Q2 2022 Cerevel Therapeutics Holdings Inc Earnings Call

Okay.

Okay.

Good morning and welcome to the Cerevel Therapeutics second quarter 2022 financial results conference call.

Okay.

Good morning, and welcome to the Servile Therapeutics second quarter 2022 financial results Conference call.

At this time, all participants are in listen-only mode. 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.

Thank you for participating.

At this time, all participants are in listen only mode.

Later, you will have the opportunity to ask questions during the Q&A portion of the call.

I will now hand the call over to Matt Calistri, Vice President of Corporate Strategy and Investor Relations.

You may now disconnect.

Please note that this call maybe recorded.

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

Thank you.

Thank you good morning, everyone. We appreciate you joining us for our second quarter 2022 earnings call.

On today's call you'll be hearing from Dr. 20, Kohl's, our chairperson and Chief Executive Officer, Dr. Rey Sanchez, our Chief Medical Officer, Dr. John Lunger, our Chief Scientific Officer, and Mark <unk>, our interim Chief Financial Officer.

<unk>, our president will join us for Q&A Dermot.

During our call today, please refer to our press release from this morning detailing our Q2 2020 performance as well as our updated corporate presentation, both of which are available on our website.

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 form 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.

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

Good morning, everyone.

We appreciate you joining us for our second quarter 2022 earnings call.

Okay.

Good morning, everyone and thank you for joining us for our second quarter 2020 to business results call at.

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 Bodenreiter, our Interim Chief Financial Officer.

Abe Cicero, President, will join us for Q&A.

That said, though it is our aspiration to become.

Our neuroscience company and we are certainly well on our way shaping this distinction with our broad and deep pipeline of new programs compelling early data in schizophrenia, which has led us to initiate a potentially pivotal large phase III program important for equity.

Five new data Readouts expected next year and a robust set of mid to late stage programs that have the potential to bring transformative medicines to the moon.

<unk> of people living with schizophrenia, Parkinson's epilepsy, and dementia related apathy.

And with our announced intention today to study <unk> in Alzheimer's disease psychosis.

And director back in panic disorder, we have even more ways to unlock the value of our rich portfolio.

We're advancing our pipeline neuroscience programs that we believe is unmatched among our peers with additional early stage programs that hold promise in major depressive disorder, and other high unmet need conditions.

For our mid to late stage programs as we mentioned, we expect a remarkable five data readouts before the end of next year.

<unk> phase three readouts for <unk> in Parkinson's disease, our phase two readout into rig about focal epilepsy and a phase two readout for <unk> 71 in the novel indication of dementia related apathy.

With so many near term milestone circle its position to bring tremendous value to both our patients.

Shareholders over this period of time as we seek to transform what's possible in neuroscience.

Following closely after the five upcoming data milestones in the first half of 2024, we expect the phase two program data readout for a record or.

Our novel Muscarinic enforced selective positive allosteric modulator or Pam.

Which we're investigating in adults living with schizophrenia.

We're rapidly advancing this very important program and we have already initiated our phase III program in June as promised.

We're all well aware that the patient need in this area is tremendous more than $2 7 million people in the U S alone, but with schizophrenia, a disease that dramatically affects families and loved ones and entire communities.

Individuals living with schizophrenia are more likely to be unemployed experienced homelessness and most sobering. There are 20 times more likely to die by suicide.

At <unk>, we're committed to advancing this program with its innovative mechanism of action leveraging a new potential approach for treatment in a condition that has not seen innovation in 50 years and we're working to do this on an accelerated basis in order to bring this potentially transformative therapy to as many <unk>.

Individuals' as possible as soon as possible.

The <unk> pathway also holds promise for other devastating conditions and not only are we committed to developing <unk> to its full potential as part of a broader <unk> franchise.

The second potential new therapy that acts as an agonist targeting the <unk> four receptor we have an additional opportunity to leverage the targeted selectivity of the <unk> pathway.

John <unk> will provide additional details on this exciting program in just a moment.

With <unk>, we intend to initiate our phase one trial evaluating safety Tolerability and pharmacokinetics in healthy elderly volunteers to support future development, and Alzheimers disease psychosis or ADP.

The behavioral and psychological symptoms of Alzheimers, such as delusions hallucination and paranoia exert an enormous toll on those suffering from them and their loved ones. We're eager to explore <unk> potential in ADP and ultimately other conditions.

Our work with <unk> in schizophrenia, and ADP is only one part of several story, though earlier this year, we announced positive anxiety data for <unk>, our selective Alpha 235, Gaba Pam could.

With rig about trial demonstrated for the first time proof of principle in the clinic that a compound targeting alpha <unk> five and sparing alpha one can generate anxiolytic activity and at the same time may be able to minimize side effects that limit benzodiazepines to only episodic use.

Anxiety is another area of tremendous unmet need in the first year of the COVID-19, pandemic anxiety and depression worldwide increased by a staggering 25%.

That figure is likely higher than reported.

Related to anxiety 17 years have passed since we have seen innovation in the treatment of panic disorder.

Following our evaluation of the results of our anxiety trial earlier. This year, we announced today that we have selected panic disorder as an additional indication for de rigueur bad behind epilepsy.

Panic is the second most common anxiety disorder and can be the most debilitating.

Sanchez will have further comment more specifically in his section of the call.

During our call today, please refer to our press release from this morning detailing our Q2 2022 performance, as well as our updated corporate presentation, both of which are available on our website.

<unk> is advancing with clear purpose and our late stage pipeline has the potential to deliver important medicines to prevent individuals living with neuroscience diseases, who need and deserve new treatment options, we believe the future at <unk>.

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.

Driven by the strength of our pipeline and our programs and we remain committed to changing the face of neuroscience.

Now I'll turn the call over to Dr. <unk> Sanchez, our chief Medical officer to provide some added color about our lead programs right.

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

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

I will now hand the call over to Dr. Tony Coles, Chairperson and CEO of CeraVel, to provide an overview of our achievements and outlook.

As Tony has outlined terrible is well positioned to open new frontiers in neuroscience, our pipeline seeks to address some of the most challenging neuroscience diseases and bring forward new treatment options with enhanced tolerability profiles.

Good morning, everyone, and thank you for joining us for our second quarter 2022 business results call.

I spent many years as a clinician and the need for better medicines with fewer off target side effects is what motivated me to transition to a career in the life Sciences industry I am excited and energized by our results so far and eager to transform what is possible and neuroscience.

At CeraVel, it's our aspiration to become the premier neuroscience company, and we are certainly well on our way to achieving this distinction.

With a broad and deep pipeline of new programs, compelling early data in schizophrenia, which has led us to initiate a potentially pivotal large Phase 2 program for it in raclidin, five new data readouts expected next year, and a robust set of mid- to late-stage programs that have the potential to bring transformative medicine to the millions of people living with schizophrenia, Parkinson's, epilepsy, and dementia-related apathy.

