Karuna Therapeutics, Inc.

THERAPEUTICS THIRD QUARTER 2023 FINANCIAL RESULTS CONFERENCE CALL. ALL PARTICIPANTS ARE IN A LISTEN-ONLY MODE. PLEASE NOTE, THIS CALL IS BEING RECORDED. I WILL NOW TURN THE CALL OVER TO ALYSSA SMITH, HEAD OF CORPORATE AFFAIRS AND INVESTOR RELATIONS.

GOOD MORNING, EVERYONE, AND THANK YOU FOR JOINING THE THIRD QUARTER 2023 FINANCIAL RESULTS CONFERENCE CALL. I'M JOINED TODAY BY BILL MURRAY, PRESIDENT AND CHIEF EXECUTIVE OFFICER and Jason Brown, Chief Financial Officer, who will begin our call with a pair of remarks. Andrew Miller, Founder and Chief Operating Officer, and Will Kane, Chief Commercial Officer, will join Bill and Jason for the Q&A portion of our call. Before we begin, I encourage everyone to visit the Investors page of our website at investors.coronatx.com to find our press release and presentation related to today's call. Forward-looking statements related to our product development, regulatory, and commercial innovation plans, our research activities, and financial outlook may be presented during this call. Please refer to today's press release and our FCC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. And with that, I'll hand it over to Bill.

Thanks, Alexis. Good morning, everyone. I want to begin by thanking our R&D team and our external partners on a high-quality and timely NDA submission for CAR-XT for the treatment of schizophrenia. many long days and weekends over the past several months to write and submit our NDA. It was a major achievement for Karuna and represents the culmination of years of preclinical, clinical, CNC and regulatory work on CAR-XT, detailed across several hundred thousand pages of information. Now, the submission, of course, is just the first step in the NDA review process. There are several other important milestones and activities ahead. including top line data from the phase 1 ABPM trial this month. We expect to hear back from the FDA on their filing decision later this month as well, and we're already preparing information for our day 120 safety update and site inspections, among other things. As we've talked about, we expect a standard review and therefore a potential approval and launch in the second half of next year. As you know, the treatment of schizophrenia has been served by one class of medication for over 30 years, and the potential approval of CAR-XT would change that for patients and their physicians. And I continue to believe this could be one of the most important product launches in biopharma in 2024-25. In terms of our pre-launch activities, they remain on track. We have the capabilities and the funding needed to optimize this program. We've built out our managed care access and MSL teams were focused primarily on pre-approval scientific exchange meetings with payers, which started several weeks ago, and on responding to medical information requests from psychiatrists and nurse practitioners. Interest and participation for CAR-XT is very high in the community right now and will continue to build over the next several quarters. We have and will continue to present and publish new data from our EMERGEN program this year and next year. Last month, we presented data from EMERGEN III at the European College of Neuropsychopharmacology meeting that highlighted CAR XT's differentiated tolerability profile demonstrated in the trial and the potential to provide clinically meaningful symptom relief. The data include New analyses on PANS responders, which was the final pre-specified secondary endpoint in the trial, in immersion three, nearly 60% of patients receiving CAR-ST achieved a 20% reduction of PANS symptoms by week five, the end of the trial. We also shared data on the PANS-MARTA symptom domain, including the PANS-MARTA positive, disorganized thoughts, uncontrolled hostility, excitement, and anxiety-depression factor. where CAR XT demonstrated statistically significant improvements from baseline to week five compared to placebo. On safety, we provided additional data to characterize the adverse events associated with CAR XT. In emergent three, where consistent with emergent one and two, the most common treatment emergent adverse events were GI in nature, primarily occurred within the first two weeks of treatment, mild in severity, and transient over time. Looking ahead, we'll be sharing pooled efficacy and safety analyses from the emergent one, two, and three trials, as well as additional analyses on negative symptoms and adverse events at NEI in Colorado Springs and CNS Summit in Boston this month. On the commercial front, preparations for the anticipated launch are on track, too, including market research, sales force sizing and deployment, and our peer-to-peer and consumer outreach programs. We have a team of people with a great deal of new product launch experience in neuroscience. They know what works and what doesn't and are carefully evaluating all strategic and operational decisions to support the launch. Equally important to our regulatory achievements and pre-commercialization work for CAR-XT is the continued execution of our ongoing phase three program, Arise and Adept, which we believe reinforced the value proposition of CAR-XT. Before ARISE, site activation and recruitment is ongoing with about 50 sites currently active across the United States and Europe. As we maintain our target of sharing top-line data in the second half of 2024, we continue to monitor site activation and enrollment rates very closely and manage factors that may impact enrollment on a day-to-day basis. Although there is no approved therapy for the adjunctive treatment of schizophrenia, The use of antipsychotics as combination treatment is seen in around 30% of patients, despite the lack of clear pharmacological rationale and clinical evidence to support adjunctive use. To arise, we hope to reinforce the uniqueness of CAR-XT's differentiated clinical profile and demonstrate that CAR-XT can be safely and effectively added on top of standard of care. I'm also pleased to share our debt program evaluating for the treatment of psychosis and Alzheimer's is fully underway following the initiation of a depth 2 and 3 in the 3rd course. We remain on track to share data from a depth 1 and 2, a relapse prevention and acute efficacy trials. In 2025, as a reminder, The fundamental concept of CARX-T originates from an Alzheimer's trial, where Zanomoyne demonstrated promising therapeutic benefit in treating psychosis and related behavioral symptoms, as well as cognition. Our ADEPT program is designed based on the insights from that initial study and our Phase 1b trial in Healthy Volunteers. And while our primary objective with ADEPT is to evaluate the efficacy and safety of CAR XT in treating hallucinations and delusions associated with Alzheimer's, we will also be collecting data, providing additional insight into the potential of CAR XT in treating other prominent and clinically relevant symptoms of Alzheimer's, including agitation, aggression, and cognition. The data from ADEPT may not only reinforce CAR XT's promise as a potential treatment for Alzheimer's psychosis, but also help inform future developments with CAR-XT. Outside of CAR-XT, we're also making headway in our early stage and discovery program, most notably with CAR-2618, our TRIP-C45 inhibitor that we acquired from Goldfinch Bio at the start of this year. We plan to evaluate CAR-2618 for the treatment of major depressive disorder and anticipate initiating a Phase 1B clinical trial in 2024 with additional details such as trial design and refined timing to be shared early next year. Now, on an earnings call earlier this year, I had highlighted three strategic and operational priorities that we set out to achieve in 2023. Those priorities were maximize the value of CarXT from a development perspective, two, expand our pipeline, and three, scale the operational capabilities of our company as we transition to a fully integrated R&D and commercial organizations. We've made excellent progress on these three fronts, which reflects the hard work and skill of our organization. With just a couple months left in 2023, we look forward to finishing the year strong. With that, I'll hand it over to Jason. Thank you, Bill. I'm pleased to be with you all today to share our third quarter financial results and to discuss our full year 2023 guidance. Q3 was another strong quarter for the company. driven by continued progress across our ongoing CAR-XT Phase III programs, the submission of our NDA for CAR-XT, pre-commercialization efforts, as well as significant growth across the organization. Total operating expenses for the third quarter were $136.2 million, compared to $81.1 million for the same period in 2022. Operating expenses were slightly offset by $17 million in interest income. resulting in a net loss of 119.1 million. Research and development expenses for the third quarter were 104 million compared to 62 million for the prior year period. The increase to 42 million was primarily driven by expenses related to our ongoing RXT clinical programs, increased employee headcount, and higher stock-based compensation. General and administrative expenses for the third quarter were 32.3 million, compared to the 19.1 million for the prior year period. The increase of 13.1 million was primarily driven by expenses related to our pre-commercialization efforts, increased employee headcount, and higher stock-based compensation. Cash, cash equivalent investment securities totaled 1.3 billion as of September 30th, 2023, compared to 1.1 billion at the end of 2022, providing us with a cash runway comfortably The increase was due to our follow-on public offering in March of this year that resulted in the net proceeds of approximately $437 million. Looking ahead at the rest of the year, we anticipate R&D to decrease in the fourth quarter relative to the third quarter and reiterate our guidance for the full year 2023, with total operating expenses expected to come in towards the top end of the range at around $470 million. Of that, we expect R&D and G&A expenses to be in the range of $355 million and $115 million, respectively, with the increase in R&D guidance being primarily driven by continued enrollment in our long-term safety trials, site activation costs associated with the ADEPT program, and costs related to our ambulatory blood pressure monitoring trials. I'll now hand it back over to Bill.

