 1%. There was only 1 SAE of suicidal behavior which occurred in the 1 milligram arm in COMP3 -- 006. The DSMB noted that there is the data monitoring board noticed that there is no evidence of a clinically meaningful imbalance between treatment arms in suicidality in either study. For both 005 and 006, most treatment-emergent adverse events occurred on the day of study drug administration and the majority resolved within a day. There were 11 treatment-emergent serious adverse events in 005, which includes both Part A and Part B and six in 006. I'll show the tables with greater detail on the next slide. Looking at the top treatment-emergent adverse events shown as percentages in brackets for Part A of both trials, you can see the relatively low number of serious adverse events and the rapid resolution of most of the nonserious adverse events within a day seen in both studies. The somewhat higher rate of treatment-emergent adverse events in 006 would be expected because it includes two administrations of drug. Next slide, please. Regarding treatment adverse events in Part A of both trials, we see the usual items, headache, nausea, hallucination, anxiety, albeit in a slightly different order between studies. The more common events clearly also show dose response, as one would expect in study with studies with different doses of COMP360. The high number of COMP360 related events is, of course, expected given the change in conscious experience it produces. Accordingly, it is important that the reported events tend to resolve so rapidly. Looking at the serious adverse events, the SAEs in Part A, you can see that across 005 and 006. The evidence assessed by the DSMB is revealing no evident clinically meaningful imbalances of serious adverse events between arms, particularly those relating to suicidality. We see a low number of suicidality events that are evenly distributed across the treatment arms and perhaps an unsurprising phenomenon in a TRD population. Next slide. Finally, considering the TAEs and the SAEs through 26 weeks through Part B in 005, there are no important additional treatment-emergent serious adverse events. Of the five instances of suicidal ideation or depression, suicidal in the 25-milligram arm, three of these events occurred in Part A, one on the day of dosing, which resolved within 24 hours and two in nonresponders also both resolved. The two additional cases in Part B also occurred on a day of drug administration and resolved in 24 hours. These events on the day of dosing appear to be transient and inconsequential. It may be important to distinguish such phenomena from the suicidality that is the usual part of depressive illness. Once our safety database is complete, we will be able to give clear guidance on this regard. There have been no attempted or completed suicides to date in these studies. In summary, we are pleased to see the emerging safety profile of COMP360 from over 1,000 patients being generally well tolerated with a safe profile. Thank you, and let me hand to Lori.

Thanks, Guy. I am thrilled to be able to speak today about the potential commercial opportunity for COMP360 based on the emerging clinical profile from the data sets presented today and update you on our commercial progress. Given we now have two positive Phase III trials, and as you heard from Kabir, our plans are to be launch ready by the end of the year. Data from these trials demonstrate that COMP360, if approved, will be highly differentiated from currently available treatment options and is well positioned to become the leading treatment for the millions of TRD patients who are underserved today. Let me start by highlighting the tremendous unmet need for patients with treatment-resistant depression. Approximately 1/3 of drug-treated MDD patients are considered treatment resistant and prevalence is high with an estimated 4 million patients in the U.S. alone. Once an MDD patient is considered treatment resistant, which is only after being failed by two currently available to antidepressants, the chance of achieving meaningful clinical outcomes from additional antidepressants is significantly diminished and the patient and economic burden of disease becomes dramatically higher. TRD has a significantly greater impact on individuals' lives compared to MDD, and those impacts start as quickly as the second treatment failure. The famous STAR D trial showed that due to ineffective treatment options, chances of achieving remission from MDD are cut in half when a patient needs to start a third-line antidepressant, the point at which they are considered to have TRD. Treatment-resistant depression is a chronic condition. These patients experience 3x longer depressive episodes, increased comorbidities, for quality of life, greater work time loss and a greater than 50% increased risk of suicide compared to MDD. Medication treated MDD represents a staggering economic burden estimated at close to $100 billion annually. Approximately 1/3 of MDD drug-treated patients are considered treatment resistant. But given the drop-off in clinical outcomes and increased health care costs after being failed by two antidepressants, TRD patients disproportionately account for almost 50% of the overall cost. This suggests that if effective treatment options were to become available, it could potentially lead to large economic and societal gains. Historically, it has been incredibly difficult to establish efficacy in a TRD patient population and clinical trials. Several MDD indicated products have tried and whereas they did prove efficacy in a broader, less severe MDD patient population, they were unable to prove efficacy in TRD. Currently, there is only one approved and used TRD indicated medicine available, Spravato, and even they failed to demonstrate efficacy in some of their TRD trials on the path to approval. Difficulty in establishing efficacy in a TRD patient population has led to extremely limited treatment options and a huge unmet need given that even when including nondrug neuromodulation treatments of ECT and TMS, less than 4% of TRD patients are receiving TRD indicated care. We released a lot of meaningful data today. From a commercial perspective, the most important takeaways are: First and foremost, COMP360 demonstrated through multiple robust clinical trials, consistent, clinically meaningful efficacy in a patient population that has limited options. With only one other medicine FDA approved being used for this patient population, the potential approval of COMP360 will bring hope to millions of patients and their providers. Second, in both 005 and 006, COMP360 demonstrated extremely rapid onset of action, with deep and dramatic reduction in depressive symptoms as quickly as the day following administration. These are impressive and meaningful results, especially in this particular patient population where nothing else has worked. Effects that quick can be life-changing for patients and may give clinicians the ability to determine as quickly as the day after dosing, if COMP360 is the right treatment for their patients. This is highly differentiated against other products that can take weeks to months to determine if the treatment is working for their patients. Third, and perhaps most impressive, in 005, COMP360 demonstrated durability that lasts at least through 6 months after only one or two administrations. This is highly differentiated versus Spravato, where per label Spravato needs to be dosed every 1 to 2 weeks to maintain durability following the high burden of 12 initial treatments. If approved, COMP360 could offer significantly reduced patient burden without sacrificing clinical outcomes. And finally, but importantly, COMP360 demonstrated a generally well-tolerated and safe profile, potentially making it easy for clinicians to try COMP360. COMP360 is redefining rapidity and durability that can be achieved in TRD. Given the data presented today, we are confident that if approved, COMP360 can provide a highly differentiated and compelling clinical profile for a patient population that has previously been difficult to treat. Given the limited treatment options available and the only other medicine being prescribed for TRD is treating less than 2% of the TRD patient population and still generating close to $2 billion in revenue. We believe COMP360 is well positioned to bring a welcomed new treatment option to patients and realize blockbuster potential. If approved, COMP360 will be the first to market in a highly anticipated new class. Given the data shown today, COMP360 could be the first and only option that demonstrates extremely rapid onset of action, with durability out to at least 6 months after only one or two doses. As we work with the FDA to seek approval for this important new treatment, the commercial team is actively preparing for launch. COMPASS has been very active with pre-commercial work over the past several years. Now with the clinical profile of COMP360 emerging, we can begin some of the more advanced commercial prep work. This includes more detailed discussions with payers, preparing effective marketing campaigns, enabling distribution and preparing the field force. All of this will be complementary to the ongoing educational efforts with patients, HCPs, sites of cater and federal and state policymakers. At launch, we are prepared to leverage the well-established existing interventional psychiatry infrastructure. These treatment sites are specifically designed to support products that require a multi-hour support and monitoring such as Spravato with over 7,000 sites across the U.S. and growing rapidly. These centers are already equipped with the staff, operational know-how, and infrastructure needed to support additional multi-hour treatments like COMP360, with many of these sites already scaling in anticipation of a COMP360 launch. If COMP360 is approved, it will undoubtedly bring a welcome and meaningful new treatment option to TRD patients and their providers as effective new treatment options are desperately needed. Our launch planning efforts remain focused on ensuring sites are prepared to administer COMP360 and that TRD patients can access COMP360 upon approval. COMP360 has the potential to fundamentally change the way that patients living with depression are cared for and COMPASS is committed to helping as many patients as possible. The launch of COMP360 is poised to be one of the most highly anticipated launches in recent history, and I look forward to discussing our launch readiness with you over the coming year. Let me hand the call back to Kabir.