And with our announced intention today to study amraclidin in Alzheimer's disease psychosis, and Darigabat in panic disorder, we have even more ways to unlock the value of our rich portfolio.

We're advancing a pipeline of neuroscience programs that we believe is unmatched among our peers, with additional early-stage programs that hold promise in major depressive disorder and other high unmet need conditions.

As Tony mentioned, we recently initiated both phase II empower trials of <unk> in adults living with schizophrenia.

I am delighted that we are dosing patients in these two trials and I'm eager to see the results, which we expect in the first half 2024.

For our mid- to late-stage programs, as we mentioned, we expect a remarkable five data readouts before the end of next year. Three Phase 3 readouts for tavapidon in Parkinson's disease, a Phase 2 readout in Darigabat for focal epilepsy, and a Phase 2 readout for CBL871 in the novel indication of dementia-related apathy.

With so many near-term milestones, Cerval is positioned to bring tremendous value, to both our patients and shareholders over this period of time, as we seek to transform what's possible in neuroscience.

For background the phase <unk> data, we announced last year were truly impressive both doses demonstrated clinically meaningful and statistically significant antipsychotic effects with no meaningful differences in gastrointestinal side effects.

And following closely after the five upcoming data milestones in the first half of 2024, we expect the phase two program data readout for Imraclodine, our novel muscarinic M4-selective positive allosteric modulator, or PAM, which we're investigating in adults living with schizophrenia.

Pyramidal symptoms or weight gain compared with placebo.

We're rapidly advancing this very important program, and we have already initiated our, phase two program in June, as promised.

We are very encouraged by these robust results, we conduct our phase II trials. These two adequately powered three arm trials are being conducted worldwide and will each enrolled 372 adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms.

The first trial will test them record income milligrams, Q day, and 30 milligrams Q day versus placebo and a second trial will test <unk> 15 milligrams per day, and 30 milligrams Q day versus placebo.

Running these two trials in parallel enables us to fully explore the therapeutic dose range of <unk>, while minimizing the number of treatment arms with the hope of reducing the variability observed in clinical trials as well as the placebo response.

We designed these trials to potentially meet the criteria necessary to serve as pivotal based on what we expect the FDA will evaluate in a registrational package.

These trials also reinforced <unk> commitment to diversity and the needs of individuals living with schizophrenia with the focused inclusion of groups often underrepresented in clinical trials.

In order to accelerate a potentially registrational package from record in schizophrenia, we expect to initiate a 52 week open label safety extension trial and power three in the third quarter of 2022 and are also conducting an eight week ambulatory blood pressure monitoring trial in <unk>.

With data expected by the end of the year.

Moving now to the potential of <unk> <unk> in Alzheimer's disease psychosis is a lifecycle management opportunity.

As Tony mentioned, we plan to initiate a phase one trial evaluating the safety Tolerability and pharmacokinetics in elderly healthy volunteers $65 to 85 years old by the end of this year.

The design of our multiple ascending dose trial will evaluate five doses, 2% to 30 milligrams and five cohorts lasting 14 days each.

Okay.

Pivoting now to panic disorder panic.

We're all well aware that the patient need in this area is tremendous. More than 2.7 million people in the U.S. alone live with schizophrenia, a disease that dramatically, affects families, loved ones, and entire communities. Individuals living with schizophrenia are more likely to be unemployed, experience homelessness, and most sobering, they're 20 times more likely to die by suicide.

Panic disorder, which is characterized by panic attacks presented a constellation of symptoms that include a rapid pounding heart rate sense of impending doom weakness dizziness, disorientation, and even chest pain, making some people feel like they are experiencing a heart attack.

Panic episodes can be quite debilitating it can be triggered by various factors, including trauma stress fear or illness.

At Cerevel, we're committed to advancing this program with its innovative mechanism of action, leveraging a new potential approach for treatment in a condition that has not seen innovation in 50 years. And we're working to do this on an accelerated basis in order to bring this potentially transformative, therapy to as many individuals as possible as soon as possible.

The M4 pathway also holds promise for other devastating conditions, and not only are we, committed to developing emraclodine to its full potential as part of a broader M4 franchise, with a second potential new therapy that acts as an agonist at targeting the M4 receptor, we have an additional opportunity to leverage the targeted selectivity of the M4 pathway.

Like to share a bit more information about our plans to pursue <unk> as a potential treatment for panic disorder, which is the second most common anxiety disorder.

We're currently developing plans for a phase II proof of concept trial, and we'll be meeting with the FDA in the fall to gain alignment on our path forward, we will provide additional updates as our plans progress.

As a reminder, this plant comes on the heels of the very encouraging positive topline data from our day rig about phase one healthy volunteer hypercalcemia trial in acute anxiety earlier this year.

These results provide strong evidence of <unk> potential as a differentiated daily maintenance treatment for exactly related disorders, while minimizing tolerability concerns in contrast to benzodiazepines.

We know that there are many people who suffer from panic disorder and need better treatment options.

We also understand the limitations of benzodiazepines with side effects that includes sedation cognitive impairment efficacy tolerance and abuse potential limiting their chronic use.

Consequently, our goal is for drill rig about to be a daily maintenance treatment for people with inadequately managed panic attacks with.

With the hope of providing much needed relief.

Turning next to <unk> or a <unk> partial agonist, which we are developing for Parkinson's disease as both a monotherapy and adjunctive treatment to levodopa for symptomatic motor control.

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

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 temple's one and two trials in early stage Parkinsons to readout in the second half of 2023.

Okay.

Turning to CBL 871, our second <unk> 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.

In June of last year, we received fast track designation for CBL 871 in this indication, which enable us 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 in this novel and much needed indications since there are no currently approved therapies.

John Ringer will provide additional details on this exciting new program in just a moment.

With that Dr. John <unk>, our Chief Scientific officer will speak about our early stage portfolio and our presentations at medical conferences John .

With emraclodine, we intend to initiate a phase one trial evaluating safety, tolerability, and pharmacokinetics in healthy elderly volunteers to support future development in Alzheimer's disease psychosis, or ADP. The behavioral and psychological symptoms of Alzheimer's, such as delusions, hallucinations, and paranoia, exert an enormous toll on those suffering from them and their loved ones.

We're eager to explore emraclodine's potential in ADP, and ultimately, other conditions.

Thank you Ray and good morning, everyone I'd like to begin this part of the presentation by providing an overview of our earlier stage clinical and preclinical programs.

Our work with emraclodine and schizophrenia and ADP is only one part of the several story, though.

First we have an active program to identify and Infor selective full agonist clinic ready molecule as part of our goal of creating an industry, leading <unk> selective therapeutic franchise.

Earlier this year, we announced positive anxiety data for Darigabat, our selective alpha-235, GABA-PAM. The Darigabat trial demonstrated, for the first time, proof of principle in the clinic, that a compound targeting alpha-235 and sparing alpha-1 can generate anxiolytic activity, and at the same time, may be able to minimize the side effects that limit benzodiazepines to only episodic use.

