Q4 2021 Cerevel Therapeutics Holdings Inc Earnings Call

Operator: Good morning, welcome to the Cerevel Therapeutics fourth quarter and full year 2021 financial results conference call. At this time, all participants are in a listen-only mode.

Good morning, welcome to the cerebellum Therapeutics fourth quarter and full year 2021 financial results Conference call.

At this time all participants are in a listen only mode. Later, you will have the opportunity to ask questions. During the Q&A portion of the call.

Operator: Later you will have the opportunity to ask questions during the Q&A portion of the call. Please note that this call may be recorded. I'll now hand the call over to Matt Calistri, Vice President, Corporate Strategy, and Investor Relations. Thank you. Good morning, everyone.

Please note that this call may be recorded I will now.

I hand, the call over to Matt <unk>, Vice President corporate strategy and Investor Relations.

Matthew Calistri: We appreciate you joining us for our fourth quarter and full year 2021 earnings call. On today's call, you'll be hearing from Dr. Tony Coles, our Chairperson and Chief Executive Officer, Dr. Ray Sanchez, our Chief Medical Officer, Dr. John Renger, our Chief Scientific Officer, and Mark Bodenrader, our Interim Chief Financial Officer. During our call today, please refer to our press release from this morning detailing our 2021 performance, as well as our updated corporate presentation, both of which are available on our website.

Thank you. Good morning, everyone. We appreciate you joining us for our fourth quarter and full year 2021 earnings call.

On today's call you'll be hearing from Dr. Tony Coles, our chairperson and Chief Executive Officer, Dr. Rey Sanchez, our Chief Medical Officer, Dr. John <unk>, Our Chief Scientific Officer, and Mark <unk>, our interim Chief Financial Officer.

During our call today, please refer to our press release from this morning detailing our 2021 performance as well as our updated corporate presentation, both of which are available on our website.

I would like to remind you that we will be making forward looking statements that reflect our current views related to among other things the potential attributes and benefits of our product candidates and the format and timing of our product development activities and clinical trials.

We strongly encourage you to review the information that we filed with the SEC regarding specific risks and uncertainties.

Matthew Calistri: I would like to remind you that we will be making forward-looking statements that reflect our current views related to, among other things, the potential attributes and benefits of our product candidates and the format and timing of our product development activities and clinical trials. We strongly encourage you to review the information that we file with the SEC regarding specific risks and uncertainties. I will now hand the call over to Dr. Tony Coles, Chairperson and CEO of Cerevel, to provide an overview of our achievements and outlook. Thanks, Matt.

I will now hand, the call over to Dr. Tony Coles chairperson and CEO of <unk> to provide an overview of our achievements and outlook.

Dr. Tony Coles: And good morning, everyone. Thank you all for joining us for our fourth quarter and full year 2021 business results call. Cerevel is well on its way to achieving our aspiration of becoming the premier neuroscience company. We've got a pipeline, the people, and the capital. We need to transform what's possible in neuroscience.

Thanks, Matt and good morning, everyone. Thank you all for joining us for our fourth quarter and full year 2021 business results call serve all its well on its way to achieving our aspiration of becoming the Premier Neuroscience company.

We've got a pipeline the people and the capital we need to transform what's possible in neuroscience and we have seen that seeing that borne out with the two positive trial results, we recently announced in schizophrenia and anxiety.

Dr. Tony Coles: And we have seen that borne out with the two positive trial results we have recently announced in schizophrenia and anxiety. First, in June of last year, we announced positive Phase 1b data for schizophrenia 4 mRaclidine, our M4-selective positive allosteric modulator, or PAM. We're eager to bring this potentially transformative therapy to as many patients as possible, as soon as possible, and we are working aggressively and creatively to do so. Earlier this year, we shared the details of our comprehensive phase two program in schizophrenia, which we expect to initiate in the middle of this year.

First in June of last year, we announced positive phase <unk> data in schizophrenia or <unk>.

For selective positive allosteric modulator or Pam.

We're eager to bring this potentially transformative therapy to as many patients as possible as soon as possible and are working aggressively and creatively to do so earlier. This year, we shared the details of our comprehensive phase III program in schizophrenia, which we expect to initiate in the middle of this year.

Dr. Tony Coles: And just two weeks ago, we announced positive anxiety data for Darigabat, our selective alpha-235 GABA-PAM. This trial demonstrated, for the first time, proof of principle in the clinic that a compound that targets alpha-2, 3, 5 selectively and spares alpha-1 can generate anxiolytic activity and minimize the side effects that limit benzodiazepines to only episodic use. Benzodiazepines are widely known to be non-selective GABA-PAMs and have a challenging side effect profile, including sedation, withdrawal, and abuse potential.

And just two weeks ago, we announced positive anxiety data for <unk> at our selective Alpha 235, Gaba Pam.

This trial demonstrated for the first time.

Principle in the clinic that a compound that targets Alpha 235, selectively and spares Alpha one can generate anxiolytic activity and minimize the side effects that limit benzodiazepines to only episodic use.

But as the days of pins are widely known to be non selective Gaba Pam and have a challenging side effect profile, including sedation withdrawal and abuse potential.

Dr. Tony Coles: These impressive clinical results support the distinct Cerevel approach to treating neuroscience disease, an approach that is grounded in a deep understanding of neurocircuitry, is focused on targeted receptor subtype selectivity, and which is distinguished through differentiated pharmacology, as illustrated on slide eight of our corporate presentation. We've grown our dynamic, innovative, and experienced team of employees, bringing forward these and the rest of our clinical programs. We've almost doubled in size from 100 core employees at the beginning of 2021 to 200 at the beginning of this year, with the majority over 70% working in research and development. Another strength of Cerevel is our robust financial position, which we bolstered in 2021 through innovative dealmaking.

These impressive clinical results.

Support the distinct circle approach to treating neuroscience disease and approach that is grounded in a deep understanding of neuro circuitry.

Focused on targeted receptor subtype selectivity and which is distinguished from differentiated pharmacology as illustrated on slide eight of our corporate presentation.

We've grown our dynamic innovative and experienced team of employees, bringing forward these and the rest of our book.

Programs, we've almost doubled in size from 104 employees at the beginning of 2021 to 200 at the beginning of this year with the majority over 70% working in research and development.

Another strength of <unk> is our robust financial position, which we bolstered in 2021 through innovative dealmaking in April we announced a non dilutive financing deal for tobacco that secured funding for our most advanced program through NDA submission.

Dr. Tony Coles: In April, we announced a non-diluted financing deal for Tevapidon that secured funding for our most advanced program through NDA submission. And we raised $250 million through a follow-on offering in July after the announcement of our positive emiraclodean data. As a result, we're very well capitalized to fund our operations into 2024.

And we raised $250 million through a follow on offering in July after the announcement of our positive <unk> data as a result, we're very well capitalized to fund our operations into 2024.

Dr. Tony Coles: Now, turning to our pipeline, which is slide nine of the presentation, we'd like to highlight the depth and breadth of the late-stage programs in the Cerevel portfolio. With two important readouts already completed, we're rapidly advancing the rest of our pipeline in the hopes of addressing the unmet needs of patients suffering from not only schizophrenia and anxiety but also epilepsy, Parkinson's, dementia-related apathy, and other neuroscience disorders.

Now turning to our pipeline, which is slide nine presentation.

We'd like to highlight the depth and breadth of the late stage programs in several portfolio with two important readouts already completed.

Rapidly advancing the rest of our pipeline in the hopes of addressing the unmet needs of patients suffering from not only schizophrenia and anxiety, but also epilepsy, Parkinson's dementia related apathy and other neuroscience diseases.

Dr. Tony Coles: Slide 10 highlights the upcoming milestones for our LEAP program. In the second half of this year, we're looking forward to Phase 2 proof-of-concept data from our ongoing trial of Darigabat in focal epilepsy. In the first half of 2023, we anticipate having data from our ongoing Phase 2a trial of CBL871 in dementia-related apathy. Also, in the first half of 2023, we expect to have Phase III tevapodon data in late-stage Parkinson's, with early-stage Parkinson's data to follow later in the year.

Slide 10 highlights the upcoming milestones for our lead programs.

In the second half of this year, we're looking forward to phase II proof of concept data from our ongoing trial of <unk> and focal epilepsy.

In the first half of 2023.

Anticipate having data from our ongoing phase two trial of <unk> 71 in dementia related apathy.

Also in the first half of 2023, we expect to have phase III tobacco on data in late stage Parkinson's with early stage Parkinson's data to follow later in the year.

In the first half of 2024, we expect to have data from our two recently announced phase III trials of <unk> in schizophrenia.

Dr. Ray Sanchez: And in the first half of 2024, we expect to have data from our recently announced Phase II trials of emarcladine and schizophrenia. We also have a robust early clinical and discovery pipeline. We are actively advancing, leveraging the state-of-the-art laboratories at our Cambridge Crossings facility. In sum, Cerevel is in an enviable position, bringing together a strong pipeline, a talented team, and a robust financial position to advance the treatment of neurosciences. Now, I will turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to review the key updates for our lead programs. Ray?

We also have a robust early clinical and discovery pipeline, we are actively advancing leveraging state of the art laboratories at our Cambridge crossing facility.

Some several is an enviable position, bringing together a strong pipeline of talented team and a robust financial position to advance the treatment of neuroscience seizes.

Now, let me turn the call over to Dr. <unk> <unk>, our Chief Medical Officer to review the key updates for our lead programs right.

Dr. Ray Sanchez: Thank you, Tony, and good morning to all of you. As Tony has outlined, Cerevel truly is poised to transform what is possible in neuroscience. Our pipeline is one of the most exciting I've seen in my career, and it is a great privilege to be part of this organization. The last year in particular has been momentous for us, as we have had two positive data readouts, which have created a lot of excitement in the physician provider community.

Thank you Tony and good morning to all of you as.

As Tony has outlined several truly is poised to transform what is possible in neuroscience.

Our pipeline is one of the most exciting as seen in my career and it's a great privilege to be part of this organization.