Thank you, Lori. Let me first thank all of the participants and clinicians involved in our COMP360 clinical program. Your support has been remarkable and has helped position COMP360 to be the first classic psychedelic to be approved by the FDA and a condition of significant unmet need where patients today have so few options. As I said earlier, we've requested a meeting with the FDA to discuss our NDA filing strategy. The agency has shown strong interest in an aggressive filing strategy, including the potential for a rolling submission and rolling review. That would enable them to review the clinical module as data comes in and not require all clinical data in the package prior to commencing review, which makes the 26-week 006 data due in early Q3, the last gating item to complete our NDA package. Practically speaking, this could shorten the review cycle and result in an acceleration of the approval time line. And as Lori said, we expect to be ready to launch commercially by the end of this year. As she mentioned also the continued increase in the interventional psychiatry clinic infrastructure driven both by Spravato and the eager interest around the potential promise for psychedelic treatments such as COMP360 is exciting for patients. We're confident that COMP360, if approved, can be effectively integrated into this growing infrastructure and offer a differentiated and compelling treatment option for patients and providers. COMP360 has the potential to transform the landscape for those living with TRD through a rapid, safe and durable treatment option. We're looking forward to meeting with the FDA to see how expeditiously we can move this forward through a potential regulatory approval process. And with that, thank you all for joining. Thank you for your attention. I will now turn the call back to the operator for Q&A. Thank you.

[Operator Instructions] The first question comes from Francois Brisebois from LifeSci Capital.

Congrats on the data and the update here. I just had a question in terms of the -- on the 006 front, the dose dependence there, I think you mentioned that the 10 mg arm seem to have worked a little better than it had in the past. And so is there a possibility here with the two doses that there's some sort of a ceiling effect may be where the 10 mg arm worked better just because there was another 10 mg, 3 weeks later? Or just any color on that dose dependency between the 10 and the 25 here that we saw.

Thanks, Frank. Just to check, you can hear us clearly?

Yes. Yes. Absolutely.

I will hand that to Guy in a second, but I think just the first thing to say, well, acknowledging that there was a modest significant effect for 10 milligrams here, we didn't see that in 001. So from our perspective, we're really focused on the 25 as the active dose that we want to take forward. But let me hand to Guy to comment on your question around the two 10s.

Yes. I mean thanks, Frank. I mean we're going to be very interested in looking at this data in detail once we have, for example, individual distributions to look at the different time points, which may give us some understanding together with a look at the intensity of the psychedelic experience, which previously was very informative and understanding who responded and who didn't. So I think I'm afraid we simply have to say at the moment, we don't really know the answer to your very good question. But we do think we have the data to approach the answer subsequently, and we'll obviously put that forward and publish it in due course.