Anxiety is another area of tremendous unmet need. In the first year of the COVID-19 pandemic, anxiety and depression worldwide increased, by a staggering 25%, and that figure is likely higher than reported.

Related to anxiety, 17 years have passed since we have seen innovation in the treatment of, panic disorder. Following our evaluation of the results of our anxiety trial earlier this year, we announced, today that we have selected panic disorder as an additional indication for dorigabat behind epilepsy, as panic is the second most common anxiety disorder and can be the most debilitating.

Graig Sanchez will have further comment more specifically in his section of the call.

We believe this novel asset will provide for additional clinical indication optionality as we consider the therapeutic utility of this mechanism of action and its demonstrated potential in treating psychosis. This additional program will also give us an opportunity to complement what we're doing to develop them or academia and expanded presence in additional neuroscience indications.

Cerevel is advancing with clear purpose, and our late-stage pipeline has the potential, to deliver important medicines to individuals living with neuroscience diseases who need and deserve new treatment options.

We believe the future at Cerevel is bright, driven by the strength of our pipeline and, our programs, and we remain committed to changing the face of neuroscience.

I'll now turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to provide some, added color about our lead programs.

Ray?

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

Second I would like to highlight our Kappa opioid receptor antagonist program CBL 354, which continues to progress in our ongoing phase one single and multiple ascending dose trials.

As Tony has outlined, Cerevel is well-positioned to open new frontiers in neuroscience.

We believe this mechanism of action has the potential to address the major depressive disorder and substance use disorder based upon prior clinical and preclinical data that have been generated with compounds that selectively targets the kappa opioid receptor.

We continue to build a robust discovery engine.

Labs in Cambridge crossing with additional ongoing discovery stage and pre <unk> programs.

Our pipeline seeks to address some of the most challenging neuroscience diseases and, bring forward new treatment options with enhanced tolerability profiles.

Leveraging our differentiated understanding of disease base, neuro circuitry and world class chemistry to develop and explore the therapeutic potential of small molecules to address major unmet patient need.

I spent many years as a clinician, and the need for better medicines with fewer off-target, side effects is what motivated me to transition into a career in the life sciences industry.

I'm excited and energized by our results so far and eager to transform what is possible, in neuroscience.

We believe this research engine, which is driven by some of the most talented scientists that I've been able to work with in my career.

As Tony mentioned, we recently initiated both Phase II Empower trials of emraclidin in adults, living with schizophrenia.

I am delighted that we are dosing patients in these two trials and am eager to see the, results which we expect in the first half of 2024. For background, the Phase Ib emraclidin data we announced last year were truly impressive. Both doses demonstrated clinically meaningful and statistically significant antipsychotic, effects with no meaningful differences in gastrointestinal side effects, extrapyramidal symptoms, or weight gain compared with placebo.

Fuel innovation for many years to come and we look forward to keeping you updated on our progress on these earlier stage efforts as appropriate.

We are very encouraged by these robust results as we conduct our Phase II trials.

These two adequately powered, three-armed trials are being conducted worldwide and will, each enroll 372 adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms. The first trial will test emraclidin 10 milligrams Q day and 30 milligrams Q day versus placebo, and the second trial will test emraclidin 15 milligrams Q day and 30 milligrams Q day versus placebo. Running these two trials in parallel enables us to fully explore the therapeutic dose range, of emraclidin while minimizing the number of treatment arms with the hope of reducing the variability observed in clinical trials as well as the placebo response.

We designed these trials to potentially meet the criteria necessary to serve as pivotal, based on what we expect the FDA will evaluate in a registrational package.

Finally, I also want to emphasize how proud I am of our team's ongoing presence at key medical meetings, which is an important facet of our journey to becoming the Premier Neuroscience company.

Our teams have recently presented our positive during about phase one hypercalcemia data at the 2022 American Society of clinical Psychopharmacology annual meeting.

In this presentation to underscore our enthusiasm for pursuing a panic disorder indication and potentially redefining how we envision the future treatment of anxiety disorders.

These trials also reinforce Cerevel's commitment to diversity and the needs of individuals, living with schizophrenia with the focused inclusion of groups often underrepresented in clinical trials.

At <unk>. We also participated in a panel discussion focused on achieving diversity in clinical trials.

In order to accelerate a potentially registrational package for emraclidine schizophrenia, we expect to initiate a 52-week open-label safety extension trial in Power 3 in the third quarter of 2022, and are also conducting an 8-week ambulatory blood pressure monitoring trial in emraclidine with data expected by the end of the year.

<unk> mosaic vision of diversity equity and inclusion touches on all aspects of our organization.

<unk>, our clinical trial enrollment and the operational barriers that can exist.

<unk> to the broad inclusion of diverse populations.

Moving now to the potential of emraclidine in Alzheimer's disease psychosis as a lifecycle management opportunity. As Tony mentioned, we plan to initiate a Phase 1 trial evaluating the safety, tolerability, and pharmacokinetics in elderly, healthy volunteers 65 to 85 years old by the end of this year.

The design of our multiple ascending dose trials will evaluate 5 doses, 2 to 30 milligrams in 5 cohorts lasting 14 days each.

Pivoting now to panic disorder. Panic disorder, which is characterized by panic attacks, presents with a constellation of symptoms that include a rapid pounding heart rate, sense of impending doom, weakness, dizziness, disorientation, and even chest pain, making some people feel like they are experiencing a heart attack. Panic episodes can be quite debilitating and can be triggered by various factors, including trauma, stress, fear, or illness.

We've developed a patient centric guidance informs our investment and focusing on the demographic distribution of both patient populations and healthy volunteers seeking.

Seeking input from advocacy organizations addressing historical precedents that may impact clinical trial participation and deploying thoughtful considerations about cultural differences when engaging with diverse communities.

Our diversity equity and inclusion principles enabled thoughtful clinical trial design and directly reflect how we embrace authenticity and diversity and service of our mission to push boundaries develop solutions and transform lives for all patients with neuroscience diseases alright.

I think the public's publicly extend my congratulations and gratitude to our teams were ongoing commitment to our company our mission and the patients who are relying on us.

I'd like to share a bit more information about our plans to pursue Darigabat as a potential treatment for panic disorder, which is the second most common anxiety disorder. We are currently developing plans for a Phase 2 proof of concept trial, and we'll be meeting with the FDA in the fall to gain alignment on our path forward.

I'd now like to hand, it over to <unk> interim Chief Financial Officer, Mark <unk> to review, our financial performance for the first quarter.

We will provide additional updates as our plans progress. As a reminder, this plan comes on the heels of the very encouraging positive top line data from our Darigabat Phase 1 healthy volunteer hypercapnia trial in acute anxiety earlier this year.

Mark.

These results provide strong evidence of Darigabat's potential as a differentiated daily maintenance treatment for anxiety related disorders while minimizing tolerability concerns in contrast to benzodiazepines.

Yes.