The last year in particular has been momentum for us as we had two positive data readouts, which have created a lot of excitement in the physician provider community.

Dr. Ray Sanchez: Let's first turn to emraclidine, formerly known as CBL-231 or M4-positive allosteric modulator. In June of last year, we announced positive Phase 1b data in schizophrenia, as outlined on slide 13. The results of that trial are very impressive. Both doses of imraclidine demonstrated clinically meaningful and statistically significant antipsychotic effects with no meaningful differences in gastrointestinal side effects, extrapyramide symptoms, or weight gain compared with placebo.

Let's first turn to <unk>, formerly known as <unk> three one <unk> four positive allosteric modulator.

In June of last year, we announced positive phase <unk> data in schizophrenia outlined on slide 13.

The results of that trial are very impressive both doses of <unk> demonstrated clinically meaningful and statistically significant antipsychotic effects with no meaningful differences in gastrointestinal side effects extra pyramidal symptoms or weight gain compared with placebo.

Dr. Ray Sanchez: The 30 milligram once daily group demonstrated an absolute improvement versus baseline of 19.5 points, while the 20 milligram twice daily cohort showed an improvement of 17.9 points on the PANS total score. Relative to placebo, both treatment groups had statistically significant reductions of 12.7 and 11.1 points, respectively. We were very encouraged by these robust results, and we are moving rapidly into our next stage of development. This past January, we were pleased to announce the details of our comprehensive Phase II program in Schizophrenia, which will begin by the middle of this year.

The 30 milligram once daily group demonstrated an absolute improvement versus basin of 19 five points, while the 20 milligram twice daily cohort showed an improvement of $17 nine points on the pans total score.

Relative to placebo, both treatment groups had statistically significant reductions of $12 seven and 11 one points respectively.

We were very encouraged by these robust results and we are moving rapidly into our next stage of development.

This past January we were pleased to announce the details of our comprehensive phase III program in schizophrenia.

Which will begin by the middle of this year.

Dr. Ray Sanchez: Now, as you can see on slide 14, this program will consist of two adequately powered placebo-controlled phase 2 trials running in parallel. Running these two trials in parallel is meant to fully explore the therapeutic dose range of emraclidine while minimizing both the placebo effect and the increased variability that can result from having four or more arms in a single trial. We designed these trials to potentially meet the criteria necessary to serve as pivotal, based on what we expect the agency will examine in a registrational package. The data we generate will determine whether these trials are sufficient. And ultimately, the final decision on the acceptability of the data package will be up to the FDA.

Now as you can see on slide 14. This program will consist of two adequately powered placebo controlled phase II trials running in parallel.

Running these two trials in parallel is meant to fully explore the therapeutic dose range of them rapidly while minimizing both the placebo effect and the increased variability that can result from having four or more arms in a single trial.

We designed these trials to potentially meet the criteria necessary to serve as pivotal.

On what we expect the agency will examine in a registrational package. The data we generate will determine whether these trials are sufficient and ultimately the final decision on the <unk> ability of the data package will be up to the FDA.

Dr. Ray Sanchez: As you'll see on slide 14, the first trial will evaluate imraquidine 10 milligrams and 30 milligrams once daily versus placebo. The second trial will evaluate imraquidine 15 milligrams and 30 milligrams once daily versus placebo. Each Phase 2 trial is 90% powered to detect a placebo-adjusted change in the PAMS total score of 7 points or greater at Week 6. We expect top-line data from both of these trials in the first half of 2024.

As Youll see on slide 14, the first trial will evaluate <unk> 10 milligrams and 30 milligrams once daily versus placebo. The second trial will evaluate them rapidly 15 milligrams and 30 milligrams once daily versus placebo.

Each phase II trial is 90% powered to detect a placebo adjusted change and the pans total score of seven points or greater at week six.

We expect top line data from both of these trials in the first half of 2024.

Dr. Ray Sanchez: In conjunction, we plan to initiate an open-label extension trial, which will accept both rollover and de novo patients in order to begin generating the required safety database to support the NDA file. Beyond schizophrenia, we also plan to evaluate this mechanism in other indications and populations, including dementia-related psychosis. Now, moving on to Rigobet.

In conjunction we plan to initiate an open label extension trial, which will accept both rollover and de novo patients in order to begin generating the required safety database to support the NDA filing.

Beyond schizophrenia, we also plan to evaluate this mechanism in other indications and populations, including dementia related psychosis.

Now moving onto to rig about.

Dr. Ray Sanchez: Two weeks ago, we announced positive top-line data from our phase one healthy volunteer trial in acute anxiety, another great proof point for Cerevel's differentiated approach to neuroscience. I was thrilled by these results and believe they represent strong evidence of Darugabat's potential as a differentiated therapy that might be a daily maintenance treatment for anxiety-related disorders in contrast to benzodiazepines. As Tony mentioned, benzodiazepines are non-selective GABA PAMs and are limited to episodic use due to their tolerability issues.

Two weeks ago, we announced positive top line data from our phase one healthy volunteer trial in acute anxiety another great proof point for serve our differentiated approach to neuroscience.

I was thrilled by these results and believe they represent strong evidence of <unk> potential as a differentiated therapy that might be a daily maintenance treatment for anxiety related disorders in contrast to benzodiazepines as.

As Tony mentioned benzodiazepines are non selective Gaba Pam and are limited to episodic use due to their tolerability issues.

Dr. Ray Sanchez: This data readout supports our thesis that Darugabat may optimize angiolytic effects by selectively targeting the alpha 2, 3, and 5 subunits of the GABA A receptor while minimizing the Alpha-1 associated tolerability concerns. We were very encouraged to see clinically meaningful and statistically significant anxiolytic effects after eight days of treatment for both doses of Darigavet. We were also pleased to see that Dorigabat was generally well-tolerated, with no serious adverse events, no treatment-related discontinuations, and no incidents of withdrawal symptoms in the Dorigabat treatment group.

This data readout supports our thesis that to rig about may optimize anxiolytic effect by selectively targeting the alpha two 3% and five subunits of the Gaba a receptor while minimizing the alpha one associated tolerability concerns.

We were very encouraged to see clinically meaningful and statistically significant anxiolytic effects. After eight days of treatment for both doses tested.

<unk> tested well.

We were also pleased to see that <unk> was generally well tolerated with no serious adverse events treatment related discontinuation and no incidence of withdrawal symptoms in the drill rig about treatment groups.

Dr. Ray Sanchez: Now, a couple of points I would like to highlight about the trial design before I discuss the specific results. First, this trial was optimized to show, in healthy volunteers, an anxiolytic effect over a relatively short duration of treatment, approximately one week. And Alprazolam was used solely to ensure the sensitivity of the hypercapia model, which it did.

Now a couple of points I would like to highlight about the trial design before I discuss the specific results.

Dr. Ray Sanchez: Second, we utilized a very quick four-day titration regimen for both doses, as again, the purpose of this particular trial design was to detect an anxiolytic effect rather than elucidate the safety and tolerability profile. With that in mind, I would like to turn your attention to slide 20 of the corporate presentation. As you can see here, the Doricabat 7.5 milligram and 25 milligram twice daily doses demonstrated statistically significant improvements of 3.9 and 4.5 points on a placebo-adjusted basis, with p-values of 0.036 and 0.008.

First this trial was optimized to show in healthy volunteers and anxiolytic effect over a relatively short duration of treatment approximately one week and in our press line was used solely to ensure sensitivity of the hyper Kathy model, which occurred.

Second we utilized a very quick for day titration regimen for both doses as again the purpose of this particular trial design was to detect an anxiolytic effect rather than elucidate the safety and Tolerability profile.

With that in mind I would like to turn your attention to slide 20 of the corporate presentation.

As you can see here the rig about seven five milligram and two five milligram twice daily doses demonstrated statistically significant improvements.

Of three nine and four five points on a placebo adjusted basis.

With P values of zero point, all three six and 0.8, respectively.

Dr. Ray Sanchez: We stated previously that a two- to three-point placebo-adjusted improvement in the panic symptoms list, or PSL-4 total score, would be considered a clinically meaningful reduction in anxiety symptoms. Hence the robustness of our results is quite impressive and clearly exceeded expectations. The clinical effects seen with Alprazolam of 1.6 points were within the range of expectations for this model and again confirmed the validity of the model for detecting anxiolytic

We stated previously that are two to three point placebo adjusted improvement in the panic symptoms Lister PSL for total score would be considered a clinically meaningful reduction in anxiety symptoms. So the robustness of our results are quite impressive and clearly exceeded expectations.

Clinical effect seen with PRASM up one six points was within the range of expectations for this model and again confirmed the validity of the model for detecting anxiolytic activity.

Dr. Ray Sanchez: Although this was a trial in healthy volunteers and not patients, we were quite pleased by the tolerability profile we observed in this study. Both doses of Darigavac demonstrated anxiolytic effects, and 97% of adverse events reported were considered mild. The incidence and temporal pattern of these AEs appear to be related to the dose and speed of titration.

Although this was a trial in healthy volunteers and not patients we were quite pleased by the Tolerability profile, we observed in this study.

Both doses of <unk> demonstrated anxiolytic effect and 97% of adverse events reported were considered mild.

The incidents and temporal pattern of these aes appear to be related to the dose and speed of titration.

Dr. Ray Sanchez: So in future trials, a longer titration period may help us better understand the actual adverse event profile we might expect to see in the relevant patient population. Later in the presentation, Dr. John Renger will provide some details on what we learned about the relationship between drug exposures and anxiolytic activity from the trial, and we look forward to presenting additional details on this trial at future scientific conferences. As a reminder, in the second half of this year, we expect results from our phase two proof-of-concept trial in focal epilepsy.

So in future trials are longer titration period may help us better understand the actual adverse event profile, we might expect to see in the relevant patient populations.

Later in the presentation, Dr. John <unk>, who will provide some details on what we learned about the relationship between drug exposures and anxiolytic activity from the trial and we look forward to presenting additional details on this trial at future scientific conferences.

As a reminder.

In the second half of this year, we expect the results from our phase II proof of concept trial in focal epilepsy.