Thank you, Jason. With that, we can open the call to questions.

At this time, if you'd like to ask a question, press star one on your telephone keypad. If you'd like to withdraw your question, press star one again. As a reminder, to ensure that we have time to answer everyone's question, please limit yourself to one question.

Please stand by for your first question. Your first question is from the line of Yatin Sanjay with Gutenheim.

Hey guys, thank you for taking my question and congrats on all the progress. Just two quick ones for me, if I may. So the first one is with regard to the DRI study. Can you maybe talk about your expectation? Would you expect the drug to behave similarly to the monotherapy in terms of the onset and the depth of responses? And how should we think about the added tolerability back? And then maybe You know, on the pipeline front, on 2618, you are prioritizing MDD. Could you maybe talk about the rationale going into MDD first over, let's say, other anxiety disorders? Thank you.

Thank you, team. Thank you for both questions.

I'm going to turn it over to Andrew. Yeah, thanks, Bill. Thanks, Yasin. So, with respect to the ARISE study from an expectations perspective, first maybe to speak to efficacy. A reminder that the primary endpoint in the ARISE study, the total PAN score is the same as the primary endpoint across emergent one, two, and three. So those do significantly inform our expectations about what we expect to see in the ARISE program. It's a key difference with the ARISE program being we do expect the baseline severity of symptoms to be lower given that patients are being actively treated with existing antipsychotic medicines. Because of that, you know, we expect a little less dynamic range, and our expectation from a statistical powering perspective is a more conservative, you know, four to five point change on total pants in comparison to the eight to 11 point change that we observed in the emergent program. That still would meaningfully clear what we would consider clinically meaningful benefit in patients. And, you know, again, it's all based on that same primary endpoint across the arise and emergent programs. With respect to safety and overall tolerability, obviously one of the things we're most excited about with CAR-XT is the completely unique pharmacology focused on the M1 and M4 muscarinic receptors. And when you look at the tolerability and safety profile, I think it's very distinct in comparison to the adverse effects that are observed on current background standard of care. So we continue to expect to see things consistent with that muscarinic pharmacology. don't expect meaningful overlap or for instance worsening of uh background side effects associated with current medicines and then you want to comment on 2618 and the pre-clinical evidence supporting uh utilization of the entity i mean i think with 2618 and in general uh trip c45 as a therapeutic target for um psychiatric illness and mental illness i think there are a lot of interesting possibilities i think that's really the basis of your question is that There's evidence broadly to support both antidepressant and anxiolytic properties. Specifically, 2618, the molecule, but more broadly, TRIPSY-4-5 as a target. I think our focus on MDD initially represents, or is representative of both our scientific confidence in that preclinical data, our ability to execute a study that we think will provide meaningful provide some insight into the potential therapeutic benefits. We certainly remain quite interested in a number of different anxiety disorders, particularly I would say generalized anxiety disorder is something that we're interested in evaluating with 2618 as well, and look forward to being able to speak more to the details of that Phase 1b study here early next year, as well as our longer-range plans for this program.