We know that there are many people who suffer from panic disorder and need better treatment options. We also understand the limitations of benzodiazepines with side effects that include sedation, cognitive impairment, efficacy tolerance, and abuse potential limiting their chronic use.

Thank you John and good morning, everyone.

Consequently, our goal is for Darigabat to be a daily maintenance treatment for people with inadequately managed panic attacks with the hope of providing much needed relief.

Turning next to Tavapidon, our D1, D5 partial agonist, which we are developing for Parkinson's disease as both a monotherapy and adjunctive treatment to leave a dopa for symptomatic motor control.

I am pleased to provide an overview of several strong financial position and our second quarter 2022 financial results.

We continue to dose in all 3 of our Phase 3 trials, known collectively as the TEMPO trials, and all remain on track.

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 trials in early stage Parkinson's to read out in the second half of 2023.

Turning to CBL 871, our second D1, D5 partial agonist, which we are currently evaluating in a Phase 2a exploratory trial in dementia-related apathy. We expect data in the first half of 2023. In June of last year, we received fast-track designation for CBL 871 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 are looking forward to interacting closely with the agency in determining the best path, forward for developing a treatment in this novel and much-needed indications, since there are no currently approved therapies.

Please refer to this mornings press release for full details of our financial update.

For the second quarter total operating expenses were approximately $93 million.

Which includes R&D expense of $73 million in G&A expense of $20 million.

As expected total operating expenses for the second quarter grew over prior quarters, driven by the continued progression of our clinical trials and increased personnel costs to support the advancement of our pipeline.

Relative to the second quarter last year.

<unk> expenses increased by approximately $35 million. This increase was primarily due to the continued advancement of our to that but on <unk> and <unk> programs.

<unk> and our preclinical and discovery efforts and increased personnel and other infrastructure costs as we expand capabilities to advance our pipeline.

On a sequential quarter basis, R&D expense grew by approximately $18 million over the first quarter of 2022.

This was primarily due to costs associated with advancing our <unk> program.

We expect R&D expense for the remainder of the year to be relatively consistent with our second quarter results.

G&A expense for the second quarter increased by approximately $7 million over last year, primarily due to higher personnel costs as we continue to grow our organization, we expect G&A expense to increase slightly to the balance of the year as we support the continued growth of our company, including the progression of our R&D programs.

And our commercial planning activities.

As of June 32022, our cash cash equivalents and marketable securities totaled approximately $531 million.

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

With that, Dr. John Renger, our Chief Scientific Officer, will speak about our early-stage, portfolio and our presentations at medical conferences.

With that I'll hand, the call back to Tony for closing remarks.

John?

Thanks Mark.

As you can see we're advancing our broad and diverse set of programs and building. What we believe is truly becoming the premier neuroscience company with the potential to unlock significant value for both patients and shareholders with five near term late stage data readouts across three development programs coming up in <unk>.

Thank you, Ray, and good morning, everyone.

23, a diverse set of therapeutic indications that were exploring robust lifecycle management plans to optimize each of our programs and a vision to transform the treatment of a broad range of neuroscience diseases share relative on the leading edge of the next great Frontier and medicine.

I'd like to begin this part of the presentation by providing an overview of our earlier-stage, clinical and preclinical programs. First, we have an active program to identify an M4-selective, full agonist, clinic-ready, molecule as part of our goal of creating an industry-leading M4-selective therapeutic franchise. We believe this novel asset will provide for additional clinical indication optionality, as we consider the therapeutic utility of this mechanism of action and its demonstrated potential in treating psychosis.

This additional program will also give us an opportunity to complement what we are doing, to develop emaracodine and expand our presence in additional neuroscience indications.

Second, I would like to highlight our Kappa opioid receptor antagonist program, CVL354, which continues to progress in our ongoing Phase I single and multiple ascending dose trials. We believe this mechanism of action has the potential to address major depressive disorder, and substance use disorder based upon prior clinical and preclinical data that have been generated with compounds that selectively target the Kappa opioid receptor.

We continue to build our robust discovery engine and our labs in Cambridge Crossing, with additional ongoing discovery stage and pre-IND programs.

Thank you for joining us this morning, I want to thank our teams, whose dedication and commitment to make this possible and I also want to extend my deepest gratitude and appreciation to the clinical trial participants and investigators who contribute to the development of these important therapies.

We are leveraging our differentiated understanding of disease-based neurocircuitry and world-class, chemistry to develop and explore the therapeutic potential of small molecules to address major unmet patient need.

We believe this research engine, which is driven by some of the most talented scientists, that I have been able to work with in my career, will fuel innovation for many years to come.

And we look forward to keeping you updated on our progress on these earlier stage efforts, as appropriate.

Finally, I also want to emphasize how proud I am of our team's ongoing presence at key, medical meetings, which is an important facet of our journey to becoming the premier neuroscience company. Our teams have recently presented our positive durative phase I hypercapnia data at the 2022, American Society of Clinical Psychopharmacology annual meeting, and this presentation underscored our enthusiasm for pursuing a panic disorder indication and potentially redefining how we envision the future treatment of anxiety disorders.

At ASCP, we also participated in a panel discussion focused on achieving diversity in clinical, trials. Sarah Bell's mosaic vision of diversity, equity, and inclusion touches on all aspects of our, organization, including our clinical trial enrollment and the operational barriers that can exist to the broad inclusion of diverse populations.

We have developed a patient-centric guidance that informs our investment in focusing on, the demographic distribution of both patient populations and healthy volunteers, seeking input from advocacy organizations, addressing historical precedents that may impact clinical trial participation, and deploying thoughtful considerations about cultural differences when engaging with diverse communities.

Our diversity, equity, and inclusion principles enable thoughtful clinical trial design and directly reflect how we embrace authenticity and diversity in service for our mission to push boundaries, develop solutions, and transform lives for all patients with neuroscience diseases.

I'd like to publicly extend my congratulations and gratitude to our teams for their ongoing, commitment to our company, our mission, and the patients who are relying on us.

I'd now like to hand it over to Cerebel's Interim Chief Financial Officer, Mark Bodenrader, to review our financial performance for the first quarter.

With that operator, let's open the call for questions.

Mark?

Thank you to ask a question you will need to press star one on your telephone please standby, while we compile the Q&A roster.

Our first question comes from Michael Yee with Jefferies. Your line is now open.

Thank you, John, and good morning, everyone.

Hey, guys. Good morning, Thanks, Tony for the updates a lot going on here I just wanted to ask on <unk>.

In spite of Alzheimers disease psychosis, and just wanted to understand maybe what were some of the drivers of announcing that today and.

Also as you think about that how important.

And one is in that type of indication can you, maybe just talk a little bit about about that move forward, there and what drove that and how you feel in regards to the confidence and then just a follow up on <unk> I know you reiterated today, you'll have an update on the blood pressure study I think later this year.

What is I guess at what.

What are the expectations here on what we actually be able to say about that study.