Dr. Ray Sanchez: We're also conducting a corresponding open-label extension trial, which continues to have a very high rollover rate. Turning next to Cabapidon are D1-5 partial agonists, which we are developing for Parkinson's disease symptoms as both a monotherapy and adjunctive treatment.

We're also conducting a corresponding open label extension trial, which continues to have a very high rollover rate.

Turning next to <unk>.

R. D. One five partial agonist, which we are developing for Parkinson's disease symptoms as both a monotherapy and adjunctive treatment.

Dr. Ray Sanchez: We continue to dose in all three of our phase three trials, known collectively as the TEMPO trials, and all remain on track with our expected time. We expect data from Tempo 3, the adjunctive trial in late-stage Parkinson's, to read out in the first half of 2023, and data from Tempos 1 and 2 in early-stage Parkinson's to read out in the second half of 2023. Turning to CBL 871, another D1, D5 partial agonist, which we are currently evaluating in a phase IIa exploratory trial in dementia-related apathy. We expect data in the first half of 2023.

We continue to dose in all three of our phase III trials known collectively as the tempo trials and all remain on track with our expected timelines.

We expect data from temple III, the adjunctive trial in late stage Parkinson's to readout in the first half of 2023 and data from <unk>, one and two in early stage Parkinsons to readout in the second half of 2023.

Turning to CBL 87, one another D. One five partial agonist, which we are currently evaluating in a phase Iia exploratory trial in dementia related apathy.

We expect data in the first half of 2023.

Dr. Ray Sanchez: In June of last year, we received FASTRAC designation for CBL 871 in this indication, which enables early and more frequent interactions with the FDA as well as the potential for rolling-in DA submission and priority review. We're looking forward to interacting closely with the agency in determining the best path forward for developing a treatment for this novel indication. Before I hand the call over to Dr. Renger, I wanted to address the war in Ukraine and any questions you may have about the IMPEC TOR trial.

In June of last year, we received fast track designation for <unk> 701 in this indication, which enables early and more frequent interactions with the FDA as well as the potential for rolling NDA submission and priority review.

We're looking forward to interacting closely with the agency and determining the best path forward for developing a treatment and this novel indications.

Before I hand, the call over to Dr. <unk> I wanted to address the war in Ukraine, and any questions. You may have on the impact to our trials.

Dr. Ray Sanchez: Our thoughts are first and foremost with the investigators and patients at clinical trial sites and, indeed, with all the people of Ukraine. Specifically for Cerevel, we do not believe our clinical trial timelines are impacted at this time, but we are acutely aware that this is a grave humanitarian crisis in an important country for clinical research and development. Among our ongoing trials for Tavapidon, we have a small number of clinical trials for the Phase III TEMPO program, less than 10% of all sites that are located in Ukraine. We are proud of the meticulous approach we take to trial execution, and, in fact, we began planning for geopolitical uncertainties and potential disruptions in the region a while ago.

Our thoughts are first and foremost with the investigators and patients at clinical trial sites and indeed with all the people of Ukraine.

Specifically for <unk>, we do not believe our clinical trial timelines are impacted at this time, but we are acutely aware that this is a grave humanitarian crisis and an important country for clinical research and development.

Among our ongoing trials for <unk>, we have a small number of clinical trials for the phase III tempo program less than 10% of all sites that are located in Ukraine.

We are proud of the meticulous approach, we take to trial execution and in fact, we began planning for geopolitical uncertainties.

Potential disruptions in the region a while ago for example in January we started taking mitigation measures as a contingency, including pre shipment of additional clinical drug product and supplies to the country.

Dr. John Renger: For example, in January, we started taking mitigation measures as a contingency, including pre-shipment of additional clinical drug product and supplies to the country, as we have in the past with the COVID-19 pandemic and as with any rapidly evolving crisis. We are constantly evaluating clinical operations across our portfolio to ensure we continue to meet our goals with respect to data integrity and quality, and Rome quality and trial time. I'd now like to turn the call over to Dr. John Renger, our Chief Scientific Officer, to speak about our Early-Stage Portfolio. John?

As we have in the past with the COVID-19, pandemic and as with any rapidly evolving crisis, we're constantly evaluating clinical operations across our portfolio to ensure we continue to meet our goals with respect to data integrity enrollment quality and trial timelines.

I'd now like to turn the call over to Dr. John <unk>, Our Chief Scientific officer to speak about our early stage portfolio John .

Dr. John Renger: Thank you, Ray. Good morning, everyone. First, I really do want to emphasize that the recent data from our acute hypercapnia panic trial on healthy volunteers represents an important scientific and medical breakthrough for scientists, clinicians, and especially patients who are desperately seeking new mechanisms for the treatment of anxiety-related disorders. These data are the first clinical validation in humans to demonstrate that robust anxiolytic benefit can be achieved by selectively targeting the alpha-2, 3, and 5 subunits while at the same time sparing the alpha-1 subunit-containing GABA receptors.

Thank you Ray good morning, everyone.

I really do want to emphasize that the recent data from our acute hypercalcemia pending trial in healthy volunteers represents an important scientific and medical breakthrough per scientists clinicians and especially patients were desperately seeking new mechanism for the treatment of anxiety related disorders. These.

These data are the first clinical validation in humans that demonstrates that robust anxiety related benefit can be achieved by selectively targeting alpha two three or five sub units while at the same time sparing the alpha one subunit containing Gaba receptors.

Dr. John Renger: In this particular clinical trial, we evaluated a broad range of drug exposures and the concurrent receptor occupancies to best inform future dose selection and for confirming the necessary drug levels required to reduce antialytic symptoms. For context, our preclinical studies have previously shown receptor occupancies of at least 50% to 60% were sufficient to demonstrate anxiolytic activity with Darugavet. In this healthy volunteer trial, the 7.5 milligram twice daily dose achieved 50 percent receptor occupancy at the alpha-2 subunits of the GABA-A receptor, while the 25 milligram twice daily dose achieved approximately 76 percent alpha-2 receptor occupancy. Importantly, as a reminder, this is relative to less than an estimated 15% or lower alpha-2 receptor occupancy achieved with Alprazolam at the one milligram twice daily dose.

And this particular clinical trial, we evaluated a broad range of drug exposures and the concurrent et cetera, occupancies to best inform future dose selection and for confirming the necessary drug levels required to reduce antibiotics symptoms.

As context, our preclinical studies previously shown the receptor occupancy of at least 50% to 60% were sufficient to demonstrate and dialytic activity with during COVID-19 .

In this healthy volunteer trial with seven five milligram twice daily dose achieved 50% receptor occupancy at the Alpha two subunits of the Gaba a receptor.

While the 25 milligram twice daily dose achieved approximately 76% of the two receptor occupancy.

Importantly, as a reminder, this is relative to less than an estimated 15% or lower altitude receptor occupancy achieved with <unk> lab at the one milligram twice daily dose of dosage level that is on the low end of what is typically prescribed as starting treatment for the reduction of anxiety symptoms in patients in the clinical practice.

Dr. John Renger: The dosage level is on the low end of what is typically prescribed as the starting treatment for the reduction of anxiety symptoms in patients in the clinical practice setting. Our goal of this study was to push the upper bounds of receptor occupancy selectively at the alpha-2, 3, and 5 subunits in order to more fully investigate the maximal level of drug activity through attaining high levels of alpha-2, 3, 5 receptor occupancy, well beyond what is achievable with non-selective benzodiazepines, which are dose-limited to the side effects of sedation, motor discoordination or ataxia, and cognitive impairment, such as amnesia.

Our goal in this study was to push the upper bounds of receptor occupancy selectively.

With two three and five sub units in order to more fully investigate the maximum level of drug activity to attaining high levels of alpha to three 5% receptor occupancy well beyond well beyond what is achievable with nonselective benzodiazepines, which are dose limited to the side and side effects of <unk>.

Asian border this coordination ataxia and cognate impairment such as MBS.

Dr. John Renger: The extended range of high receptor occupancies achieved in this trial were multiple folds higher than the 15 to 20% that's normally achieved for the non-selected benzodiazepines at clinically used doses. Our data give us great confidence in sparing the GABA Alpha 1 receptor and selectively targeting the GABA Alpha 2, 3, and 5 receptors at these occupancy levels may provide anxiety benefit while avoiding the issues that underlie dosomotations associated with From this data, we also have gained important insights into the exposures needed to be achieved for exploring beneficial effects, and the culmination of this information will help our teams as we consider future options for alternate dosage formulations.

Extended range of high receptor occupancy achieved in this trial were multiple folds higher than the 15% to 20% that's normally achieve for the non selected benzodiazepines it clinical use dosages.

Our data give us great confidence of sparing the gab Alpha one receptor and selectively targeting the gamba Alpha two three and five receptors that these occupancy levels may providing diluted benefit while avoiding the issue that underlies dosing occasions associated with benzodiazepines.

From this data we also gained important insights into the exposures needed to be achieved we're exploring beneficial effects on the culmination of its information will enable our teams as we consider future options for alternate dosage formulations.

Dr. John Renger: We're eager to keep you updated as we pursue the development of Darigabat as a potential daily dose therapy for the treatment of anxiety disorders, giving patients who are counting on Cerevel the potential for new options for maintenance therapy. In our early pipeline, I'd first like to highlight CBL354, our highly selected Kappa opioid receptor antagonist, as a potential therapy for the treatment of both major depressive disorder and substance use disorder.

We are eager to keep you updated as we pursue the development of <unk> as a potential daily dose therapy for the treatment of anxiety disorders, giving patients who are counting on sorry, well the potential for new options for maintenance therapy.

Within our early pipeline I would first like to highlight CBL three five for our highly selective Kappa opioid receptor antagonist is a potential therapy for the treatment of both major depressive disorder and substance use disorder.

Dr. John Renger: The FDA recently accepted our IND for this program, and we are currently conducting phase one, single, and multiple ascending dose trials in healthy volunteers. We're very excited about the potential for this program to be differentiated in multiple areas of high and met patient need, particularly due to recent clinical validation by others in a phase 2 depression study and an extensive amount of our internal preclinical work that supports the potential for this mechanism of action. We are also well-positioned as the scientific leader in identifying and progressing a host of selective M4 muscarinic receptor-directed compounds with a range of pharmacological profiles, complementing our promising M4-PAM and Miraclidine.