Okay. Great. And then I'll sneak in a quick one here. There's a lot of data. Just can you help us understand, you mentioned maybe the difference that you're seeing between a true placebo and the 1 mg arm and the implications of that? And then lastly, was safety here, how happy are we with the data, the safety seems very, very clean off two doses within 3 weeks. Is that something that is almost surprising or we're just happy and we're moving forward here.

Well, we're certainly happy about the second of the points you make, and particularly that in fact, if anything, the side effect profile reduces a little bit with the second administration, so in a sense, it becomes more tolerable. On the first issue, I'm not sure that we have a really clear answer to that. So we're going to have to see how we go. It's most important really that the 1 milligram gives validity to the trial. The usual criticism, of course, is that inert placebo is fully unblinding and any comparison with that and an active drug is invalid or at least really is just a safety study. We designed both 001 and 006 to overcome that by having a low dose, which was the main -- so the low expectancy response arm of the study was actually active drug and then patients when they were consented would be told truthfully that they would definitely receive the drug. It's just they would get different doses. So we think that the validity from the point of view of this interpreting efficacy is very good. The difficulty, of course, is it means the comparison with -- if it's an active treatment, then, of course, in a sense, diminishes the difference that you see between it and the 25-milligram dose. So yes, it's a very -- it's going to be a very interesting debate that we have subsequently. And there are further data that will weigh on, particularly relating to expectancy that we'll be able to clarify in due course.

The next question comes from Paul Matteis at Stifel.

Can you hear me okay? Excellent. Great. Congrats on the data. A couple of questions for me, if you don't mind. So on the durability data, I appreciate the transparency there. How do you expect FDA to evaluate and do sensitivity analyses on the durability data? And I know it's premature to talk about what a label looks like, but even just generally, what do you see as the likely directive that's going to be provided to physicians on when and how to redose? And then second, I appreciate that a second dose in the 006 study is showing some evidence of additive efficacy, is it your perception that most patients will get these two doses for induction? And is that how you think might be the best way to position this commercially? And then I have one follow-up.

All right. Thanks, Paul. So I'll ask Guy initially to comment just on how the FDA might view some of this from a durability and then come to Lori to talk about the label and the commercial implications. So Guy?

Yes. I mean it's certainly the case that in their guidance, the FDA have emphasized that they want to see evidence for durability. We're providing that in spades. I mean, they're, in fact, only requesting 12 weeks. We're going to provide 26 weeks. I think it would be a little bit presumptuous for me to suggest how they should analyze it and I'm reluctant to. We have a very good relationship with the staff at the FDA, and we think we should leave them to make their own decisions about how they analyze the data.

Paul. So from what we expect from the label, I mean just based on what we're seeing from the data now, it will likely be more of a one or two induction-ish type phase to start a patient and then less directive on winter retreat and likely will be more on an episodic base, well so that would translate like the -- based on the data that we're seeing, obviously, we'll be up to physician discretion and patient discretion, but I don't expect the label to be restricted to or directive to dosing. I also would love for Steve Levine to chime in here from a physician standpoint on what he thinks from based on the data in terms of dosing, what might look like in the real world.

Thanks, Lori. Yes. So as Lori said, likely some language related to one or two initial administrations. I think that in clinicians' hands and in discussion with their patients, given that we're able to see the impact of that first treatment almost immediately, that will give them very quick and useful information to make a determination about whether a second dose initially may be indicated and then following them clinically over time when it may be appropriate to retreat. One thing that I'll point out is that one of the things we saw very clearly in Part B of 005 related to a second dose is that group that had at least a 25% reduction in their MADRS, which is clinically meaningful. These are partial info responders. Those that received a second dose 40% of them went into remission. I'll repeat that because it bears repeating. Of the 25-milligram arm, those that had at least a 25% meaningful reduction in their MADRS who got a second dose, 40% went into remission, which tells us that not only can this group have a very meaningful initial response, but a second dose might deepen that. This is a group that's very heterogeneous and so this will be a matter of discussions between patients and their doctors over time. But the sum total of this data suggests to us that one or two treatments with either on a fixed interval or over a longer period of time can have significant durability at least out to 6 months.

The next question comes from Judah Frommer of Morgan Stanley.

Congrats on the update. Maybe just to follow up on Steve's comments there. Could you help us parse out kind of MADRS reduction versus responder remitter rates and how those can be viewed or will be viewed by both regulators and clinicians. I think investors are kind of laser-focused on that MADRS separation. But how should we be thinking about remission rates and how will docs think about those? And then just on the safety profile with the suicidal ideation, it sounds like it's largely transient and kind of goes away on day of dosing. How could that factor into monitoring time lines and potentially monitoring profile that you'll be able to tie into the CPT codes you've talked about.

Thanks, Judah. So I'll hand to Steve to talk about that.

So first, on the question about the MADRS separation, the meaningfulness of the different categorizations of response. Certainly, initial remission is wonderful. This, as a reminder, is a very different population than MDD though, patients living with treatment-resistant depression have a severe and chronic refractory course of care. And anyone who's cared for patients living with TRD know that even small reductions in MADRS can have outsized impacts on their clinical course, on the quality of life, on the resources that they consume and receiving their care, et cetera. That can be even minimal change can have an outsized impact, but a robust reduction of 25% of their MADRS will frequently result in significant improvements in quality of life and level of function. And so that's why it's important, I think, for us to consider not just the typical categories of remission or full response as a reduction of 50% in symptoms. But the way the clinicians will look at this is what can I expect in terms of the impact on the course of my patient's illness. And today, they really have very, very few options that will make that meaningful impact. In terms of the second part of your question about monitoring and how that relates to the CPT codes, yes, we'll be -- as we dive deeper into this data, we will learn more about the total time that patients were monitored and supported on this administration day ultimately with the new CPT codes because they're reported on an hour-by-hour basis regardless of the needed length of monitoring, all of that time will be fully reimbursed for providers.