I'm pleased to provide an overview of Cerebel's, strong financial position in our second quarter 2022 financial results. Please refer to this morning's press release for the full details of our financial update. For the second quarter, total operating expenses were approximately $93 million, which includes R&D expense of $73 million and G&A expense of $20 million.

Okay, Mike good morning.

As expected, total operating expenses for the second quarter grew over prior quarters, driven by the continued progression of our clinical trials and increased personnel costs to support the advancement of our pipeline. Relative to the second quarter last year, R&D expenses increased by approximately $35 million. This increase was primarily due to the continued advancement of our Tavapidon, Imraculidin, and Darigabat programs, investment in our preclinical and discovery efforts, and increased personnel and other infrastructure costs as we expand capabilities to advance our pipeline.

Thanks for the question.

I think one of your questions was.

About our announcement of the pipeline updates.

We've been working on our next steps.

For director back in anxiety after we got the data earlier this year.

So the announcement today about during the bad is just keeping everyone apprised of our latest thinking now that we have more firmly planted our feet and panic disorder and the same is true for <unk> and Alzheimer's.

On a sequential quarter basis, R&D expense grew by approximately $18 million over the first quarter of 2022. This was primarily due to costs associated with advancing our Imraculidin program.

We expect R&D expense for the remainder of the year to be relatively consistent with our second quarter results. G&A expense for the second quarter increased by approximately $7 million over last year, primarily due to higher personnel costs as we continue to grow our organization.

We expect G&A expense to increase slightly from the balance of the year as we support the, continued growth of our company, including the progression of our R&D programs and our commercial planning activities.

As of June 30, 2022, our cash, cash equivalents, and marketable securities totaled approximately $531 million. In closing, we remain well capitalized. We expect our cash resources to fund our current operations into 2024.

We look forward to multiple, value-creating data readouts over the next couple years, and we will continue to think creatively and opportunistically about further strengthening our balance sheet.

Dementia psychosis, we've been looking at this opportunity for quite a while we said before that we wanted to very carefully lay out the next steps.

With that, I'll hand the call back to Tony for closing remarks.

The teams now prepared with a full development program to study pharmacokinetics in healthy elderly and these are just part of our regular pipeline updates with regard to our <unk> study I'm, perhaps going to ask ray to just cover that notably what what can we say what can people expect from there.

That later this year and then we're certainly feel free to add any additional comments on either the rig about in panic group or <unk> and ADP right.

Thanks, Mark.

Sure good morning.

Michael and thank you for that question.

As you can see, we're advancing our broad and diverse set of programs and building, what we believe is truly becoming the premier neuroscience company with the potential to unlock significant value for both patients and shareholders.

The five near-term, late-stage data readouts across three development programs coming up, in 2023, a diverse set of therapeutic indications that we're exploring, robust lifecycle management plans to optimize each of our programs, and a vision to transform the treatment of a broad range of neuroscience diseases, Cerevel is on the leading edge of the next great frontier in medicine.

You are correct that we are as I mentioned earlier expecting the results of the ambulatory blood pressure monitoring trial later this year.

Thank you for joining us this morning.

I want to thank our teams whose dedication and commitment make this possible, and I also, want to extend my deepest gratitude and appreciation to the clinical trial participants and investigators who contribute to the development of these important therapies.

With that, operator, let's open the call for questions.

As you know that is a phase one trial that per guidance is <unk>.

Thank you.

Required for any therapy that has shown a pressure effect.

To ask a question, you will need to press star 1-1 on your telephone.

Please stand by while we compile the Q&A roster.

Their development.

But just to remind you that those pressure effects for transient de minimized overtime.

Our first question comes from Michael Yee with Jeffries.

The average.

At the end of six weeks in our six week phase one b trial or showed no clinically meaningful differences versus placebo. So the the agency is really interested in understanding as are we.

Your line is now open.

Hey, guys.

This sustains us.

Bob.

Her effects in systolic blood pressure over an eight week period and this is a trial that is required per guidance like other phase one trials or drug drug interaction trials from and to understand the pharmacokinetics as well.

So it's just another trial that is required for registration.

But it is not gating to approval. So it's really to inform practitioners and patients in terms of the labeling on how to best leverage <unk> when it's approved.

Okay.

Thanks, Mike and Jay or maybe if you could expand on.

The mechanism aspect.

Mike's question I think the question had to do with how do we think about selectivity for <unk> four in the ADP indication versus in one.

Yeah sure. Thanks, Tony Thanks, Michael for the question So as you know.

Very early on the muscarinic.

<unk> was established in the Alzheimer's patient population with an early study that demonstrated that.

Normally by itself had a in patients who could tolerate the drug.

Just had a benefit in localization outburst paranoia and some other measures and so we really believe it is the <unk> receptor that's driving the change in dopamine levels decreasing the hybrid dopaminergic activity that's associated with.

The psychosis part of all farmers disease.

As you know there have been in one compounds that have gone into all timers in terms of cognition.

With prior companies compounds and so they have not shown benefit. So we really think that the important productivity is really what we'll be able to drive efficacy and looking at the psychosis symptoms in alzheimers patients and so we don't believe that the in one will confer a benefit but we will we'll be finding out as we pursue this indication.

Thanks, Tony.

Alright, Thank you very much operator, we'll take the next question.

Our next question.

Comes from Matthew Harrison with Morgan Stanley . Your line is now open.

Good morning.

Great. Good morning, Thanks for taking the question I was hoping to ask on <unk>.

I guess a two part question here. So so first obviously tempo three is going to come first before tempo one.

And two can you just talk about how you view the results in late PD to have a read through to early PD or not and then.

And then secondly can you talk about what you view as a clinically meaningful result in terms of separation.

In those studies.

Thanks, Tony, for the updates.

Yes.

Ray if you'd be kind enough.

A lot going on here.

Thank you Matthew first of all for the question I think this would be.

That's a good time to just overview the tempo program and draw the distinction between the temporal III data that we expect in the first half of next year and the temporal one and two data that we expect in the second half of the year I think Matthew's question about the REIT potential read through for our results in the temple three togethers.

Would be.

Focus and then we will come to the specific question of clinical efficacy standards in Parkinson's and what we might consider success.

I just wanted to ask on emaraclidine and the announcement of Alzheimer's disease psychosis, and just wanted to understand maybe what were some of the drivers of announcing that today and also, as you think about that, how important hitting M1 is in that type of indication.

Sure sure. Thank you Tony and good morning, Matthew So Matthew as you know this is a novel mechanism and there hasnt really in the last 20 years has been any novel therapies to address the symptoms of Parkinson's disease.

So maybe just talk a little bit about that move forward there and what drove that and, how you feel in regards to confidence.

And we have a comprehensive program that we think will address at the benefits of <unk> at the inception of being diagnosed all throughout the course of the disease. So temple three is adjunct of treatment to levodopa. So the primary endpoint there is the.

The on time without troubling dyskinesia, and the clinically meaningful threshold as of at least one hour.