The only other thing I would add is that everything available today in MDD is effectively serotonergic and neuroendocrinergic. And so we, of course, have some work to do to produce human efficacy data. But MDD is attractive because this would essentially be to the depression market what, in many respects, CARXT could be to the schizophrenia and the atypical market, which is a completely novel pharmacological approach.

But we'll know more at the end of 24, early 2025. Thank you.

Your next question is from the line of Laura Chico with Redbush Securities.

Hi, this is Ingrid Ahn for Laura Chico. Thank you for taking our question. I wonder if you could talk a little bit about your expectations around real-world duration of treatment for CAR-XT. Cycling among therapies and even completely discontinuing therapies represents a hallmark of this schizophrenia space. How would you describe your base case expectations now that you've had longer-term experience with CAR-XT in clinical trials? Thank you.

I'll make a few comments first Ingrid and then turn it over to Will Kane, our chief commercial officer. What I can tell you right now is that when you look at real world experience with the second generation atypicals, adherence rates are in the range of about only 50 to 60%. And the number of missed days of therapy each year is probably between 100 and 150 depending on which real world observational study that you you look at and so non-compliance is a real problem given the efficacy and safety experience some patients have that results in relapse that results in er visits and then of course hospitalizations and increased health care costs we of course don't have real world experience yet um But we would expect that adherence with CAR XT in a real world setting could be higher, persistency could be longer, and missed days of therapy lower. And I'll just turn it over to Will to add a little bit more color.

Thanks, Bill. I'll just echo some of the comments Bill made, which is, you know, in the marketplace, when we talk to clinicians and also the payers, you know, they see the potential for increased adherence as a real value add for CAR XT. And as Bill mentioned, you know, there was the incremental increase from the typicals to the atypicals, and given the new mechanism and the clinical profile we've seen so far in the emergent program, you know, there's strong interest in seeing long-term data to realize the full potential of CAR-XT. And so, you know, when we don't have real-world data, the data is indicating and signaling that there could be an opportunity here for increased adherence. And as we've talked about on many occasions, there's a really high rate of non-adherence. You know, patients typically about three quarters of them or 75 percent will discontinue in the first 18 months and that's driven by a lack of you know either adequate embassy or intolerability and car xp may have the opportunity to really address both of those um those needs in the market thanks for the question your next question is from the line of miles mentor with william blair

Hey, congrats on the quarter. Thanks for the questions. First one's just clarifying. Are you going to announce the NDA filing acceptance if you do get that? And would you also use that as a forum to give us the ambulatory blood pressure monitoring data at that time? And then the second one is emergent five's been fully enrolled since the second quarter. That's patients that are treatment-naive to CAR-XT in an outpatient setting. Can you just give us an update on the dropout rate and how that compares to emergent four that's ongoing in patients that have been experienced? Thanks very much.

Great. I'll take the first part of the question and turn it over to Andrew to answer your question. your second question. As it relates to the acceptance, we will announce that. We expect it at the end of the month. And then as it relates to the ABPM results, we expect to have those announced in the middle of the fourth quarter, which is only a couple weeks away.

Andrew? Yeah, Miles, with respect to Emergent 4 and Emergent 5, obviously those studies continue to be ongoing, as you mentioned. It's sort of premature to comment too specifically on any conclusions from those studies. I think we do look at those as being overall consistent with what we spoke to earlier, the pharmacology of CAR-XT unique being at the both M1 and M4 receptors. And our expectation is we'll see in those long-term studies something that looks quite consistent with the data we've been able to release from the short-term studies emerging 1, 2, and 3, where we see, you know, predominantly you know, an efficacy profile characterized by a robust effect, a broad effect, and a safety and tolerability profile generally characterized by mild to moderate transient GI side effects. We'll, of course, look forward to, you know, releasing all of that data at the right time here in 2024 as those studies complete. But again, I think those studies are a great opportunity for us to further demonstrate the potentially differentiated profiles for our state.

Thanks for the question, Myles.

Your next question is from the line of Paul Mathis with Stifle.

Hey, thanks for taking the questions. Ahead of the ABPM data, I was just curious, what's your level of confidence right now that that data with the FDA will not serve as a major amendment? Any more color you can provide or any analogs? And then just more broadly, how are you thinking about business development and the possibility of doing another TRIPSY 4.5-like deal in the next year or so before the launch. Thanks.