And Judah, if I may, I'm actually going to ask Guy, just to comment on your question around the transient nature of the suicidal ideation and perhaps give some actual concrete examples of what we saw in the study. Guy?

Yes. I mean it's very striking that we see these very brief transient effects in the 25-milligram arm in 005. We haven't actually yet seen them in 006, but obviously, we're still collecting data there. Looking at the detail, they're somewhat unusual in that -- to give an example, one of the cases with someone who had the full day of 25 milligrams, they went home and in a somewhat altered state was struck by the surroundings being extremely messy in the house being in a tip. And out of that grew the conviction that if this woman could sit there and will herself to die, that she might be able to do it and that she should do it. And that lasted -- that state lasted for another about an hour or 2 hours, and then finally passed in the next morning, she was completely without these symptoms. Now that seems to me potentially something that one needs to understand as a manifestation of the -- some of the unusual features of having exposure to high-dose psilocybin. On another occasion, a lady was the next day, had a very strong flashback to the face of a friend who she pictured during the dreamlike state of the 25-milligram experience. And this had a very big impact on her transiently that she became very tearful and felt suicidal for about, again, a couple of hours. Now these phenomenon being described during a very intense supervision by medical staff. So we don't know whether they would occur naturally in the course of illness. But I don't think I've heard patients really describe that very frequently. And so I think it's something we may have to factor in as a feature of the management of these patients that we have to maybe warn them about and think about incorporate into clinical management. But they're not very common, and they don't seem to carry the same kind of threat as if depression -- the impulse to kill oneself arises in the course of a depression where the other symptoms are present. And therefore -- and it may last quite a long time. So some of the other instances we see not related to dosing are of that kind. So these are nonresponders. They have a lot of depressive symptoms. Their suicidality goes up that's a very kind of well understood and common phenomenon of severe depression, in particularly TRD. And that just as a clinician feels different from this kind of rather transient effect we observed with the dosing. Rare though it nevertheless also is. But it's going to be part of the risk benefit as we understand it, and we're clearly going to be transparent about anything that we see in this area.

And Judah, just one final point to reiterate something Guy said, we are not sharing remission and response data from 006 at this point because that study is ongoing, and there are still some ratings to be done for patients remaining in Part B and that would run the risk of effectively unblinding the final part of Part B if we were to share the arms for now. So I just wanted to reiterate something that Guy mentioned.

The next question comes from Josh Schimmer at Cantor.

The Part B component of the 005 study, what percent of patients were redosed and what do you expect the real-world redosing spectrum to look like? You talked a little bit about how you expect kind of the initial one or two doses to evolve. But how do you see it occurring for the rest of the treatment phase?

Yes. So what we know, Josh, is that on the 25-milligram arm, 70% elected or retreatment and on the placebo arm that was just over 50% that elected a retreatment. In terms of how we think that's going to translate into practice, let me turn to Steve.

Thanks, Kabir. Josh. In part, I think we're going to want to see the 26-week Part B data for 006 to inform that as well. Because what we're seeing in Part B for 005 is the rates of retreatment after a single initial treatment, which might look somewhat different than after two initial treatments. Nonetheless, and repeating some of what I had said earlier, this is a heterogeneous population. Ultimately, it's going to be a conversation between patients and their clinicians evaluating their initial response to one or two doses to make that determination. But given what we've seen now, we have the two fixed doses in Part A of 006 as well as the effect of a second treatment in Part B from 005. It certainly is a very exciting finding that one or two treatments can have such a durable response after 6 months and potentially longer.

Can I just quickly ask Guy the suicidal ideation cases and it sounded a little bit like reactivations that are characterized through some of the other psychedelics, is that a reasonable comparison in terms of what these patients are experiencing?

Reactivations as in the sort of HPPD diagnosis. I'm not -- I don't think that we really picked up all the phenomena that are associated there. There was some visual imagery for one of the examples that we gave. Maybe that's a little bit related. But you'll appreciate our understanding of even that phenomenon is something that is developing as we see greater use of these drugs in controlled settings. I mean, clearly, many of the more florid consequences of taking these drugs have been described in recreational settings with uncertain doses and co-administration of other drugs. So I think we have to watch this space. We're developing the biggest database that you could over 1,000 patients and many exposures. And I think when we get to summarizing that, we'll be a lot clearer about whether there is a relationship or not to the sort of phenomenon that you just mentioned.

The next question comes from Gavin Clark-Gartner at Evercore.

So I just had one set of questions for COMP005 on Part B. What were the percent discontinuation for any reason on both of those arms. When did those happen over the course of the 26 weeks? Also, what percent of patients in either arm received any rescue treatment, not retreatment, but rescue. And then finally, can you just remind us if any data gets imputed during this period and how it's done.

Yes. Guy, do you want to take those?