It's powered accordingly.

<unk> at least one hour of on time with up troubling dyskinesia and so the read through is.

There is really not balanced in terms of what we expect in the.

Early <unk>.

<unk> trials those are powered differently to look at it.

Different in the unified Parkinson's disease rating scale and as you know in the 15 week trial are very impressive four eight points was achieved in part III.

In those early trials.

The primary endpoint is the <unk> parts, two and three which we saw another robust outcome in the 15 week trial that was conducted several years ago. So our hope is that in the 2007 weeks that we can show a significantly improved benefit not only on the motor symptoms, but is also in the functionality of the <unk>.

<unk> is a SaaS bye bye part two so our hope is that the collective trials will show the benefits of <unk> again going back to my earlier comment of being a really backbone therapy from its inception, when you're diagnosed throughout the course of the disease.

Thanks Ryan.

You might want to add your perspective as you think about how we might think about commercialization competitor profile why some of that.

Existing launches haven't met standards, maybe just expand on those topics just a minute.

Sure Toni Thank you.

So one of the things that we reflect on as the Parkinson's patient population.

Outlined.

<unk> continues to have significant unmet need.

And when we look at the history and really kind of the recent launches of Parkinson's therapies. A couple of things really come forward for US one is as Ray mentioned, there hasn't been much innovation.

There has not been novel mechanism of actions introduced to this patient population and ultimately goes those profiles really havent led to a strong commercial presence of most recent therapies that have been launched and in the Parkinsons space. When we step back and we look at to drop it on.

C. A novel mechanism of action that we think can offer a lot of benefit to patients, but also a very robust.

Data package that really supports as ray said to <unk> potentially being a backbone therapy across the spectrum of Parkinson's disease early initiation, but also really supporting patients through base stage, Parkinson's as well, which we think.

We will really set us up well for I think.

<unk> commercial.

Presentation, as we think about tobacco.

Great. Thank you Larry.

With that operator, let's take the next question.

Okay.

Thank you. Our next question comes from Paul <unk> with Stifel. Your line is now open.

And then just to follow up on emaraclidine, I know you reiterated today you'll have an, update on the blood pressure study, I think, later this year.

Hey, Thanks, so much I had one and rapid and rapid being question and then one question on the Capex on the ambulatory blood pressure monitoring study.

I guess what are the expectations there and what will you actually be able to say about, that study?

But you're going to disclose some data from by the end of this year can you walk a little bit through your thought process around the math regarding the primary goal of that study I think you said, you're hoping to rule out statistically at three millimeter Mercury increase in blood pressure.

Understanding that the error bars are reflecting a small sample size in the phase one b I think they were pretty wide in the the upper bound there is above three.

Maybe you could just kind of comment on why you're confident that this study is likely to meet its typical goal and if we're kind of mismatch on time points and comparing and then on the cap compound.

I was curious if you have direct plans there yet or might soon to study that in major depressive disorder.

Given the J&J data that are flown somewhat under the radar. Thanks, so much.

Yeah, Good morning, Paul and thank you for that.

They are probably a couple of things to level set from your question.

Notably the three millimeters of Mercury aspect of your question and the primary goal of the study right why don't we just provide the context for everyone. So we have a good understanding for thinking about this particular study is a phase one requirement from the FDA.

Thank you.

Alright, so good morning, Paul and.

Okay.

As you know as I mentioned earlier that this is a.

Phase one trial that per guidance is required for agents have shown a pressure effect.

Mike, good morning, and thanks for the question.

And they are in their development and so its another phase one trial like any other phase one trial, that's required for registration really to inform the labeling but it is not gating to approval and what we're really trying to understand here is not the absolute as you know the absolute.

Presser effect at any given time, but really over the eight weeks is there a sustained.

Systolic blood pressure effect over those eight weeks and so the the goal here is really.

To look at the two doses of 10 milligrams and 30 milligrams, so the low dose and high dose.

To understand is you are meant as you mentioned correctly.

Is there a greater than three millimeter of mercury sustained effect over time.

And that really it's powered 90% powered.

To show a probability of a 95% confidence interval for change from baseline for 24 hour baseline mean to.

To ambulatory systolic blood pressure at we gain and so understanding understanding that dynamic and looking at the upper bound of the confidence interval is what we'll be looking forward with the agency, we will be looking for an understanding.

What that outcome is.

But again this is really more informative for labeling than it is for approval, but it's needed for registration.

Great I think its fair just to add that this really is about sustained increases in blood pressure I know, you said that but I want to draw everyone's attention to.

I think one of your questions was about our announcement of the pipeline updates.

To that because I think one of the points in the question asked was did we have episodic increases in blood pressure above three millimeters in mercury.

That is of course, not the point of this particular study because what the agency cares about is the sustained elevation of blood pressure, but I don't know if you had any more than you wanted to add beyond that clarification and that not so subtle distinction.

You know, we've been working on our next steps for Dorigabat in anxiety after we got the, data earlier this year.

No I think what we're looking at is really 24 hour blood pressure monitoring.

So the announcement today about Dorigabat is just keeping everyone apprised of our latest, thinking now that we have more firmly planted our feet in panic disorder.

Using IP Ed at the gate versus the baseline.

And so understanding the average during that 24 hour measurement is really what's important but if we look at the week six average in the phase one b trial.

That gives us confidence that we'll be able to really describe the benefits of them rapidly without concerns of.

Pressure effect.

Overall, but.

In case the data suggests differently that we will then inform labeling but we still are confident that <unk> has great benefit for the patients who need it.

And the same is true for emaraclidine in Alzheimer's, dementia, psychosis.

Yes, hi, good morning, if I could just clarify in the <unk> study the data you've shown so far what time point was that taken in was that was that closer to C. Max.

We've been looking at this opportunity for quite a while.

We've said before that we wanted to very carefully lay out the next steps.

Versus I think the study is 24 hours just trying to understand the context around the six week data that we saw in the one day.

The team's now prepared with a full development program to study the pharmacokinetics in healthy, elderly, and these are just part of our regular pipeline updates.

With regard to our ABPM study, I'm perhaps going to ask Ray to just cover that, notably, what can we say or what can people expect from that later this year, and then, Ray, certainly feel free to add any additional comments on either Dorigabat in panic or emaraclidine in ADP.

Right. So it was the measurements were taken at several points, but one of them. They were taken two hours post dose.

So closer to closer to <unk>.

The data that we showed was the seven day average of <unk>.

Daily measurements at week six.

And so thats closer to.

What ultimately we will want to show because it really shows the average over time, which is what we will see in a 24 hour period Paul.

And so that's that's the difference in that it shows it speaks to the sustainability of the effect and not just an acute effect at any given time point.

Sure I know that your team was.

Involved in leading that phase one study.

Additional comments on the <unk> aspect of the question just to complement what brands often and maybe if you would lateral from that into the answers around our intention our intention for the core program and MDT.