The FDA recently accepted our IND for this program and we are currently conducting phase one single and multiple ascending dose trials in healthy volunteers.

We're very excited about the potential for this program to be differentiated in multiple areas of high unmet patient need.

Taken any due to recent clinical validation by others in our phase II Depression study.

And an extensive amount of our internal preclinical work that supports the potential for this mechanism of action.

We are also well positioned as the scientific leader in identifying and progressing a host of selective <unk> muscarinic receptor directed compounds with a range of pharmacological profiles.

Complementing our promising <unk> equity.

Dr. John Renger: Our teams of scientists are actively evaluating additional highly potent muscarinic M4 receptor-selective folaginase and allosteric modulators to potentially advance into the clinical setting to expand upon our lead molecule amiraclidine. These additional molecules are expected to expand the clinical utility that we've already demonstrated with amiraclidine in multiple additional psychosis-related therapeutic indications, potentially further increasing our lead in the targeted M As you can see, 2021 has been an extraordinarily productive year for Cerevel, and we are looking forward to many exciting updates in 2022 and beyond.

Our teams of scientists are actively evaluating additional highly potent muscarinic receptor selected full agonist, an allosteric modulators to potentially advance into the clinical setting to expand upon our lead molecule <unk> equity.

These additional molecules are expected to expand the clinical utility that we've already demonstrated with them or equity and multiple additional psychosis related therapeutic indications potentially further increasing our lead in the targeted <unk> muscarinic receptor therapeutic area space.

As you can see 2021 has been an extraordinarily productive year for <unk> well, we're looking forward to many exciting updates in 2022 and beyond.

Dr. John Renger: I'd now like to turn it over to Mark Bodenrader, our Interim Chief Financial Officer, to review the specifics of our financial performance and our outlook for this year. Thank you, John. I'm pleased to provide an overview of Cerevel's strong financial position, which was bolstered by our capital raises in 2021. I'll start by discussing our 2021 financial, and then I'll spend a few moments on our cash position expected. Full-year 2021 total operating expenses were approximately $220 million, which included R&D expenses of $162 million and GNA expenses of $58 million.

Now I'd like to turn it over to Martin <unk>, Our interim Chief Financial Officer to review the specifics of our financial performance and our outlook for this year.

<unk>.

Mark Bodenrader: R&D expense for 2021 increased by approximately $59 million over 2020, primarily due to the continued advancement of our later stage clinical programs, increased investment in our early discovery efforts, and an increase in personnel and other infrastructure costs to support the continued growth of our pipeline. R&D expense for 2021 also included $9.2 million of equity-based compensation expense versus $3.2 million last year. G&A expense for 2021 increased by approximately $12 million over last year, primarily due to a full year of public company operating costs and higher personnel and other costs to support organizational growth.

Thank you John I'm pleased to provide an overview of <unk> strong financial position, which was bolstered by our capital raises in 2021.

I'll start by discussing our 2021 financial results and then I'll spend a few moments on our cash position and expected runway.

Mark Bodenrader: G&A expense for 2021 also included $14.7 million of equity-based compensation expense relative to $7.3 million for 2020. As of December 31st, 2021, our cash and marketable securities totaled $618 million compared to $384 million as of December 31st, 2020. Our cash position was bolstered by the $350 million follow-on offering completed in July, shortly after the announcement of the positive Phase 1b data for amraclidine in schizophrenia. In addition, we received approximately $55 million in the third quarter from the redemption and exercise of our public warrants.

Full year 2021, total operating expenses were approximately $220 million, which includes R&D expense of $162 million.

And G&A expense of $58 million.

R&D expense for 2021 increased by approximately $59 million over 2020, primarily due to the continued advancement of our later stage clinical programs increased investment in our early discovery efforts and an increase in personnel and other infrastructure costs to support the continued growth of our pipeline.

R&D expense for 2021 also included $9 $2 million of equity based compensation expense versus $3 $2 million last year.

G&A expense for 2021 increased by approximately $12 million over last year, primarily due to a full year of public company operating costs and higher personnel and other costs to support organizational growth.

<unk> expense for 2021 also included $14 $7 million of equity based compensation expense relative to $7 3 million for 2020.

As of December 31, 2021, our cash and marketable securities totaled $618 million compared to $384 million as of December 31, 2020.

Our cash position was bolstered by the $350 million follow on offering completed in July shortly after the announcement of the positive phase <unk> data for <unk> in schizophrenia.

In addition, we received approximately $55 million in the third quarter from the redemption and exercise of our public warrants and in April we received the first funding payment under active app on financing agreements of $31 million and we anticipate receiving an additional $37 $5 million under these agreements in the second quarter. This year.

Mark Bodenrader: And in April, we received the first funding payment under our Tavapidon financing agreements for $31 million, and we anticipate receiving an additional $37.5 million under these agreements in the second quarter of this year. Looking forward, we expect R&D expenses to continue to increase this year as we initiate our Comprehensive Phase II program for Imraclidine, continue to advance our Phase III program for Tevapidone, and continue to invest in Trigobat, CVL-871, and our Early Discovery efforts.

Looking forward, we expect R&D expense to continue to increase this year as we initiate our comprehensive phase III program for <unk>.

To advance our phase III program for <unk> and continue to invest into rig about <unk> 71, and our early discovery efforts.

Mark Bodenrader: In addition, we expect R&D personnel costs to continue to grow this year to support the advancement of our pipeline. We also expect GNA expenses to increase as we support the continued growth of our research and development efforts and initiate pre-commercialization activities. In closing, we remain well-capitalized. We expect our cash resources to fund our operations into 2024.

In addition, we expect R&D personnel costs to continue to grow this year to support the advancement of our pipeline. We also expect G&A expenses to increase as we support the continued growth of our research and development efforts and initiate pre commercialization activities.

In closing, we remain well capitalized we expect our cash resources to fund our operations into 2024, we look forward to multiple value, creating data readouts over the next couple of years and finally, we continue to think creatively and opportunistically about further strengthening our balance sheet to support our extensive pie.

Dr. Tony Coles: We look forward to multiple value-creating data readouts over the next couple of years. And finally, we continue to think creatively and opportunistically about further strengthening our balance sheet to support our extensive pipeline. I would now like to hand the call back to Tony for his concluding remarks. Thanks, Mark. At Cerevel, we continue to advance our mission to improve the lives of people living with neuroscience diseases. We've reported two successful data readouts in less than a year, and we continue to make progress in the rest of our extensive pipeline of both clinical and preclinical programs, and we've secured the people and the capital we need to continue our journey to become the premier neuroscience company.

Your line.

I would now like to hand, the call back to Tony for concluding remarks.

Thanks Mark.

At <unk>, we continue to advance our mission to improve the lives of people living with neuroscience diseases. We've reported two successful data readouts in less than a year continued to make progress in the rest of our extensive pipeline of both clinical and preclinical programs and we secured the people and the capital we need.

To continue our journey to become the Premier Neuroscience company. Our programs are focused on addressing high unmet needs for millions of patients with neuroscience diseases.

Dr. Tony Coles: Our programs are focused on addressing high unmet needs for millions of patients with neuroscience diseases, including schizophrenia, anxiety, epilepsy, Parkinson's, dementia-related apathy, and now depression. At Cerevel, we're leveraging our unique expertise in neurocircuitry to advance our deep portfolio and ultimately to bring new medications to the patients who need them. Before I conclude, I'd like, as I always do, to thank our employees who are so committed to making a positive impact on patients' lives and live that mission every day.

Schizophrenia anxiety epilepsy, Parkinson's dementia related apathy and now the pressure at.

At <unk>, we're leveraging our unique expertise in neurosurgery tree to advance our deep portfolio and ultimately to bring new medications to the patients who need them.

Before I conclude I'd like to as I always do thank our employees, who are so committed to making a positive impact on patients' lives and live that mission every day.

Dr. Tony Coles: To the physicians, caregivers, and participants in our clinical development programs, we say thank you. And I also want to thank you, our investors, for your support and belief in our mission. And I can tell you that we truly couldn't do this without you.

To the physicians caregivers and participants in our clinical development programs. We say, thank you and I also want to thank you our investors for your support and belief in our mission and I can tell you that we truly couldnt do this without you.

Operator: With that, Sarah, let's now open the call for questions. Thank you. We'll now begin the question and answer session. As a reminder, if you would like to ask a question, please press star 1 on your keypad and wait for your name to be announced. And to cancel that request, you can press the hash key.

Sarah Let's now open the call for questions.

Thank you we will now begin the question and answer session. As a reminder, if you would like to ask a question. Please press star one on your keypad I might see your name to be announced at the council that request compressor hacky.

And one for questions.

Operator: So it's Star and 1 for questions. Your first question today is from the line of Michael Yee from Jeffreys. Please go ahead. Hey, good morning, Tony and team.

Your first question today is from the line of Michael Yee from Jefferies. Please go ahead.

Hey, good morning, Tony and team. Thank you.

Michael Yee: Thank you. We had a question on Darigabat. Appreciating the recent exciting data, I think you've presented in anxiety. I know there's a little bit of debate there, but I think we all agree there was proof of concept and proof of biology.

You had a question on day rig about appreciating the recent exciting data I think you've presented an anxiety I know theres a little bit of a debate there, but I think we all agree there was proof of concept and proof of biology.

Michael Yee: We were wondering how you have thought about that data now that it's out there and how you think about the translation to the epilepsy study later this year, both from an efficacy scenario standpoint and from a safety tolerability standpoint. What you think the bar is for efficacy is and how you think about those scenarios. Thank you so much.

Wondering how you have thought about that data now thats out there and how you think about the translation to the epilepsy study later this year.

And efficacy scenario standpoint kind of safety Tolerability standpoint, what do you think the bar is for efficacy and how to think about the scenario. Thank you so much.