Yes, yes. The discontinuation rate in both arms of the study was about 28%. And most of the discontinuations in Part B, and that isn't all of them because, of course, people also discontinued in Part A. Most of them -- all of the distribution has taken place by the -- by 10 weeks. So by 10 weeks, almost all the patients who are going to drop out or dropped out, and the numbers were about 28%. Bear in mind that one of the features of the design was access to open-label treatment in Part C of the study. And so we had hoped that we would retain patients very well. Overall, that was true. So that dropout rate is very low compared to standard antidepressant trials, for example, in MDD or indeed TRD. Sorry, what was your other -- the other question was the number of rescue treatments. We don't have that data yet. Much of this was -- is fairly detailed in 005. It's not the full data set, and we don't have that yet.

And Gavin, just to add the dropouts to Part A, were well within our planning assumptions from our power calculations and actually somewhat lower than you would typically see in a depression trial even to week 6.

And by the way, just on the stats, we had not -- there's no imputation at all for the data given beyond 6 weeks. There is an invitation for missing values, missing at random model in up to 6 weeks, obviously.

The next question comes from Ritu Baral at TD Cowen.

Two for Guy and Steve and forgive my voice this morning. And then a follow-up for Lori. One, just given that intriguing 40% remission rate, what in 005. Guy and Steve, can you disclose at this point what the criteria, the prespecified criteria for that second dose was that possibly drove that week 10 to 14 change in the 005 MADRS line? And two, can you talk to any details around the time -- average time to discharge readiness? And as part of that question, could you just address any cardiovascular heart rate or blood pressure excursions that you might see? There didn't seem to be a lot of detail in the safety event, and I just wanted to make sure that, that was because there were no events. And then I have a follow-up for Lori, please.

Thank you. So I think guy, if you could take the criteria for redosing in Part B, please, if you start there?

Yes. We have actually that public in the current summaries of the data in public. So I'm not sure that we want to give that as a help to our competitors. But suffice it to say, there is a criteria in which was carefully exercised.

I think we can add though that high level, it was those who have not yet achieved remission at the end of Part A or those who had subsequently relapsed.

Got it. And time to discharge?

On the day of administration, you mean?

Yes, including any CV parameters or CV excursions you saw?

I don't know that we have time to discharge data. I'm not aware of that. That's something that may come in due course, but we don't have that at the moment. And then Guy, if you could just comment, I mean, on the blood pressure side, specifically.

Yes. I mean, certainly, we see blood pressure -- there is a blood pressure signal, and this is already well known with COMP360. And similar drugs. As you can see, we have -- we will be describing that in full detail in due course, but there was nothing that was concerning and there was certainly no subsequent consequences of elevations of blood pressure. Most of them were -- virtually all of them were within the sort of excursions you would see during moderate exercise.

Got it. And then the follow-up for Lori. Lori, you mentioned on your slide that some of the activities would be enabling distribution activities at this point as you have the data in hand. What sort of activities will you be embarking upon for, I guess, helping set up distribution sites for later in the year and next. What can you help sites with?

So it's -- I think of distribution as more of this product being shipped through a distributor to specialty pharmacy or to sites of care for buy-and-bill situation. So there are a couple of things to that enable distribution, and that is one working with the FDA -- I mean, the DEA after FDA approval to get the product rescheduled so that it can be successfully distributed as well as states to make sure that state-level rescheduling is also done so that physicians can prescribe and the product can be distributed to two sites of care during immediate as quickly following approval as possible.

The next question comes from Patrick Trucchio at HC Wainwright.

Congratulations on the data. A couple of questions from us. First, I'm wondering if you could further elaborate on how the Phase III program design, particularly the use of the 1-milligram active comparator in 006 and blinded remote MADRS raters helps to mitigate any questions around functional unblinding and expectancy effects. And then secondly, can you walk us through the regulatory path forward from here? And specifically, I'm wondering if there have been any meaningful shifts in FDA feedback, personnel or perspective as the program has progressed over the last year that could impact the rolling submission. And as you look toward a potential 2026 launch, what would be those key gating items we should look for between now and year-end, including 26-week durability data from COMP006, is that required for approval? Likelihood of an advisory committee and anticipated timing and mechanics of DEA rescheduling.

Okay. Thank you. So I'll ask Guy to comment first on the question around the 1 milligram dose and the central raters and how we do believe that, that should deal with the functional unblinding question. Guy?

Yes. I mean we believe it will have fixed it. But in addition, we built into this design additional to what we did in 001 pretreatment measures of expectation and post-treatment measures of unblinding. So we'll have some idea of both what patients expect to happen, whether that in any way predicts response, which in some other studies, it hasn't with psilocybin and also whether post hoc, we see differences in conviction and accuracy in guessing what dose was delivered. So we will be able to deliver an assessment of whether our design has achieved what we believe it is likely to have achieved.

And from the regulatory perspective, Patrick, let me -- last year when we had the primary endpoint from 005, we said we'd met with the agency. They were intrigued and we're clearly open to discussing a rolling submission and review. But clearly, they needed a reason to believe. And that's one of the reasons why we put all this data together in a simultaneous release today. This data is now with the agency. We believe that this does give a strong reason to believe and a confidence in potential approvability. We have requested a meeting at which we would hope to align on that potential for a rolling submission and review. In parallel, we've obviously been doing work at risk so that we would be in a position to put in modules effectively very quickly, such as on a preclinical and CMC side. And as we said, if in fact, they are open to that review, for instance, this pretty significant amount of data at this stage, than the 006 26-week data, which we expect in early Q3. Our ability to integrate that into the submission becomes the final gating item for the submission. And that's how we're thinking about it. As I also mentioned, we do have breakthrough designation. While that does not guarantee priority review. It's historically been pretty highly correlated with priority view. We would expect to get that -- and again, with an NDA being completed in Q4, and obviously, we would target sooner in Q4 if we could. But with an NDA be completed, that gives you some sense of the potential approval time line. On the DEA side, the formal process is that while the FDA makes their own recommendation on rescheduling based on analysis and so, the DEA independent, but subsequently, does it as well. But I'll ask Lori to comment a little more on that because clearly, we have had some engagement around that.