Sure. Thanks Toni.

Thanks, Bob for the question yes.

The data that was reported for six weeks was it the two hour time point and so that is what we estimate to be C. Max based on average pharmacokinetics, what we've seen.

And so what you are looking at really is it what is the worst.

Deviation that you wouldn't expect to see based on what we know about when we did see the transient increases which maximize it seemed.

C Max and so what you saw was the worst that we can see and then what you have to consider is if you take the fact that there is a transient effect, even though in the first days of dosing.

That transient effect goes away over overtime, and so if youre, averaging over 24 hour time period and this what <unk> seen is the worst that it could be.

We don't anticipate that will be.

In an area, where we will have to have to worry about the three millimeters at this point, but we're doing the study to confirm that but.

Later, we reported was it that was it right at around the estimated seem ex point.

To your second point, Paul around Cora so.

Yes.

Very excited about our molecule. So as you know J&J has reported positive data in our phase II design study in depression.

We do know that there are additional studies with their molecule around Gi Tolerability has been reported on.

The nickel trials Dot Gov.

Our molecule.

<unk>.

Tolerability and safety perspective, based on preclinical Tox and what we've seen to date in the clinic is very promising.

And so the data that we're getting back shows.

It's very well tolerated within a sad study so.

I think what we're looking forward to is being able to take the next steps once we've completed the sad and Mad portion obviously were.

Very engaged in planning what those next steps look like to maximize the understanding of the molecule and giving us options for next indications.

But we are considering how those trials will be dose and design based on what we're seeing as far as feedback and data that we're getting in the clinical study.

Great well, thank you Robert color I appreciate it thanks.

Ray?

Okay, Operator, we'll take the next question.

Sure.

Our next question comes from Tiffany <unk> with J P. Morgan Your line is open.

Good morning, Michael, and thank you for that question.

Hey, guys. Good morning. Thanks for the question can you provide some more color on the key next steps for <unk>, you mentioned prioritizing moving forward.

The non clinical safety pharmacology studies, CMC manufacturing scale up et cetera, and what's the expected timelines for these and more broadly what do you expect to be a gate keepers.

Or are the 52 week safety trial. Thanks.

You are correct that we are, as I mentioned earlier, expecting the results of the ambulatory, blood pressure monitoring trial later this year.

Great. Thank you Tiffany for the question.

I think I'll ask.

Two of you to respond Jr. Largely on the product development CMC side, but if you don't mind, providing an overview of the phase III program that we've been talking about that would be terrific and.

I think we will be able to answer tiffany's questions.

As you know, that is a phase one trial that, per guidance, is required for any therapy, that has shown a pressure effect in their development.

Yes, good morning, Tiffany yes.

But just to remind you that those pressure effects were transient.

Yes, so as you know as we mentioned that we are conducting a robust phase II program that consist of two six week trials of 372 individuals living with schizophrenia each.

As well as the 52 week open label, which.

Is slated to start soon since these individuals are not the opportunity to rollover into into the open label extension. We will also be adding de novo patients in the future to ensure that in fact, the open label extension does not become rate limiting to our being able to file if indeed the data.

Ports, both trials data supports potential for registration.

But we are.

We've started dosing in both trials.

They are being conducted in the U S. In.

In Bulgaria, Serbia and Hungary.

Countries have been separated between the two trials so from that perspective.

Spectrum, we're meeting what we believe the agency is looking for which is of course, the long term safety data, but as well as understanding and characterizing the full dose range, which we're doing and then of course showings statistically.

They minimized over time, and the average at the end of six weeks in our six-week phase, one B trial showed no clinically meaningful differences versus placebo.

So the agency is really interested in understanding, as are we, the sustained.., pressure effects and systolic blood pressure over an eight-week period.

Separation from placebo.

There's a lot of other a lot of work that's being conducted in terms of technical operations and preclinical work and pharmacokinetic work and so forth that John can outline, but our hope is that if the data reads out as we hope it will that we will have a package that can be.

Provided to the agency and with their support I tried to get them rapidly to patients as soon as possible John .

And this is a trial that is required per guidance, like other phase one trials, you know, drug-drug interaction trials to understand the pharmacokinetics as well.

Sure. Thank you Ray and things differently. So.

Yes, so from a from a tech ops perspective.

So it's just another trial that is required for registration, but is not gating to approval.

So it's really to inform practitioners and patients, in terms of the labeling on how to best leverage, MRAC libidin when it's approved.

We are being very aggressive about being able to bring forward a registrational package. So that we have.

Okay, thanks.

<unk>.

Done all of the Tech ops work on the manufacturing and the quality controls et cetera.

You know what, thanks Mike.

And all the qualification and stability work that will be necessary to support that successful NDA filing if the data comes back.

And JR, maybe if you could expand on, the mechanism aspect of Mike's question. I think the question had to do with, how do we think about selectivity for M4 in the ADP indication versus M1?

Positive.

Preclinical work.

Yep.

As you know one of the things that usually takes a lot of times of Kersey work the kersey work.

Sure, thanks Tony.

We will be done in time to support NDA.

NDA submission around the time that we're getting the other key data points and so.

That has been initiated its on track to deliver the necessary.

Submission package.

And the timeframe that we expect the other studies to complete including the oil.

I think your question about mix.

Extra indications.

Had a very constructive meeting with the FDA around our plan for going into the elderly population as already mentioned the same doses that we've covered in the younger healthy population will be carried forward and so we will be including from two milligrams up to the highest dose that we think that we would need to achieve which is the 30 milligram dose.

That study that we've announced today and so we're excited to get that safety and Tolerability data in the elderly population to support.

Cycle management.

Opportunities in ADP so.

We do have.

Slip vendor selection to support all the compound manufacturing to support this on a commercial scale.

And so we're getting ready to have successful.

Follow up work won't give the positive data from the phase II studies.

I hope that helps Tony.

Yes, no thats perfect I think the thrust is we are doing everything we can in parallel to ensure that when the clinical data already we're ready with everything else. So thank you guys for that operator.

Next question.

Our next question.

Comes from Douglas Tsao with H C. Wainwright. Your line is now open.

Thanks Michael for the question.

Hi, Good morning, Thanks for taking my questions. The first on Georgia back in the queue and disorder.

So as you know, very early on the muscarinic pathway, was established in the Alzheimer's patient population with an early study that demonstrated that the anomaly by itself had a, in patients that could tolerate the drug, had a benefit in vocalization, outburst, paranoia and some other measures.

And so we really believe it is the M4 receptor, that's driving the change in dopamine levels, decreasing the hyperdopaminergic activity that's associated with the psychosis part of Alzheimer's disease.

As you know, there have been M1 compounds, that have gone into Alzheimer's in terms of cognition with prior companies' compounds and so they have not shown benefit.

So we really think that the M4 selectivity, is really what will be able to drive efficacy in looking at the psychosis symptoms in Alzheimer's patients.