Dr. Tony Coles: Okay. Thanks, Michael, and good morning. The first point I'd like to make is that we are really excited, as Ray said in his prepared remarks, by these results because they demonstrate that it is possible to achieve the efficacy that we see with benzodiazepines, the non-selective GABAs, without any alpha-1 activation. So, that's a really important demonstration of the power of this particular mechanism, and it's alpha-1 sparing.

Okay, Thanks, Michael and good morning.

The first point I'd like to make is we are we are really excited as ray said in his prepared remarks by these results because they demonstrate that it is possible to achieve the efficacy that we see with benzodiazepines. The non selective Gaba is without any alpha one activation. So that's a really important demonstration of.

Power of this particular mechanism.

Dr. Tony Coles: And now we've seen this clinically for both epilepsy in our earlier studies and anxiety. The other thing I'd like to point out is that this is further validation of this selectivity that I've just spoken about, and it complements all the work that we do, both in healthy volunteers, which was this study, and in patients. I don't think I'd specifically read through either the safety tolerability or efficacy findings from the anxiety trial, but there are some important differences.

And it's being alpha one sparing and now we've seen this clinically for both epilepsy and our earlier studies and anxiety.

The other thing I'd like to do is highlight this is further validation of this selectivity that I've just spoken about.

And it complements all the work that we're doing.

Dr. Tony Coles: I'll ask, perhaps, Ray to comment or J.R. to comment in just a moment. There are some really important differences between healthy volunteers as distinct from patients. And we've discussed this previously because obviously healthy volunteers, this particular trial for healthy volunteers was shot for shorter duration and had a much more rapid titration than we would expect to be in either common practice or in clinical trials in patients with anxiety. So I think in some, Mike, we really are excited about the mechanism, its potential across multiple disease opportunities, and what this can mean, and we'll know soon about epilepsy.

Both in healthy volunteers, which was this study and in patients.

Think I'd, specifically read through either safety tolerability or efficacy findings from the anxiety trial. There are some important differences I'll ask perhaps ray to comment or Jr. To comment in just a moment.

Dr. Tony Coles: But J.R., let me turn it over to you for any additional details. Specifically, on the bar, how you're thinking about the bar there for effort, whether we should just compare the other in sets out. Mike, I'm sorry. You broke up on my end.

There are some really important differences in healthy volunteers as distinct from patients and we've discussed this previously because obviously healthy volunteer this particular trial for healthy volunteers with strokes shorter duration had a much more rapid titration, then we would expect to be any of the common.

This important clinical trial in patients with anxiety.

I think in some Mike we really are excited about the mechanism its potential across multiple disease.

Opportunities and what this could mean and we'll know soon about epilepsy, but Jr. Let me, let me turn it over to you for any additional detail.

Specifically on the bar, how youre thinking about the bar for efficacy and whether we should just compare to other data sets out there.

Michael Yee: Would you just repeat the second half of your question? Yes, specifically on how you think about the bar for efficacy, assuming it could be positive, what magnitude and what reduction of seizures would you like to see, and should we just compare that to other data sets out there for other drugs? Do you mean for epilepsy specifically? Yes, yes, yeah.

Mike I'm, sorry, you broke up on my end would you just repeat the second half of your question yes.

Specifically on how you think about the bar for efficacy accumulate it could be positive what magnitude and what reduction appears you would you like to see and should we just compare that to other data sets out there for other drugs.

You mean for epilepsy, specifically, yes, yes, yes, okay. Okay. So Jerry why don't you provide some additional detail on won't have ray answer that part of the question separately chair.

Michael Yee: Okay. Okay. So, J.R., why don't you provide some additional detail, and we'll have Graig answer that part of the question separately. Okay. Okay.

Dr. John Renger: Sure. Thank you, Tony. Yeah.

Sure. Thank you Tony.

Yes, so Mike I think I think.

You referenced in the data and how we interpret it you can speak to that and then where you can speak to the clinical meaningful difference for <unk> for the treatment and epilepsy, we designed that trial and powered it.

Dr. John Renger: So, Mike, I think you're referencing the data and how we interpret it. You know, I can speak to that, and then we can speak to the clinically meaningful difference for treatment in epilepsy and how we designed that trial and powered it. I just want to reemphasize that this is really the very first time that a selective compound has demonstrated the ability to achieve a resolution of panic symptoms. And, you know, this is a healthy trial.

Wanted to reemphasize that this is really the very first time.

<unk> compound has demonstrated the ability to achieve resolution of panning symptoms and even though this is a healthy trial.

Dr. John Renger: We think that this has a very strong read-through to the potential for demonstrating efficacy in anxiety-related disorders. Of note, the receptor occupancies that we targeted in this study were very similar, identical, in fact, to the ones that are being used in the epilepsy trial.

We think that it has a very strong read through to the potential for demonstrating efficacy and anxiety related disorders of note. The receptor occupancies that we targeted in this study.

Very similar identical and track to the ones that are being used in the epilepsy trial. So what we know is with the doses that we've used it we again demonstrated efficacy.

Dr. John Renger: So, what we know is that the doses that we've used have, again, demonstrated efficacy in the dose ranges that are also being used in the epilepsy trial. So, as you know, in the photoepilepsy study, we've shown efficacy in treating epilepsy before. In this one, this is a second indication now looking at different neural pathways in the brain that underlie the feeling of panic that patients can have.

And the dose ranges that are also being used in the epilepsy trial. So as you know in the photo epilepsy study.

Joan.

Efficacy in treating epilepsy previously and this one this is the second indication now looking at different neural pathways in the brain that underlies the feeling of panic.

Dr. John Renger: We've also demonstrated efficacy in treating those symptoms in this healthy study. So, what this indicates to us is that we understand the effective dose range, and we believe that, you know, in either population that we're actually covering, the important receptor occupancy range that we want to cover to demonstrate CNS activity. So, I'll let Ray speak, actually, about the design of the epilepsy trial and what we've come to see there. Thank you, John. Good morning. Good morning, Michael.

It is going to have we've also demonstrated with the same dose range efficacy in treating those symptoms in this <unk> study. So what this indicates to US is that we understand the effective dose range and we believe that.

In either population that we're actually covering important receptor occupancy range that we want to cover the demonstrates CNS activity.

I'll, let ray speak actually to the designs of the epilepsy trial and what we believe are powered to see there Rick.

Dr. Ray Sanchez: Thank you for the question. As you know, the ongoing epilepsy trial is 80 percent powered to show a reduction of 31 percent in seizure frequency. To give you some juxtaposition in terms of the other therapies in the landscape, Keppra is about 28 percent effective, which is what they demonstrated. So we're hoping to show at least 31 percent, if not higher, given the selectivity of the mechanism, but also the data that's been generated to date in the Kufra principle photosensitivity trial.

Thank you John and good morning, Good morning, Michael. Thank you for the question. So as you know that the ongoing epilepsy trial is 80% powered to show a reduction of 31% in seizure frequency.

To give you some juxtaposition in terms of the other therapies and the landscape capitalized about 28% is what they demonstrated.

Dr. Ray Sanchez: So we'll stay tuned for that data later this year, but we're encouraged by what we've seen in anxiety and what we've seen in epilepsy to date and hoping that we can see the benefits of this therapy in the epilepsy population as well. Thank you. Good. Thank you, Ray. Michael, thank you for the question. Cerevel, take the next question.

Hoping to show at least 31% if not higher given the selectivity of the mechanism, but also of the data that's been generated to date in the proof of principle photo sensitivity trial. So we'll stay tuned for that data later this year, but we're encouraged by what we've seen in anxiety and what we've seen in epilepsy to date and hoping that we can.

The benefits of this therapy in the <unk> population as well.

Thank you very much.

Great. Thank you Michael Thank you for the question Sarah will take the next next question. Please.

Operator: Thank you. The next question is from the line of Matthew Harrison from Morgan Stanley. Please go ahead. Great. Good morning. Thanks for taking my questions. I guess I have two.

Thank you. The next question is from the line of Matthew Harrison from Morgan Stanley . Please go ahead.

Matthew Harrison: So, first on schizophrenia, can you just comment on the trials and the potential to pool those? So, for example, could you have the 30 mg dose in two trials? Would you be able to pool them if the effect size was smaller than the seven-point delta that you were assuming?

Great. Good morning, Thanks for taking my questions I guess.

I have two so first on <unk>.

Can you just comment on the trials and the potential to pool. Those so for example, because you have the 30, Meg dose and two trial, but would you be able to pull them.

The effect size was smaller than the seven point Delta that you are assuming and then second just on to that the Don can you remind us how youre in commuting for missing data, there and sort of what percentage of dropouts, we were expecting in the original plan.

Matthew Harrison: And then, second, just on to Vapidon, can you remind us how you're calculating for missing data and sort of what percentage of dropouts you were expecting in the original staff plan? Thanks. Okay, Ray, why don't you, if you would, take both of those? But I'd really appreciate you perhaps underscoring that part of your prepared comments about how we design these trials and what we think that they can do in terms of answering the essential registrational questions. We all know that the agency is going to be looking for a full characterization of the dose range for enraclavine.

Okay.

Ray why don't you if you.

It would take both of those but I would really appreciate your perhaps underscoring that part of your prepared comments about how we designed these trials and what we think that they can do in terms of entering the central Registrational questions.

The agency is going to be looking for a full characterization of the dose range for <unk>. The one long term safety and there are of course to adequately powered placebo controlled trials. So we think we've got the right. We're asking the right questions for the FDA to evaluate what we know there'll be looking form registration but.

Dr. Tony Coles: They'll want long-term safety, and there are, of course, two adequately powered placebo-controlled trials. So we think we've got the right questions for the FDA to evaluate what we know they'll be looking for in registration. But, Ray, why don't you just expand on that and speak to the specific question about the possibility of pooling data for the effect size and then take the tab. Right, right. So, good morning, Matthew.

Ray why don't you just expand on that and speak to the specific question about the possibility of pulling data for the effect size and then take the tariff question.