Yes, Patrick. So the DEA has 90 days after an FDA approval to reschedule the products right now currently. We are obviously doing some work. It's been pretty well publicized. The work that we're doing, especially with this class being Schedule 1 products, almost all psychedelics have breakthrough therapy, doing some work with the FDA and DEA to help tighten up those time lines. So that is work that is in progress. We're trying to educate as much as possible and push there. And then after DEA from a federal side reschedules, then the states need to reschedule before any prescribing and distribution is allowed in the states. And so that -- we are actively working there to make sure that, that is done as quickly as possible after federal DEA reschedules.

That's helpful. And just lastly, as you think about the emerging product profile, how would you expect payers, clinicians and patients to position COMP360 relative to Spravato when making treatment and coverage decisions, particularly given this rapid onset we've seen a potential for durability with one or two administrations.

Yes, thank you for picking up on how impressive that is because it's a very -- I can sit here and scream from the rooftops, how incredible it is to see this dramatic decrease, especially for the patients that are responding on day 1, this is a patient population that has never had efficacy or most generally never had efficacy. This is truly unlike anything we've ever seen before and it gives you -- the durability data is really quite impressive. I think you've heard Steve and Guy so you've got two in-house physicians who can comment on that, and I'll pass to Steve in a minute to add a little more commentary. But from a payer standpoint, remember, there is only one product that payers are covering right now in this patient population, and that is Spravato and even though we believe that the efficacy and durability that we're seeing and economic benefit potentially for patients on COMP360 exceeds that of Spravato. Spravato is already pretty broadly covered after two failed treatments, which would be a prior authorization to label. And so we expect payers to react pretty positively to this, especially given the patient population that we are studying. But I'll hand it to Steve to see if we must add anything from an HCP receptivity of this.

Thanks, Lori. Patrick, from a psychiatrist and patient perspective and particularly from as a psychiatrist who has treated thousands of patients with TRD, this emerging profile that we're seeing, the possibility that with one treatment, a product that is generally safe and well tolerated, then you will know almost immediately, if your patient is going to benefit from this treatment. And then with that one treatment or maybe a second could have durability out to 6 months relative to the couple of other options that are available today, and I'm glad they exist, but they do require patients and their caregivers to have multiple treatments, especially initially, really a high burden of initial treatment with those other options, and it still takes weeks or even longer to know if you're going to benefit from those treatments. So with an option that you know almost immediately with one safe treatment that could be so durable. This is what I've been waiting my whole career for.

The next question comes from Leonid Timashev from RBC.

I had maybe two related to baseline characteristics and the correlates of response. I guess, first, is now that you have two trials under the belt, two Phase IIIs, anything you're seeing with what's correlating between deeper responses, those that remit and sort of the patient baseline characteristics that you can use to steer physicians towards who they might want to treat first? And then the second question is, obviously, across these trials, we've been very careful about selecting patients that are actually treatment-resistant, you had international sites as well. But I guess how do those patients compare to what you might expect in a real world U.S. treatment setting? And would they be more or less likely to respond and remit, I guess how should we think about how the real-world data might evolve once this is actually in physician hands.

Thanks, Leo. So I will hand the second question to Guy and Steve sequentially. Just in terms of your first one, that is analysis we don't yet have. I mean, clearly, it is a very interesting question. But right now, we have none of that looking at the baseline epi, looking at pretreatment, looking at psychedelic naive and so on. So there are a bunch of interesting questions there, but we don't yet have that analysis. But clearly, we will be doing that, and we'll be reporting that as and when. But let me then hand first to Guy and then to Steve to talk about how this population, frankly, differs from what a real-world TRD population we look like.

Yes. I think just to add, I mean, we will also be looking at the characteristics and intensity of the experience, which we think may be somewhat predictive, not a baseline characteristic admittedly, but nevertheless, something that we think may be mediating. I think when it comes to what these patients how they're mapped onto the real world. We are looking at that in pragmatically within COMPASS, and we'll have something to say about that systematically. Just anecdotally, it seems to me that by setting the bar as high as using the questionnaire that we required to screen patients for failure to respond to antidepressants, the Massachusetts General Hospital test that we used is extremely exacting and requires patients who have been treated for longer than is common in ordinary practice. So I think we will have selected patients who were more chronic and therefore, probably more difficult to treat. But I'm not a U.S. clinician. So I hand to Steve at this point, and he can comment further.

Thanks, Guy. No, you may not be a U.S. clinician, but I fully agree with you. And I'll just add that, yes, these likely these participants in our trials likely map pretty well on to patients living with treatment-resistant depression in U.S. clinics. But it is also the continuing reality that if we look at the treatments available today for people with TRD, they tend to get them too late. Spravato is widely covered PA-to-label. And so patients will be eligible for that treatment after they've been failed by two treatments. Yet what we see in claims is that it's often five to seven treatments before they're getting Spravato. And that means that there is ongoing work to do to educate clinicians, those that provide these treatments as well as those that refer to them on the importance of early referral once patients meet the criteria of TRD and think earlier about treatments that have proven efficacy in this population. And so this is work that our field medical team has been doing. They've been out educating for the past couple of years that we will continue to do and expand. And certainly, as we build more of our commercial infrastructure. And so to directly answer your question, I think they're representatives, but it also points out to us really the larger opportunity to make sure that our treatment can get to more of the patients that are waiting.