Thanks, Paul, for the questions. I'll let Andrew tackle the first question, then I can answer the second question for you.

And I think with respect to the ABPM study, that was specifically a topic of discussion with the FDA at our pre-NDA meeting in second quarter earlier this year. specifically the idea that that study, which again is a phase 1B safety study, would be submitted at the day 120 safety update, which obviously based on our submission in late September will happen in the late January timeframe. And again, I think we're highly confident that would not result in any sort of major amendment to the NDA and NDA review process. Again, because of specifically that conversation with the agency at the pre-NDA meeting, but also I think the general precedent

that a study that's a phase one safety study submitted prior to midpoint review or certainly prior to team 120 we would not expect to result in extension to the producer today great thanks andrew and then um paul as it relates to business development it's a good question it's the it's a real a very important priority for us to build the pipeline i would say it's second only to the approval and launch of car xt which is obviously our most important priority You mentioned the Goldfinch transaction, the TRIP C-4-5. Look, we look at new opportunities on a weekly, monthly basis. We think about them strategically, scientifically, financially, and I think that the TRIP C-4-5 uh inhibitor check to all of those boxes we think about neuroscience fairly broadly with a focus on schizophrenia alzheimer's depression anxiety several other conditions if we see something that we like fits our balance sheet makes sense given our capabilities and our neuroscience focus yeah we would we would do something um obviously our number one priority right now is correct state But number two is building the pipeline, and new product flows for any company, the lifeblood. And so we'll continue to look at things, and if we see something we like, well, of course, we'll do it.

Thanks for the question.

Your next question is from the line of Ash Verma with UBS.

Hi, good morning. Thanks for taking my question. So on the ABPM study, I wanted to ask, so I know we haven't seen any present effect for CAR-XT in previous studies, and Cerebral's M4 molecule was pretty clean on the ABPM. But just mechanistically or theoretically for CAR-XT, could the additional M1 agonism in any way impact on patients' blood pressure?

Thanks.

Thanks for the question. I'll turn it over to Andrew. thanks ash so specifically from a pharmacology perspective it's often challenging to separate the individual contributions when you have a molecule hitting multiple targets that being said i think when you look at the data that exists for some of the allosteric modulator programs etc i think you tend to see any potential pressure effect being tied to the m4 receptor so you know our expectation is not that you know we will see any meaningful pressure effect with CAR-XT, certainly on the basis of an M1 and then M4 pharmacology. And I think as you referenced, we don't seem to see a sustained chronic increase across the emergent program already. I think the ABPM study offers us the ability to further confirm that, and we certainly remain confident here with the final data coming quite soon. that we'll be able to reject that statistical hypothesis of any sort of sustained 3-millimeter increase in systolic blood pressure.

Thank you.

Your next question is from the line of Mahit Bashal with Wells Fargo.

Great. Thank you for taking my question, and congrats on all the progress. I just wanted to ask regarding your competitor's data on TRIP-C4 and 5, and there was this small increase in suicidal ideation. Again, the numbers are small. I just wanted to understand, is it just the law of small numbers, or is there any theoretical reason why you would see high suicidal ideation with this mechanism?

Thank you. Mohik, we had trouble hearing what you said. Would you mind just repeating the question?

Sure. So this is regarding the TRIPSY-4 and 5 and the data we saw in early October from Boeinger Ingelheim. So the trial was terminated due to slow recruitment, but there was a 15% rate of suicidal ideation in the treatment arm versus 4% in placebo. I'm just trying to understand, is this anything, has this anything to do with the mechanism, or is this just a law of small numbers? These are really small numbers here. Thank you.

Thank you. Andrew, go ahead. Yeah, thanks. So, you're referring to a study where the results were recently posted on clinicaltrials.gov that was actually a remote, mobile-based study that was done by VI, really as a result of the pandemic. um that study was terminated early i think the final enrollment um was like low single digit number of subjects i think given that and some of the considerations around mdd and more generally studies um in depression or things like schizophrenia i think it's really premature to read too much into that study those study results particularly when you speak to um adverse effects or things like suicidal ideation, which tend to be rare. It's often more challenging to make any conclusions about that until you get larger numbers. There's also, I think, more details with respect to things like suicidal ideation. There are specific rating scales for that. We implement that across the immersion program as well. So simply looking at TAEs is not, I would say, a thorough assessment of the potential effects. I would further say that, you know, from our perspective, we certainly don't see any preclinical evidence or specific scientific rationale for why that could be an adverse effect associated with TRIPS-E4 or 5. We'll certainly obviously be carefully assessing that as anyone would in being diligent in conducting studies in depression when we, you know, push forward into our study next year with the 2618 program.

Great. Thank you for the question.

Your next question is from the line of David Amselem with Piper Sandler.

Hey, thanks. So on ARISE, can you talk to pace of enrollment and are you still onboarding sites? Just wanted to get a flavor for where things are on that trial. And then secondly, on ADEPT and AD psychosis, more specifically, how are you thinking about it vis-a-vis AD agitation? You know, some companies that are looking at agitation, you guys are looking at psychosis. Do you think that agitation and psychosis is sort of a distinction without much of a difference? And just wanted to pick your brain on that. Thank you.