Dr. Ray Sanchez: So as you know, as Tony has mentioned, and I've said before as well, that these two trials were designed to potentially be pivotal in nature, really looking at the full dose range of the top dose of 30 milligrams and the minimum effective dose of 10 or 15 milligrams. In order for them to be registrational in nature, they each have to separate from placebo, as you know, so the opportunity to actually combine the data is probably not an approach that the agency will likely accept.

Alright, right. So good morning, Matthew So as you know the as Tony has mentioned and I've said I think before as well that.

These two trials were designed to potentially be pivotal in nature really.

Looking at the full dose range of the top dose of 30 milligrams in the minimum effective dose of 10 or 15 milligrams.

In order for them to be Registrational in nature, they each have two.

<unk>.

Separate from placebo.

So the opportunity to to actually combine the data.

It's probably not the approach at the agency will likely accept they've not done that historically in very few cases, but with very different populations and different trial designs. So we'll stay tuned to present the data that we generate to.

Dr. Ray Sanchez: They've only done that historically in very few cases but with very different populations and different trial designs, so we'll stay tuned to present the data that we generate to the FDA at our end-of-phase 2 meeting to see the viability of the program in terms of its registrational potential. But the plan is not to pool that data moving forward in order for them to be registrationally viable in their potential.

<unk> to the FDA at our end of Phase II meeting to see the viability of the program in terms of its registrational potential but.

But the plan is not to pool that data moving forward.

In order for them to be Registrational in there in there.

<unk> potential.

Dr. Ray Sanchez: The second question you asked about Kevapadon, and in terms of imputation of data, we're using a mixed model of repeated measures, MMRM approach, as you know. We anticipate, when we design the trials, approximately a 27% discontinuation rate. We'll obviously see how that fares versus what the trial actually produces once it reads out, but that's our assumption going into it based on historical trials and precedent from other trials in Parkinson's disease. Okay, very good. Thank you, Ray. Sarah, we're ready for the next question. Thank you. The next question is from the line of Paul Matteis from Steefel. Please go ahead. Great, thanks so much.

The second question you asked about <unk>.

And in terms of amputation of data, we're using a mixed model repeated measures. The MRM approach as you know.

We anticipate.

When we design the trials approximately at 27% discontinuation ranked discontinuation rate.

We'll obviously see how that fares versus what you know.

What the trial actually.

The producers once it reads out.

But that's our assumption going into it based on historical trials and precedent from other trials in Parkinson's disease.

Okay very good thank you.

Sarah we're ready for the next question.

Yeah.

Thank you. The next question is from the line of Paul Matteis from Stifel. Please go ahead.

Great. Thanks, so much.

Operator: I had two questions about the M4 program. One, about the cardiac safety study that you're doing, can you maybe talk a little bit more about why you decided to do this study and, I guess, maybe just sort of set it up? What are you hoping to sort of describe, and do you view the cardiac changes that you see, changes in blood pressure, changes in heart rate, as things that are likely maybe more labeling or monitoring issues, or how should we sort of be thinking about this?

Two questions on the <unk> program.

One on the cardiac safety study that you're doing can you just maybe talk a little bit more about why you decided to do this study and.

And I guess, maybe just sort of set it up what are you hoping to sort of describe then.

Do you view the cardiac changes that you see changes in blood pressure changes in heart rate is as things that are likely maybe more labeling our monitoring issues or how should we sort of be thinking about this and then.

Paul Matteis: And then, just separately, I was wondering if you could talk about any plans you have for the elderly with things like Alzheimer's psychosis. Thanks. Okay, let me just, I'm gonna ask Greta to take the question, but let me just make a couple of quick comments, Paul. I appreciate the question, but this ambulatory blood pressure monitoring study isn't really a cardiac safety study that would be designed very, very differently. This is to look at the more narrow question, specifically heart rate pressure.

Just separately I was wondering if you could talk about any plans you have to go into the elderly with things like all timer psychosis.

Okay.

Let me just I'm going to ask Rita to take.

The question, but.

But let me just make a couple of quick comments Paul I appreciate the question but.

This ambulatory blood pressure monitoring study isn't really a cardiac safety study that would be designed very very differently. This is to look at the more narrow question specifically.

Apart right.

Sure.

Dr. Tony Coles: As we showed in phase 1B, we did not have AEs associated out of proportion to placebo, and what we did observe was, as you certainly know, tolerated over time. So I just don't want the notion that this is a cardiac safety study. We're answering a pretty specific and narrow question that we know the agency will ask about blood pressure and heart rate, so I wanna make that distinction. But Ray, why don't you add to my comments in any way you like?

As we showed in the phase one b.

Did not have.

Aes associated out of proportion to placebo and what we did observe as you certainly know.

Tolerated over over time, so I just don't want the notion that this cardiac safety study we're in some pretty specific and narrow question that the agency will ask about blood pressure and heart rate. So I want to make that distinction, but ray why don't you add to my comments.

And any way you like.

Dr. Ray Sanchez: Yes, yes. Thank you, Tony. Good morning, Paul.

Yes, yes. Thank you Tony Good morning, Paul So Paul as you know and I think Tony mentioned here that we were very encouraged at the end of our six week trial. The phase one b trial for <unk>, where we saw negligible.

Increases in really heart rate and blood pressure versus placebo, but really what's of interest to the agency is really the sustained effects in blood pressure not so much heart rate.

Dr. Ray Sanchez: So, Paul, as you know, and I think Tony mentioned here that, you know, we were very encouraged at the end of our six-week trial, the Phase 1B trial for emarcladine, where we saw negligible increases in really heart rate and blood pressure versus placebo. But really, what's of interest to the agency is really the sustained effects on blood pressure, not so much heart rate. And that's why we're conducting the ambulatory blood pressure monitoring trial as outlined in the guidance that was developed in 2018, but really to understand whether there is a sustained increase or a sustained effect on systolic blood pressure.

And Thats why we are conducting the ambulatory blood pressure monitoring trial as outlined in our guidance that was developed in 2018, but really to understand is there a sustained.

Increase our sustained effect in systolic blood pressure and that's what the BPM trial does in fact, it's an eight week trial as you know and it's 90% powered to rule out.

Dr. Ray Sanchez: And that's what the ABPM trial does. In fact, it's an eight-week trial, as you know, and it's 90% powered to rule out a greater than 3 millimeters of mercury effect that is sustained in systolic blood pressure over the baseline. So, patients get recorded at baseline, they get recorded at Weed 8 during 24-hour monitoring, and then the blood pressure sustained effects are evaluated. And, of course, it's powered, as I mentioned, to rule out greater than 3 millimeters of mercury.

Later than three millimeter of Mercury effect that is sustained in systolic blood pressure over that over and over over the baseline so patients get.

Recorded at a baseline they get recorded a <unk> date at 24 hour monitoring and then the <unk>.

<unk> pressure sustained effects are evaluated and of course, it's powered as I've mentioned to rollout greater than three millimeters of mercury. So.

That's what we're trying to understand and better elucidate.

Dr. Ray Sanchez: So, that's what we're trying to understand and better elucidate. But based on the Phase 1B results at six weeks and the study being at eight weeks, we don't have any concerns. But, again, it's something that we have to do in order to characterize the effect per the FDA and per guidance as well. Yeah, the only point I'll underscore there, Ray, is that the FDA only recently instituted this guidance, say the last two or three years, for ambulatory blood pressure monitoring studies. So, this is part of the registration package that any company in our situation would have to do. I know, Paul, you asked a question about dementia-related psychosis.

Based on the phase <unk> results at six weeks in this study being at eight weeks, we don't have any concerns and but again, it's something that we have to do in order to characterize the effect.

Per the FDA and for guidance as well.

Yes, the only point I'll underscore there.

Ray is that the FDA only recently instituted this guidance say the last two or three years for ambulatory blood pressure monitoring study so.

This is part of the registration package that any company in our situation would have to do.

I know Paul you asked a question about <unk> related site.

Psychosis.

Dr. Tony Coles: I think, J.R., if you would take the first part of that, because there's a clear mechanistic rationale that we should go through. And then A.C., our president, who has responsibility for commercial, is available to answer questions. Abe, why don't you take the second half of that?

I think Jay or if you would take the first part of that because there's a clear mechanistic rationale that we should go through and then agencies, our president who has responsibility for commercial is available to answer questions. Dave Why don't you take the second half of that.

Sure. Thank you Tony and good morning, Paul Thanks for the question so.

Dr. John Renger: Sure, thank you, Tony, and good morning, Paul. Thanks for the question. So, absolutely. So we completely and fully appreciate that there is a potential for the MFOR mechanism to work in dementia-related psychosis, as you well know. One of the first studies that was actually completed was enomaline, which was actually done in an AD population and showed a benefit in treating the psychotic symptoms in an AD population. As you know, the interpretation of that study was somewhat confounded, however, because of the high dropout rate and because of the tolerability issues.

Yes, so absolutely so we completely and fully appreciate that there is.

Potential forward the important mechanism to work into Mitch related psychosis is as you well know one of the first studies.

Was there a should complete was anomaly was actually done in an aging population and showed a benefit in treating the psychotic symptoms. In this population as you know the interpretation of that study was with somewhat compounded however, because of the high dropout rate because the tolerability issues and so we do believe that those responsive effect that they saw their really demonstrated.

Dr. John Renger: And so we do believe that those responsive effects that they saw there really demonstrated that the muscarinic approach, which we've refined with our MFOR selectivity with emaraclidine, is an appropriate and very promising and potentially validated way to approach that indication. And so we're absolutely aware of that and focused on that. But what I want to emphasize is that we like to proceed very thoughtfully and carefully here because what we want to do is fully understand the dose range that we want to take forward in that population, but we also have to establish the tolerability and safety profile of the compound.

The muscarinic approach, which we've refined with our enforcement activity within <unk> is an appropriate and very promising and potentially validated way to approach that indication and so we're absolutely aware of that and focused on that.

I want to emphasize is that we want to proceed very thoughtfully and carefully here because what we wanted to do is fully understand the dose range that we wanted to take forward in that population, but we also have to establish the tolerability and safety profile of the compound. So we have to think about the most efficient approach and the.