The next question comes from Thomas Shrader of BTIG.

Congratulations just remarkably reproducibility, amazing data. I have just a couple of patient level questions and I'm worried you won't have answers for, but how clear are the repeat effects? If a patient gets nothing on the first dose, do you ever see one get something significant on the second dose? And then the slide went by quickly, but it looks like you have about a 10%, I would say, miracle response group, people who get a MADRS below 12, is that a real group? Did they start with high MADRS? And do you ever see that kind of effect in the placebo group?

Thank you, Tom, and I'll ask Guy to comment on that, please?

Yes. I mean just on the -- this very small group who do really well, we have not really looked in yet had the chance to look in detail at them for their particular characteristics. I mean they're certainly within this sample, they're relatively small, but they're so striking in terms of how completely they remit that it's most impressive to me as a clinician. There is the odd -- I mean we have not looked in detail yet at the placebo group to be fair. We know at least 1 patient who showed that kind of response in the placebo group. But we need to absorb this fully to make sense of it. Only the question of whether or not you kind of get a different response depending on the first or the second administration, that's a great question that we will be looking at in detail, but we don't -- we haven't yet had the bandwidth to do that at this point. We haven't had the data for that long.

The next question comes from Sumant Kulkarni at Canaccord Genuity.

Nice to see you advancing the field with data and thanks for taking our questions. I have three. First, other than staying responders or remitters, what were the key reasons for patients not opting for retreatment.

We don't yet know that. We don't actually -- I think as Guy said in answer to an earlier question, we actually don't have the analysis of antidepressant use and so on. So we don't have -- we will get some more insight on that. Obviously, secondary scales, including PROs and so on could be interesting to that, but we don't have any of that at the moment.

Got it. And then given the 6 weeks primary endpoint in Part A of COMP005 is somewhat arbitrary in the first place, how soon do you think patients could opt for retreatment or physicians might like to retreat in the real world?

Steve?

That's a great question. I think while we have a clearer picture of the profile with this data, we don't yet have the full picture of that, and it will really take the Part B of 006 to have more of that information. I think given what we're seeing so far, that one or two treatments, whether it's at that fixed interval 3 weeks later in Part A of 006 or the retreatment in Part B of 005, seeing the initial durability of this treatment, I think it's less likely that commissions will jump to retreat in the very, very near term, although that will be individual clinical decision-making. And rather I think people are going to be really encouraged that this appears to be quite a durable treatment for those who benefit. But again, I think we're going to want to see the really large data set of Part B of 006 to really further guide our expectations of the frequency of retreatment.

And my last one, I think, is perhaps my most important question. A real world again, how important do you think a more active level of psychological support as part of the dosing experience might be for eventual clinical outcomes for COMP360?

So I'll start and then hand again back to the rest of the team. So I think as part of the dosing experience, we would absolutely say that is not relevant. We are clear that the psychedelic experience with psilocybin itself does not require or justify therapeutic intervention in the dosing. The container for the patient is a different question, so I'll hand to Guy and Steve to take that. Maybe we'll do the Steve, Guy order this time.

Yes, so as Kabir started with, let's exclude that administration day where there isn't a role for any more active support than what we're providing in order to safeguard patients receiving COMP360. There is a question of whether some more active psychotherapy and evidence-based psychotherapy might enhance outcomes in the period following administration. That will be an open set of questions. Of course, it's not what we studied. We are really excited what we've been able to demonstrate purely with the effects of one or two administrations of COMP360, I think there are a lot of people who assume intuitively that some ongoing therapeutic process after this treatment might be beneficial. But that will be an interesting set of questions that will maybe have the opportunity to explore hopefully prior -- excuse me, subsequent to an approval, okay?

I think just to say that I think post approval, when this drug actually becomes more available and less restricted by current scheduling, we expect to see innovation around the container that Kabir has described. And I think it's going to be a very exciting time to be some people working in this field and treating patients with these conditions and with these drugs.

The next question comes from Jay Olson at OpCo.

Congratulations on these landmark results and thank you for hosting this event. We have a few questions. Do you anticipate any learning effects on the average time to discharge for patients who receive a second dose? We're curious if you expect monitoring requirements to decline after a second dose as patients and their caregivers gain experience and maybe require less monitoring. And then how will you guide the treatment of Spravato experienced patients in terms of when and how those patients could or should be switched from Spravato to COMP360? And finally, is there any read across from today's results that inform your thinking about PTSD or other indications that you plan to study?

Thanks, Jay. So I'll ask Steve to take the first two in terms of how we're thinking about the monitoring and then Spravato experience in the relationship to treatment.