Thanks for the questions. David, go ahead. Yeah, specifically for the first question around the ARISE program, We have continued to activate sites over the course of this year. Really, in the second and third quarter, we initiated two new countries as part of that program, Bulgaria and Serbia. Across those two, there's about 20 sites that are active at this point in time. I think, as Bill maybe mentioned a little earlier, obviously, whenever we're managing studies, it's always a day-to-day, week-to-week basis. I do think you're likely to see some additional site activations across the ARISE program. Again, that's that'll drop off over time who aren't actively enrolling. But I think we feel good about where we are with the ARISE program, continue to see momentum as part of that program, and obviously we'll provide any additional updates going forward to the extent there are any. And then with respect to the ADEPT program and our focus on psychosis, I think if you rewind the clock 10 to 15 years, there perhaps wasn't as much distinction among psychosis and agitation. We really look at that as a separating out of an agitation-related indication over the last five to 10 years, given, frankly, the lack of approval for anything more broadly for psychosis. Specifically, agitation and aggression, I think, are potentially more, I think, affected by drugs that have somnolence or sedative-based effects, fundamentally that sort of behavioral paradigm. Whereas when you look at hallucinations and delusions and that sort of core psychosis, That's really where we look at taking advantage of the known antipsychotic effects of denomaline and as part of CAR-XT. Bill referred to this in the original or the opening of the call, that that is the population, Alzheimer's patients, where the antipsychotic effect of denomaline was first discovered. And when you look at that data, which is all published, you see benefits specifically on hallucinations, delusions, agitation, and aggression. across that program. So we really look at the opportunity with CAR XT as something to capture that broad effect, but specifically starting with hallucinations and delusions as the basis for the primary endpoints in the ADAPT program.

And the only other thing I'd add, David, we know that the product has a pro-cognitive effect, which was observed in the very same trial that Andrew just talked about. And so when we think about that Alzheimer's population, of course, the first step would be a an official indication or an FDA-approved indication for psychosis, but we know that there's data on other aspects of Alzheimer's disease, both agitation and aggression and cognition, which I think, you know, creates a compelling opportunity for us as we go into in this area.

Thanks for the question.

Your next question is from the line of Jay Olson with Oppenheimer.

Oh, hey, congrats on all the progress and thank you for taking the question. Since there seems to be a lot of interest in the ABPM study, can you just remind us what blood pressure signals have you seen in the past? What's the rationale behind running this study? And ultimately, is there a legitimate blood pressure concern for CarXT that investors should be concerned about? Or is that just a false narrative contrived by competitors? Thank you.

Thanks for the question, Jay. Go ahead, Andrew. Yeah, sure. I'm happy to speak to sort of what we've seen and how that projects in ABPM. And, you know, I think maybe I just start with, I think with respect to ABPM, it's not something that, you know, we have a lot of concern about internally. Obviously, we're running the study to provide a more definitive data point about what any blood pressure effective CAR-C could be. But when we look at the immersion program, which has the same dosing also in patients living with schizophrenia, fundamentally the same paradigm as the ABPM study, even in that setting where we're measuring vital signs at C-max of the drug two hours post-dose, we don't see a three millimeter increase even in that setting, which you would describe more as kind of a fundamentally worst case scenario. So we translate that data into the ABPM paradigm. You know, that's why we have such a high level of confidence in having a successful outcome from that study. You know, consistently across the program with CAR-ST, we generally have not observed any meaningful pressure effect and not something that was a historical consideration with this mechanism really until you've seen some of the M4 selective compounds come into early stage clinical development over the last couple of years. So from our perspective, We're obviously, you know, greatly looking forward to be able to see the final ABPM data and get that out into the public domain, which I think will provide, you know, in our minds, the most definitive data point around any potential pressure effects. But we expect that to be consistent with what we've already seen in our clinical assessments in the emergent program.

Thanks for the question, Jay. Thank you.

Your next question is from the line of Jeff Honk with Morgan Stanley.

Thanks for taking my question. What is the latest feedback you're hearing from payers on CAR-XT, and how is the benefit on cognition resonating with payers and clinicians? Thanks.

Yeah, great question, and I'll just make a couple comments, and then I'll turn it over to Will Kane. We've already started scientific exchange meetings with Medicaid. programs all across the United States. So we're now more than 12 months away from launch. We're going to have plenty of opportunity to sort of lay the proper groundwork so that we achieve a relatively high level of formulary coverage during the first year on the market. I think we've already been to about 14 Medicaid programs, maybe more over the past several months. And I think the opportunity here for us to carve out a position on formularies for CAR-XT is pretty significant. They haven't had a novel pharmacological class in three decades. I think if we were getting ready to introduce another D2 antagonist, I think conversations with payers may be a little bit different, but this isn't that. With that, I'll turn it over to Will.