Dr. John Renger: So we have to think about the most efficient approach and the best approach to demonstrate in an elderly frail population, the appropriate dose range, the safety tolerability profile, and then, you know, really go after replicating what we believe is the clinically validated approach of using the muscarinic pathway as a way to treat psychotic symptoms there. So absolutely in line with what your question is getting to, and we're actively pursuing that. Abe, I don't know if you would like to take over the second part.

<unk> approach to demonstrate in an elderly frail population the appropriate dose range.

Safety Tolerability profile, and then really go after replicating what we believe is a declining clinically validated approach of using the muscarinic.

<unk> pathway as a way to treat psychotic symptoms there so absolutely.

Your line with what you are what your question is getting too and we're actively.

Tactically pursuing mix.

No if you would like to take over the second part.

Dr. John Renger: Actually, J.R., I've just been informed that Abe doesn't have a speaker line this morning, so let me take the second half of it. I think we all see the great potential and the potential benefit that we can bring to elderly patients with amyraclidin. I think J.R. has made the point about ensuring that we have a good handle on both the dose range and the safety profile in the elderly population, which is work that will be ongoing. And this is 50 million people who suffer from dementia globally, with 10 million new cases every year, and it's quite debilitating.

Actually Jay or I've, just been informed that doesn't have a speaker lines. This morning. So let me take the second half of it.

We all see the great potential in.

And the potential benefit if we can bring to it.

Elderly patients with more equity.

I think you guys made the point about making ensuring that we have a good handle on both the dose range and the safety profile in the elderly population, which.

He has worked at will be ongoing.

And this is 50 million people, who suffer from dementia globally with 10 million New cases every year and it's quite debilitating. So this is this is of the utmost urgency urgency for us to figure out path forward and to do that as we sort through the schizophrenia requirements for registration so.

Dr. Tony Coles: So this is of the utmost urgency for us to figure out a path forward and to do that as we sort through the schizophrenia requirements for registration. So it is very important to us, and we will figure this out. Thank you. Thank you. Thank you. The next question is from the line of Douglas Sell from HC Wainwright. Please go ahead. Hi, good morning.

It is.

Very important to us and we will figure this out.

Sir we will take it.

Thank you. The next question is from the line of Douglas Tsao from H C. Wainwright. Please go ahead.

Hi, good morning, Thanks for taking the questions. So first on <unk> I was just curious I think in the <unk> B study the.

Operator: Thanks for taking the question. So first, I'm from Rackley, and I was just curious. I think in the 1B study, the patient population was enriched for certain types of schizophrenia or certain symptoms. I'm just curious if you're going to be enriching the population for the Phase II studies. And then, I guess my second question is, from a big picture standpoint, how are you prioritizing or thinking about prioritizing assets in terms of, you know, sort of advancing new... Thank you. Okay, great. Thank you for the question. Ray, if you could take the American question about population enrichment, and I'll answer it in a second. Thank you, Tony. Good morning.

Patient population was enriched for certain.

Types of schizophrenia, a certain symptoms I was just curious if youre going to be enriching the population for the phase II study and then I guess my second question is from a big picture standpoint, how are you prioritizing or thinking about prioritizing <unk>.

Assets in terms of.

Sort of advancing new.

New.

New drugs versus expanding the ones that you have which have broad utility into new indications and then also maybe sort of related follow up.

Individual assets into new indications versus potentially tuning them further which you've shown an ability to do.

Four achieve greater effect, our specific effect for certain indication. Thank you.

Alright, great Doug Thank you for that.

Question.

Great. If you could take the requisite question about population enrichment and I'll answer the second.

Dr. Ray Sanchez: So, in the Phase 1b trial, we didn't enrich the population per se, but what we did was make sure that the patient, like we do with all our trials, that the patient profile was actually the one that could be sensitive to detect drug signals. And we did that by making sure that we had a population that was a bit more severe, so severity played a role. And then we did that also by breaking it down in terms of the positive symptoms, showing that they actually met a certain threshold in terms of individual positive symptoms on the PANS sub-scale scores.

Thank you Tony and good morning.

In the phase one B trial, we didn't enrich the population per se, but what we did do is make sure that the patient like we do with all our trials at the patient profile.

Actually the one that could be sensitive to detect drug signal and we did that by making sure that we had.

A population that was a bit more severe so the severity played a role.

And then we did that also by breaking it down in terms of positive symptoms that they actually met us a certain threshold in terms of individual positive symptoms on the pants.

Score sub salesforce, so not enrichment per se, but I would say refining the patient population is something that's critical across all trials, regardless of population, but thats what our approach was in the one b and our approach will also be in the phase two program as well.

Dr. Ray Sanchez: So, not enrichment per se, but I would say refining the patient population is something that's critical across all trials, regardless of population, but that's what our approach was in 1b, and our approach will also be in the Phase 2 program as well. There are a number of applications. Yeah.

Mobile application.

Dr. Ray Sanchez: And then, Doug, I think that the second half of your question, which is a really important one about asset prioritization, and I'd like to make a couple of contextual points. First of all, we've built an internal capability to analyze the portfolio, to assess different opportunities, to try to figure out where to place our next capital dollar, and to do the kind of trade-off that companies that have a portfolio like ours need to do.

And then Doug I think the second half of your question.

<unk> is a really important one about asset prioritization.

Let me let me just make a couple of contextual points first of all we built an internal capability to analyze the portfolio to assess different opportunities to try to.

Our next.

Dollar and to do the kind of trade off that companies that have a portfolio like ours.

Need to do so.

Dr. Ray Sanchez: So that integrates – that function is very much alive and well and really guiding the strategic decision-making for the organization. I'll also comment that we're in a strong cash position and are clearly well-capitalized. You heard Mark's report on our year-ending cash balance.

Desktop function.

It is very much alive, and well umbrella guiding the strategic decision, making for the organization.

I'll also comment that we're in a strong cash position and clearly well capitalized you heard Mark's report on our year ending cash balance and the current.

Dr. Tony Coles: And the current operating plans we have really are driven by following the science, and that is what I'd say. When we took over these particular programs at the formation of Cerebel from Pfizer, we realized that there were some new opportunities. Anxiety is a great example.

Operating plans we have.

Really are driven by following the science.

And that is what I would say when we took over these particular programs.

As the formation of <unk> from Pfizer.

Realized that there were some new opportunities anxiety is a great example that had not been fully exploited previously so I think our not only our track record of designing the trials.

Dr. Tony Coles: That has not been fully exploited previously. So I think not only our track record of designing the trials and really trying to pay very careful attention to what the science is telling us is really how we'll think about this. To the extent that there are multiple indication opportunities for the same asset, we'll pursue those if that makes sense. But we also know that given the richness of the portfolio and the pipeline that we have, and we have an extensive, for instance, muscarinic program with a number of import agents that we have, or Agnes and Alastair's muscarinic program. We've got additional opportunities to really build and deepen a franchise, and we'll be thinking about that as we prioritize. So I love the fact that we're well-capitalized.

Really trying to pay very careful attention to what the science is telling US is really how we will think about this to the extent that there are multiple indication opportunities for the same asset.

We'll pursue those if that makes sense, but we also know that given the richness of the portfolio and pipeline that we have and we have an extensive for instance, muscarinic a program with a number or agents.

Or agonists and Alastair.

We've got additional opportunities to build and deepen our franchise and we will be thinking about that as we prioritize so lumpy.

Dr. Tony Coles: I love the fact that we've got a really strong and well-integrated portfolio analysis approach to how we invest the dollars, and importantly, we will just follow the science and really do so on behalf of the benefit of patients. Great, thank you.

I Love the fact that the world capitalized I Love. The fact that we've got a very strong role integrated portfolio of analytic approach to how we are invested dollars and importantly.

But we will just follow the science and really do so on behalf of the benefit of patients.

Great. Thank you.

Thank you Okay, operator, we'll take the next question.

Operator: Okay, operator, we'll take the next question. Thank you. The next question is from the line of Madhu Kumar from Goldman Sachs. Please go ahead. Hi, this is Omari from Modulin. Good morning.

Thank you. The next question is from the line of Martin <unk> from Goldman Sachs. Please go ahead.

Madhu Kumar: Thanks for taking our questions. So first, how do you think about the efficacy and tolerability in initial pivotal studies in schizophrenia compared to long-term oily studies in terms of product profile? Okay, and did you have more than one question? Because we'll take both together, please.

Hi, This is omar.

Hello, Good morning, Thanks for taking our questions. So.

So first how do you think about the efficacy and Tolerability and initial pivotal studies in schizophrenia compared to long term all of these studies in terms of product profile.

Okay and did you have more than one question because we'll take both together please.

Madhu Kumar: Sure. And then the second question is, what are your, can you just walk us through the expectations for doing that in realizing epilepsy? Okay, sure. You know, I think on the, I just want to make sure I understand the first question.

Sure and then second question is what are your can you just walk us through the expectations for a good bet and realized with epilepsy.

Okay sure.

I think on the I just want to make sure. The first question I think youre asking about.

Dr. Tony Coles: I think you're asking about what we see as the potential differentiation for emraclavine versus currently available therapies or other agents. So I'll ask Ray to talk through both what we believe mechanistically and also about the potential efficacy and tolerability profile, which is what I think the thrust of your question was. So Ray, if you would take that one, that would be terrific.

What we see as the potential differentiation differentiation for <unk> versus currently available therapies or other agents.

So I'll ask rate through both what we believe Mechanistically and also about the potential efficacy tolerability profile, which is what I think the thrust of your question was.

So if you would take that one that would be terrific and then we'll come back around and would you look at that question just to clarify and make sure we're answering it.

Dr. Ray Sanchez: And then we'll come back around with the Rigobac question just to clarify and make sure we're answering it. Sure, so thank you for the question. You know, as you know, that there is a great need in the schizophrenia population for novel therapies other than the D2 antagonists or partial agonists that don't have the side effect profile that can be quite malignant for patients with schizophrenia.

So thank you for the question.

As you know that there is a great need in the schizophrenia population for novel therapies other than the <unk> antagonist or partial agonist that don't have the side effect profile.