Yes. That's a really interesting question about a learning effect and whether there could be a reduced requirement for monitoring with a subsequent or potentially multiple subsequent treatments. I think we'll need to spend more time with this data and dive into the time and other aspects of readiness for discharge within our clinical trial setting. I think you're thinking along the right lines, and that's certainly a possibility. We'll just need some more information to better understand that. As far as potential considerations of switching from Spravato to COMP360. I think if we are approved and at the time of launch, there will be at least two buckets of patients, those who have not yet tried Spravato and maybe making a decision between the two possible treatments and those who already are on Spravato and might think about switching. And in that second group that you're asking about, I think there's a number of considerations. There likely are a number of patients who maybe have had some benefit from Spravato, don't have other options. And so continuing maintenance even if they don't feel that they've had the full benefit that they would have hoped for. And also those who continue to have the burden of the frequency of maintenance treatment with Spravato and it's a burden that falls both on them as the patient as well as their caregiver who needs to drive them. And as a reminder, after the 12 initial treatments with Spravato, eight in the first month, four in the second, maintenance is typically weekly or every other week, which really can be a challenge logistically in terms of time, but also when patients are better and may be able to return to work that can be inconsistent with working a full-time job. So I think those may be some of the switching considerations. And then as we were saying earlier, in terms of initial decisions, the possibility with a generally safe and well-tolerated treatment knowing almost immediately as of the next day, whether you've benefited and that having the potential, maybe with one more treatment to be durable out to 6 months, we think is really compelling as far as stacking that up against your other options.

Thanks, Steve. And in handling the final part around other indications to Guy, I'll also just repeat something Guy mentioned, which is we saw a trend that we wouldn't yet say it's a conclusion that the side effect profile from the second administration may be slightly lesser from the first, which would also kind of support your first question. Guy, if you want to comment on cross indication learning space?

Yes. I think we're impressed by the second administration, frankly. And that's a reason to think about that in relation to PTSD. Ditto the 10-milligram dose. I mean, clearly, we probably have to know a little more about that. But it's a little premature to pontificate on that. We're still in the process of finalizing the protocol for our first -- our second study in PTSD, and rest assured we'll be thinking this through in the next few days around exactly these questions.

I'd say certainly, this -- I think the safety may read across, and this very large safety database at this point is very encouraging as we look to new indications like PTSD.

I think the last question will come from Michael Okunewitch from Maxim.

Congratulations on what looks like great data so far. I guess to start, I'd like to see if you're planning any qualitative analysis into the nonresponder population to see if there are any identifiable factors going into the session or in the reaction or even external factors that might contribute to the lack of response and may be able to inform that container that you're discussing once you get into a real-world use.

Yes. So I think, as Guy mentioned earlier, we don't yet have, in particular, the measure of the subjective experience, the dimension or the state of consciousness, which in the IIb turned out to be a potentially useful diagnostic tool. So again, when we have that, other PROs, other secondaries. I think we'll be in a better position to answer that question. It's clearly a question we would like to be able to contribute towards answering given the level we saw of nonresponse. But right now I'm not sure we have any, Guy, anything you want to add on that?

Yes, I think we do -- we will have something to add because although we didn't put qualitative interviewing into the main body of the protocol because it might have been unblinding, it might have interfered with various kinds of nicety around the design of the trial. We have put in a sort of free text questionnaire at the end of the study where patients will get asked about the experience, about their preferences, about the experience with the person who's the support provider or a kind of stuff that you're intimating may become important. And so we may very well get something from that, which is quite useful given that we're having quite so many patients going all the way through the protocol and staying with us. But this will be kind of at the end. So we don't know yet how complete the coverage will be and how useful it will be. But we've certainly thought about that, and we hope that we'll have something interesting to share in due course.

I do appreciate that. And then one last follow-up for me, and I'll jump back off the call. I'd just like to see if you could clarify what you mean specifically by launch ready by year-end '26, given the submission is expected to complete in the fourth quarter. Is that just getting everything lined up ahead of approval? Or is there an expectation that the rolling review could enable approval actually within 2026.

So I'll answer the second part and then hand back to Lori for how -- so no clearly, we are not saying that we are expecting -- we're not giving any guidance for an approval time line but we're conscious of the fact that there is a lot of interest behind this is the first-in-class psychedelic. We appear to have a motivated agency. And I think with this data, we are optimistic that continued dialogue will be very positive and actually even accelerate. But we're not giving specific guidance on approval, Lori?

Yes. And when you think about getting prepared for commercialization, commercial has to back up to the best possible scenario to be ready because the worst thing that could happen is we receive an approval and we're not ready. And there's a lot of lead time required to make sure that we are prepared to successfully launch that includes preparing the market earlier in terms of disease state education, like Steve mentioned, our MSLs out and the field force will be doing other efforts around that, including thinking about how we ensure training of the sites so that when an approval comes, they can very easily adopt COMP360 in a fast and early adoption fashion. So our goal is to just make sure that if something were to move quickly or quicker than normal time lines, we are ready to go.

This concludes today's Q&A session. I'll now turn the call back to Kabir for concluding remarks.

Thanks very much. So thank you all for your time and attention this morning. Again, let me thank the participants and the clinicians and the COMPASS team who have worked so hard to get us to this point. As you've heard, we're incredibly excited about these results. We believe that with COMP360 with the emerging profile, we have the ability to redefine rapidity, durability for patients with TRD who today only have one possible available treatment option. So with this data showing the rapidity of onset, that consistent separation from day 2, showing significant numbers of responders, partial responders who with one or two doses are able to sustain response out to 26 weeks. We truly believe this is the start of a novel compelling paradigm for patients and providers. We're excited. We've already sent the data down to the FDA. We've requested a meeting and we look forward to working expeditiously with them to see whether we can move this towards regulatory approval and provide another treatment option for 4 million patients who desperately needed. So again, thank you for your time and attention, and have a great day, everyone.