Sure. Thanks, Bill. So I'm particularly pleased with the interactions we've had to date with the payer community. Since we initiated scientific exchange in September, we've had over two dozen interactions across channels, Medicaid, Medicare Part D, and also commercial. And we have more than a dozen additional meetings scheduled between now and the end of the year, and that number continues to go up. I think it reflects a couple of things. One is there is interest, and I've heard this directly, in new treatment options. for patients with serious mental illness, in this case, particularly schizophrenia. There is, you know, one of the things the pre-approval information exchange allows is the opportunity to learn, if you will, almost in real time as data is presented into medical meetings, et cetera. And so they look forward to that interaction, which is something we can really capitalize on over the next 12 months. The data is well-received. I think they certainly appreciate the unique mechanism of CAR XT relative to the products that they're currently offering on their formularies. They really dive into some of the data we present, particularly the total PANS, but questions about the subscales, which we find to be encouraging. And of course, the fundamentally different safety and tolerability profile that's reflected in the data to date. They do, to your question, have a real appreciation for the three symptom domains of schizophrenia, the positive, the negative, and the cognitive. And they know just as the clinical community knows where the deficits are. They have relatively good drugs on the positive symptoms, but where the needs are negative and cognitive. So, they're very interested to learn more about CAR-XP's evolving clinical program and where the drug may actually be able to offer potential benefits there. So, so far, I think really engaging and positive. And every one of them has welcomed the opportunity to come back in the future as we present more clinical data to continue to learn more of the next 10 to 12 months.

The only thing I would add is just in general in the area of mental health, I would say every corner of the healthcare system right now is moving in the right direction. In other words, we just talked about payers, even state governments are rethinking policies as it relates to formularies and reducing the use of certain drug utilization management sort of techniques to control prescribing. And we see fewer and fewer states using prior authorizations. In fact, I think in 14 states, there's no PA allowed. You also see the elimination or the reduction in the use of step edits. And I think these are very, very good trends. If you take a look at patient advocacy groups, they're doing more work than ever before to reduce stigma and isolation. And if you look at the providers, there are more community mental health centers being set up in communities all across the United States. And I think all of these trends are more tailwinds than they are headwinds and will enable coverage and access to car xt and frankly and the other new compound that's introduced in the united states for serious mental illness and i think it's a very different dynamic in mental health as compared to other therapeutic areas across those um aspects of the market and there's more momentum than there has been in years and so that puts us in a very good position when we start to introduce car car xp in the united states next year thanks for the question

Next question is from the line, Salveen Richard with Goldman Sachs.

Good morning. This is Anomid An for Salveen. Thank you for taking our question. Just on the CAR-XB launch next year, could you provide some color on what the early days of launch could look like? Are there specific physicians or geographies that you're most interested in? And then on CAR-2618, I guess, is there a certain population within MDD that would be most suitable for this asset? Thank you.

Yeah, thank you for the question. I'll turn it over to Will. I would just say, as we think about the introduction of CAR-XT in the United States, this is going to be a broad-based program. There is great anticipation in the psychiatry community and the nurse practitioner community for CAR-XT, and we're going to cover as many physicians, as many nurse practitioners, as many community mental health centers as can be covered. And of course, we have a lot of data that will instruct exactly where we deploy our sales organization, our managed care access team, but there'll be There'll be a full, comprehensive, well-funded program here. And I don't think that there's a psychiatrist or a nurse practitioner in the United States that's not interested in at least evaluating CAR-X2. The data from the Emergent 1, 2, and 3 program, of course, still under review at the FDA, but it's very, very compelling. It's a completely novel approach. It may be complementary to the D2 antagonists. And so our job is to make sure everyone is aware of those data. that they get a complete, accurate, balanced presentation of all the information that we have, which would be consistent with our label. And then they'll try it in patients that are either new patients, switched patients, or patients perhaps that they see a utility and add-on, although we wouldn't have that indication at launch. And so there'll be no aspect of this market that we leave out in preparing it for launch.

Thanks. I would just add on to that, to build on those early comments about what we referred to as this mental health moment, where we see opportunity, particularly in states, since the Medicaid population is so important to CAR XT, particularly out of the gate, where we see states that don't require prior authorizations or have zero or one step, those would be high priority states. And they tend to be a mix, but some large states are in that mix. So, you know, we'll be fully prepared to capitalize on that opportunity. We'll be fully loaded. We'll have, you know, a very robust sampling program. Our Salesforce analysis and structure is nearly complete, so we will go to market. It'll be a launch that will support the potential of CAR-XT across clinicians and payers. And to this point, and again, to echo something Bill said, in any engagement we have with the psychiatry community, whether it's psychiatrists or nurse practitioners, et cetera, there's a high level of interest and excitement about CAR-XD, and they're looking to see our progress and to see potentially when that drug will be available to them. Great.

Andrew, do you want to take the second question? Yeah. Specifically with respect to the TRIPSY 4-5 program, 26-18, at this point, we speak to our focus in MDD or major depressive disorder. We think about that broadly or being broadly applicable to that patient population. We're not at this point focused on a particular subset of MDD patients. I do think we believe that there's potential benefits from a depression perspective, but also from an anxiety perspective. There's a substantial comorbidity between MDD and anxiety disorders, so that would be a natural place for us to look at the right time for specific benefits, given the preclinical and scientific rationale for antialytic and antidepressant effects. But I think at this point, our focus remains on a broadly applicable sort of potential treatment for MDD.

Thanks.

Your next question is from the line of Jason Gabary from Bank of America.

Hi, good morning. This is Dina Ahn for Jason. Congrats on the progress with the NDA submission this quarter, and thank you for taking our question. Just a quick one on CAR-2618. I'm curious just how you're leveraging all the prior data with this molecule, specifically referring to the molecule's failure in the FSGS trial. Was this because it was the wrong target and, you know, sort of just what underpins your confidence that it has the right profile for MDD and other CNS disorders. Thank you.