That is can be quite quite malignant patients with schizophrenia, and so we have an agent here, who that actually has shown a very favorable tolerability profile in our phase one b trial to date.

Dr. Ray Sanchez: And so we have an agent here who actually has shown a very favorable tolerability profile in our phase 1B trial to date, but with also very robust PANS total score reductions of close to 20 points. And so that's something that really excites us because it gives us the opportunity to provide a therapy that not only has an efficacy profile that is very exciting and encouraging but also a safety tolerability profile that is relatively benign compared with what's available on the landscape.

But we are also very robust.

Pans total score reductions of close to 20 points and so thats something thats very excites us because it gives us the opportunity to provide a therapy that not only has an efficacy profile that is very exciting and encouraging but also safety tolerability profile that is.

Relatively benign.

Compared with what's available on the landscape.

In terms of your question of acute versus long term we.

Dr. Ray Sanchez: In terms of your question of acute versus long-term, we are, as you know, starting the acute trials later this year, and we've powered them accordingly to show at least a seven-point placebo-adjusted difference. And that's really based on the landscape and what's been shown historically, but we hopefully expect to see a more robust outcome.

We are doing starting the acute trials later this year and we.

Powered them Accordingly to show at least a seven point placebo adjusted difference and Thats really based on the landscape and what's been shown historically, but we hopefully expect to see a more robust outcome.

Dr. Ray Sanchez: In terms of the long-term effects, that would be something that the agency would most likely require for us to show in a phase 4 commitment to understand the longer-term maintenance treatment effect, but it's not something that we will be including in the immediate MDA package. It will be a subsequent approach. The open-label extension, as you know, and I think you mentioned that, is really more to collect longer-term safety and tolerability data as required by the agency at six months and one year.

In terms of the long term effects that would be something that the agency would most likely require for us to show in a phase four commitment to understand the longer term maintenance treatment effect.

But it's not something that we will be including in the immediate NDA package will be as a subsequent approach.

The open label extension as you know and I think you mentioned that.

It's really more to collect longer term safety and tolerability data as required by by by the agency at six months in one year.

But it is very difficult to really ascertain any efficacy longer term from an open label extension as you know so that's that's our approach and we're excited about the potential for this therapy and how it will be transformative to the landscape.

Dr. Ray Sanchez: But it's very difficult to really ascertain any efficacy longer-term from an open-label extension, as you know. So that's our approach, and we're excited about the potential for this therapy and how it will be transformative in the landscape. And Ray, thank you.

Great. Thank you and then I think the second half of March question really had to do with what we might consider success from the <unk> about epilepsy phase II study, obviously MRI were hoping to extend what we saw in the phase Iia.

Dr. Tony Coles: And then I think that the second half of Omari's question really had to do with what we might consider success in the Darigabat epilepsy phase 2 study. Obviously, Omari, we're hoping to extend what we saw in the phase 2a photosensitivity epilepsy study. But Ray, I think, if you don't mind, just touch on the 31% difference in how we powered the study, please.

Photosensitivity epilepsy study.

But ray I think if you don't mind, just just touch on the 31% difference in how we powered the study please.

Dr. Ray Sanchez: So, the trial was powered at 80% to detect a 31% seizure reduction. We're hoping that with the data that's been seen to date in the photoepilepsy trial, that it suggests that it actually could be even more robust. I mentioned in an earlier question that you see about a 28% seizure reduction. With Kepper, as you know, it's used quite often.

Alright, so the trial was powered 80% to detect a 31%.

C. A seizure reduction we're hoping that with what the data that we've seen today and in the form of epilepsy trial that has suggested it actually could be even more robust I mentioned in an earlier question that you see about a 28% seizure reduction with <unk> as you know it's used quite often.

So we're hopeful that we can.

See even greater benefit than what we've powered for but obviously later this year, we'll have more clarity in terms of how to rig about performs in the vocal that plus population.

Dr. Ray Sanchez: And so, we're hopeful that we can see even greater benefits than what we hoped for. But obviously, later this year, we'll have more clarity in terms of how Darigabat performs in the focal epilepsy population. Okay, thank you, Ray. Thank you, Omari, for the question. Operator, I think we've got time for just one more question. Thank you. The last question is from the line of Corey Casimov from J.P. Morgan. Please go ahead. Hi guys, thanks for the question. This is Tiffany on behalf of Corey.

Okay. Thank you. Thank you Mario for the question operator, I think we've got time for just one more.

More questions.

Thank you. The last question is from the line of Cory <unk> from Jpmorgan. Please go ahead.

Operator: Just one that we get a lot of investors' questions on. How might you be thinking about career and phase three data readout mid-year? So obviously, it's a similar MOA, and it could potentially provide some positive read-throughs to wrap within a perspective, but any initial thoughts or feedback or market research there? And then, a follow-up to that, just thinking about the required safety database and OLE, are these anticipated to be the gating factors of filing? Thanks. Okay. I think on the Karuna question, I'd make a couple of really quick comments.

Hi, guys. Thanks for the question simply answer.

Corey just one that we got a lot of investor questions on how might you be thinking about is there any.

Data readout midyear, so obviously, it's a similar.

It could potentially provide some positive read through is that lack of that in a second but just any initial thoughts or feedback from market research there and then.

So up to that just thinking about the required safety database.

Is that anticipated to be the gating factor for filing.

Dr. Tony Coles: Obviously, we're focused on what is our most important next clinical data milestone, which is the Dirigibat Epilepsy Program, and that's certainly going to be an important catalyst for the company. Clearly, we're rooting for Karuna's success and certainly support innovation in the antipsychotic space, where there's, as we've said a couple of times, a really great unmet need. We know there's plenty of room for multiple players in the market, but we have a deep belief that the musculinic pathway has a lot of potential as an exciting new mechanism. Having said all of that, there are some important features that make our MFOR selective approach particularly interesting, including the reduced GI side effects, the once-daily administration, and the no need for titration.

Okay.

I think on the Corona question.

A couple of really quick comments, obviously, we're focused on what is our most important next clinical data milestone, which is the direct about epilepsy.

Program, and that's certainly going to be an important catalyst for the company clearly we're rooting for Corona is success and certainly support innovation in the antipsychotic space, where there is.

As we've said a couple of times, we really great unmet need.

There are plenty of room, there is plenty of room for multiple players in the market, but we have a deep belief that the muscarinic pathway is a lot of potential is as an exciting new mechanism having.

Having said all of that there are some important features that make our enforce selective approach, particularly interesting.

Leading to reduced Gi side effects. The once daily administration, the no need for titration and those are features that we hoped to both confirm and leverage as we do move to phase II programs. So clearly for patients.

Dr. Tony Coles: Those are features that we hope to both confirm and leverage as we do move to the Phase II program. Clearly, for patients, it would be wonderful if we could document success anywhere in the antidepressant field, but we've got strong reason to believe that we have a differentiating profile with imrequiline, and that's where we're focused at the moment. The second question about the OLE: Ray, do you mind just taking that one and explaining what we're looking for there? Sure. So you are correct. The open label extension is needed for registration.

Be wonderful if we can document success anywhere in that new therapies, but we've got strong reason to believe that we've got a differentiated profile with with <unk> and that's where we're focused at the moment.

Second question.

About the OLED right do you mind, just taking that one and what we're looking for there.

Sure. So you are correct. The open label extension is needed for registration we have to have three patients exposed six months.

Dr. Ray Sanchez: We have to have three patients exposed for six months at least, and at least 100 patients at one year. Our approach is always to exceed those numbers, of course, per FDA. And we're going to be using an approach where we not only have the patients roll over from the pivotal trials, but we're also adding additional sites for de novo exposures. And so that will get us the exposures we need by the time we file the NDA.

At least in at least 100 patients at one year our.

Our approach is.

Always to exceed those numbers of course per.

Per FDA, and we're going to be using an approach where we not only have the patients rollover from the pivotal trials, but we're also adding additional sites for de Novo exposures.

And so that will get us the exposures, we need by the time, we file the NDA. So in terms of rate limiting that's something that of course, we've always thought about so it doesn't become the critical path. The open label extension and our hope is that it will not be.

Dr. Ray Sanchez: So in terms of rate limiting, that's something that, of course, we've always thought about so it doesn't become the critical path, the open label extension. And our hope is that it will not be and so that we will have all the data that will be necessary if, indeed, both phase two trials are positive, and we're doing our other preclinical and other CMC work and so forth to try to get this medicine to patients sooner than later, but we'll have to wait and see how that all transpires once the results come in.

We will have all the data that will be necessary, if indeed that.

Both phase II trials are positive and we are.

Our other preclinical and other other CMC work and so forth to try to get this medicine to patients sooner than later, but we'll have to wait and see how that all transpires once the data readout.

Dr. Ray Sanchez: Thank you, Ray, and Tiffany, thank you for that question. I think that's going to wrap it up for us. Thank you guys for joining us. We're off to a really strong start this year with the great anxiety data that we've talked about. We'll close the year in the second half with the epilepsy data. So there are a lot of really important value drivers both coming up this year and in subsequent years. The balance sheet is strong.

Okay great.

Thank you Ray and Tiffany. Thank you for that question I think thats going to wrap it for us. Thank you guys for joining us we're off to a really strong start on the year with the great anxiety data that we've talked about we will close the year with in.

In the second half with the epilepsy data. So a lot of really important value drivers both coming up this year and subsequent years. The balance sheet is strong. The team is strong. So I think we've got all the right elements to continue to deliver great results.

Dr. Tony Coles: The team is strong. So I think we've got all the right elements to continue to deliver great results, and we appreciate you guys in the conversation this morning. I think we've given a good picture about how confident we are about our ability to change the landscape.

We appreciate you guys saw in the conversation. This morning, I think we've given a good perspective about how confident we are about our ability to change the landscape. So thank you guys for joining and have a good day.

Operator: So thank you guys for joining us, and have a good day. Thank you, that does conclude the conference for today. Thank you for participating, and you may now disconnect. [music] David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Amsellem, David Am

Thank you that does conclude the conference for today. Thank you for participating and you may now disconnect.

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