Sure. Happy to speak to that. previous development program that was run in renal disease. Obviously, indications are unrelated to depression or anxiety, but TRIPSY-4-5 being a target that we've been following, given the biological rationale and preclinical data which suggests both antidepressant as well as anxiolytic effects, we've replicated that data specifically with 2618. The molecules are not relying on other target compounds or tool compounds, but specifically with 2618. looking at those preclinical models. So that's really the basis of our confidence with respect to this molecule. I think it does offer us a great opportunity to leverage the previous human experience with 2618. Specifically, the program was administered to over 100, 100 humans, 100 patients. and up to a duration of 48 weeks. So that provides us a substantial amount of safety and tolerability data that we think is informative and we believe quite positive with respect to the profile of 2618. So given that it's a molecule, substantial previous human experience, given the biological preclinical rationale for potential efficacy in treating MDD as well as anxiety disorders, that's kind of the basis of our confidence going forward and how we think about designing the right clinical trial to highlight those potential benefits. Thanks for the question.

Thank you. Just one quick follow-up, sorry. Would you anticipate being able to go straight into phase three trials from phase 1b, given you do have all this prior safety data, or is it still to be determined? Thank you.

Yeah, I mean, I think we don't want to speculate too far in the future about our development with 26 to 18, but I think what you're hearing us say is we do think we're ready to go into a phase 1b study in patients with major stress disorder. I would say if you look at the program that we've run with CAR-ST in schizophrenia, there's not a substantial distinction between phase 2 and phase 3. Our emergent 1 study and our phase 2, emergent 2 and 3 being the phase 3 studies are identical from a protocol perspective. Again, I think we'll await future results from that Phase 1b study prior to commenting to you specifically in our plans going forward from there. But we do think, given the substantial safety and tolerability data that already exists, it does offer us the opportunity to run, you know, an accelerated development program for 2016.

Your next question is from the line of Jessica Fay with JPMorgan.

Hey, this is Nick on for Jess. Thanks for taking our questions. You previously talked about your commercial preparedness in the U.S. and kind of your thoughts on an initial ramp there, but can you also recap your commercial strategy outside the U.S. and which countries could be logical first choice?

Yeah, it's a good question, Nick. Thanks. Outside the United States, we, of course, and China with Tsai. And then the other two important geographies would be the EU and Japan. And as we said before, we'll clearly need a partner with regulatory development and commercial capabilities. CAR XT has value outside the United States in both of those geographies. And we hope that that is a strategy that will come into focus in the 2024 period mid-24, late-2024, and more to come.

Thank you.

Your next question is from the line of Mark Goldman with Lyric Partners.

Thanks for taking my question. This is Rudy on the line for Mark. So can you talk about your current strategy for cognitive impairments in schizophrenia? Are you starting pivotal trials to pursue this as a separate indication. And secondly, can you also provide more color on your pre-commercialization work? How should we think about spending moving into 2024? Thanks.

Great. Thanks for the question, Andrew. We'll take the first part, and then we'll take the second part.

Yeah, specifically with respect to cognitive impairment associated with schizophrenia, obviously we're able to collect cognitive performance data that will also be included as we think about future data with respect to emergent four and five as well as the arise program are all opportunities to just further collect cognitive data there of course with cognitive data collection and demonstrated benefit in the original studies with synonyming as well in patients with alzheimer's and patients with schizophrenia going forward i do think we're contemplating additional work specifically designed, recruited, and have a primary endpoint that reflects cognition rather than other symptoms of schizophrenia. So that's something that's certainly under consideration for us. We believe there is a broadly applicable potential benefit of CAR-XT across psychosis and cognition in a number of potential different indications. And I think you'll expect to hear more from us in 2024 specifically about dedicated development towards cognition and schizophrenia. Great. Thanks, Andrew. Will, you want to take the second question?

Sure. Then on the Pre-Commercialization Award, so first, as we've indicated, our leadership is in place from a commercial perspective, and the team is really focused on developing the right go-to-market strategies. As we mentioned before, you know, we expect this to be a fully loaded campaign out of the gate. We see great opportunity for CarXT and a marketplace that is eagerly awaiting new treatment options. Our scientific exchange, as we've mentioned, has begun, and I think begun in great form. That's a collaboration between our account director team and our medical science liaison team. So they're able to continue that dialogue with clinicians, particularly with payers and clinicians on the MSL side, to the extent they have questions that we can react to and provide information to. Our Salesforce planning and design work is nearing completion, as I said. That will give us the opportunity to go to markets and really address healthcare prescribers, both psychiatry practitioners and psychiatry and a group of primary care physicians that are obviously very active in this area. But it also allows us to cover a broader landscape, if you will, to ensure we cover those certified community behavioral health centers, that we provide adequate reimbursement support to help help the offices get through any prior authorization or step processes that need to be in play. We'll have a full sampling program that's all designed and ready to roll. So we're in a very good position. We still have more work to do. Obviously, we're a ways away from a potential approval, and we'll want, obviously, final labeling to inform our messaging, et cetera. But I think, you know, to this point, I'm very pleased, and we're in good shape.

Yeah, I would just second what Will said. We are on track. I would say we're ahead of schedule as it relates to getting

getting ready and you know the beauty here is that the psychiatry community is anticipating car xd there's a great deal of interest here of course we can't promote it until we get approval uh but you know all systems go thanks for the question your next question is from the line of jason butler with jmp securities hi thanks for taking the question and i'll add my congrats in the progress um just another follow-up on commercial prep can you maybe speak to what you're hearing from physicians about how they're thinking about using the drug early in the launch, and specifically with regards to dose flexibility, how willing they'll be to push the dose to optimize efficacy early in their experience versus taking it slower and gaining experience with tolerability. Thank you.

Great. Thanks for the question. I'll just make an opening comment and then turn it over to Will. I've been involved with probably seven or eight neuropsychiatry launches over the course of 25 years. And in my experience, psychiatrists are the most adept at dosing and generally follow a principle of start low and go slow. I think that's true whether you're dealing with antidepressants or atypicals for schizophrenia or a novel compound like CAR XT for schizophrenia. And I would expect that they'll follow the same practice with CAR XT.

using the label of course as as guidance as they do with with other atypicals i'll turn it over to will let him sort of add his comments sure i'll just um add on to that that we we will go to market to enable that flexibility for the prescribing community to tailor the use of the drug per the label but also for their clinical experience so that they can maximize the patient experience with the product right right out of the gate in terms of the approach of the patient segments, et cetera. It's a broad-based one, right? There are many patients with schizophrenia looking for new treatment options. We've reiterated that many times in terms of the high rate of non-adherence and discontinuation, whether it's patients that have lapsed and therefore not in any therapy for which CAR-XE could be a new patient start, if you will, or those that are experiencing inadequate efficacy or tolerability effects that are looking for a switch, or in the case of this market with the increased use of polypharmacy of 2D2s, There will be some physicians who, even though we will not promote for that until we have an indication, they will see the opportunity to potentially add CAR-XT on to maybe help patients who are not adequately addressed from an efficacy perspective. And so it is a broad-based population. Again, there's been very little novelty in this area mechanistically for a long time, for decades. And so, you know, that really has, I think, captured their interest. And they're already thinking about the breadth of patients that may benefit from CAR-XT.

I think Will's right. If you had another D2 antagonist, you might be thinking about the market more narrowly, a second or a third line type of treatment. But that's not what we're talking about here. And I think whether you go on the far left of the continuum first episode psychosis all the way to patients, who are not on therapy and who have relapsed, I think the opportunity for CAR XT is that broad, and it should be that broad, given what we've seen in the emergent program. Thanks for the question.

Your next question is from the line of Charles Duncan with Kantor Fitzgerald.

Hi, this is Pete Stavropoulos from Kantor. Great to hear all the progress made in 3Q. Two questions for us. Can you talk about the progress of CAR XT study in psychosis and Alzheimer's, and what are, if any, the rate-limiting factors for patient enrollment? And the second question is, for CAR XT for schizophrenia, what are your expectations for an adcom, and what are possible key topics for that discussion? Thank you for taking our questions.

Great. Thank you. Good questions, Andrew. With respect to the ADEPT program, obviously the ADEPT-1 study has been ongoing since the second half of 2022. ADEPT-2 just started more recently here in the third quarter. So those studies at slightly different points from an operational perspective, certainly in ADEPT-1, but also in ADEPT-2, focus on finding, recruiting the right patients into that study. I think in any study in psychiatry, finding patients criteria with respect to diagnosis, symptom severity, as well as general health tend to be the sort of limiting factors. That's all built into our assumptions around number of sites and duration of time needed to successfully recruit those studies. So nothing specifically that I would point to for the ADEPT program outside of sort of more general considerations. With respect to an adcom, we certainly have already begun our preparation process for a potential adcom. I think our view is we're less likely than 50% to receive an outcome. That's really on the basis of having a clinical program for an indication treatment of schizophrenia adults that's well-precedented from a clinical trial design and endpoint and general methodology perspective our development program follows those precedents over the last several decades but of course that's up to the fda discretion whether they'd like to add an adcom and what the topic of that would be but it's certainly something that you know we're already getting ready for and we'll certainly be ready for if an adcom does happen

Our final question comes from the line of Greg Silvano with.

Hello for Greg. So, just 2 questions from us in terms of the day 120 update, can you elaborate a little bit more specifically regarding will be part of the update besides the data and additionally with a potential launch next year. How are preparations for FDA manufacturing inspections going? Thank you.

Yeah, so with respect to the day 120 safety update, really the bulk of that information is simply a 120-day roll forward in all the patients that are currently ongoing in the immersion program. So typically for the NDA and then for the day 120 safety update, there's simply a date on the calendar by which all data that's been collected prior to that date is included in the submission. So we'll have a four-month roll forward of that safety data set as part of the program. There's less about completing studies or specific data, but more a general roll forward of that safety database. With respect to manufacturing, inspection readiness, et cetera, I think in general, from a CMT perspective, we feel, I think, in a very good place from a submission perspective, from a potential inspection, as well as supporting the launch. We've been manufacturing, you know, CAR-XT at multi-hundred kilogram scale commercial ready for a potential sale, assuming that we get approval. You know, we use manufacturing sites that are known to the agency, have been inspected previously by the agency, and so we feel quite confident going forward that we have a CMC manufacturing strategy to support the potential approval as well as the launch. Great.

Thanks, Andrew. Thank you for the question.

Thank you. This does conclude today's call. Thank you for joining. You may now disconnect your lines.