Just curious do you have a sense I think in the earlier study with 8-K endpoint the duration of dosing and the primary endpoint for the.

For the Phase II study.

And so we don't believe that the M1 will confer a benefit, but we'll be finding out as we pursue this indication.

Yes.

Doug Let me just make sure.

Got the question because you broke up a little bit you are asking about duration of focusing in which study.

Thanks Tony.

For the third about the panic disorder study.

Great, thank you J.R., very much.

Yes, Okay Ray do you want to we haven't finished with all the details Airways indicated we're going to talk to the agency, but Greg what.

Operator, we'll take the next question.

What can you say.

Sure So Doug as you know.

Our next question comes from Matthew Harrison, with Morgan Stanley, your line is now open.

There hasn't been a drug approved for the treatment of panic disorder. Since 2005, so 17 years ago.

Great, good morning, thanks for taking the question.

The duration of trials historically in terms of press and they've been anywhere from eight to 12 weeks.

I was hoping to ask on to Vapidon, and I guess a two-part question here.

We are currently finalizing our proposal for a proof of concept trial in patients with panic disorder.

So first, obviously Tempo 3 is gonna come first, before Tempo 1 and 2.

And we will be going to the agency this fall.

Can you just talk about how you view the results in late PD, to have a read-through to early PD or not?

Aligned to ensure that there hasnt been any change of thought within the agency given that it's been a long time a lot of changes within the FDA.

So we want to make sure we're aligned but obviously are our construct for that program is really based on precedent and we just want to make sure that precedent still upholds currently.

And then secondly, can you talk about what you view, as a clinically meaningful result in terms of separation in those studies?

Okay, great. Thank you and then just a follow up in terms of.

The <unk> study.

Thanks.

Dementia related psychosis, just curious I think you John just mentioned that youre going to testing doses as low as two milligrams I'm. Just curious do you anticipate or how are you thinking about that study and the readout and what youll get in terms of potential dosing.

Yep, Ray, if you'd be kind enough, if you just, thank you Matthew, first of all, for the question.

For a patient driven steady I mean, do you think the dosing will differ significantly from what you've seen.

For schizophrenia. Thank you.

Jarrod.

Tim is going to be conducting that that particular program why don't you start with the answer.

I think, Ray, this would be perhaps a good time, to just overview the Tempo program and draw the distinction between the Tempo 3 data that we expect in the first half of next year and the Tempo 1 and 2 data that we expect in the second half of the year.

Good question.

Sure. Thanks, Toni Thanks, Doug Yeah.

I think Matthew's question about the potential read-through, for results in the Tempo 3 to the others would be a main focus.

So as you know we've had to date, a very well tolerated profile.

Both patients and healthy we need to confirm that is the next step before we go into the ADP study. So we are covering the full dose range in the multiple dose study that we've announced.

We don't expect the elderly to have a shift in their dose response based on what we know about how the drug is metabolized in the things that can impact metabolism and the elderly.

So what we anticipate is based on the side effect profile that we've seen to date based on what we know about how the drug is cleared we don't expect to see differences in PK or expect to need to dose adjustment, but obviously, we'll get the data and determine whether that's the case with us.

And then we'll come to the specific question, of clinical efficacy standards in Parkinson's and what we might consider a success.

Appointing going in.

Okay got it and so just to confirm so it sounds like this is more sort of confirmatory rather than sort of an exploratory study.

Sure.

Thank you, Tony.

Well I mean, we have to get the data so we will be.

We'll be making sure that what we've seen to date is extended into the elderly population before we go into the patient population, but based on what we know to date, we don't expect to see something that would.

We would forecast that we would need to do a dose adjustment elderly, but again, we have to get the data first.

And good morning, Matthew.

Great. Thank you so much.

So Matthew, as you know, this is a novel mechanism.

There hasn't really, in the last 20 years, been any novel therapies to address the symptoms, of Parkinson's disease. And we have a comprehensive program that we think will address the benefits of tavapidon at the inception of being diagnosed all throughout the course of the disease. So TEMPO3 is adjunctive treatment to levodopa.

Okay. Thank you Doug Thanks for the question.

So the primary endpoint there is the on-time, without troubling dyskinesias, and the clinically meaningful threshold is at least one hour. So it's powered accordingly to achieve at least one hour of on-time without troubling, dyskinesias.

Operator, we'll take the next question.

And so the read-through is really not balanced in terms of what we expect in the early Parkinson's trials.

Our next question comes from Madhu Kumar with Goldman Sachs. Your line is now open.

Those are powered differently to look at, different in the Unified Parkinson's Disease Rating Scale.

And as you know, in the 15-week trial, a very impressive, 4.8 points was achieved on Part 3.

Hey, Thanks for taking my question. This is Rob on for Madhu I was just wondering for the rig about panic disorder. How are you thinking about the target population of that patients.

Already on benzodiazepines refractory or something broader.

In those early trials, the primary endpoint is the UPDRS Parts 2 and 3, which we saw another robust outcome in the 15-week trial that was, conducted several years ago.

Okay. Good.

What what can we say.

Given our upcoming plan discussions and our further work.

So our hope is that in the 27 weeks that we can show a significantly improved benefit, not only on the motor symptoms, but also in the functionality of the patients as assessed by Part 2.

Right right. Thank you Matt so the the plan is really to.

So our hope is that the collective trials will show the benefits of tavapidon.

That's, again, going back to my earlier comment of being a really backbone therapy from its inception when you're diagnosed throughout the course of the disease.

Enrolled patients who are suffering from panic disorder in meaning they have panic attacks.

Thanks, Ray.

And the frequency of course, it's something that we'll have to understand better in terms of what that threshold days because the patient profiles is critical and drives the success and outcomes of trials.

You're still looking at that internally, but we will be making that proposal based on historical precedent.

So we'll stay tuned for those details as soon as we align with the agency.

And Abe, you might want to add your perspective as you think about how we, might think about commercialization, competitive profile, why some of the existing launches haven't met standards.

Okay, great. Thanks, and then just one other quick question on.

On <unk> are you thinking of any drug drug interactions with elderly population that might differ.

Maybe just expand on those topics just a minute.

From previous population.

Jerry do you want to hit that one quickly.

Sure. So there is.

As you can see from clinical trials that we have excluded some of the strong.

Sip compounds and so whether they're inducers or.

Inhibitors, and so there is a potential for that we have.

We have data to collect yet did inform that.

That's what we'll be looking for.

I think that this is not something that's unusual in this and this policy with population and so there is the ability obviously to.

Inform physicians about that should it occur, but we'll get there as well.

Alright, Thank you you.

You don't expect anything out of the ordinary just because it's an elderly population I think that was the second part of the question.

The answer is no.

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

Thank you as a reminder to ask a question. Please press star one on one our next question comes from.

Greg <unk> with Mizuho Your line is open.

Good morning line is open.

Please check your mute button.

Alright can you hear me.

Now we've got you Greg go ahead.

So much thanks for taking the questions.

Tony I was wondering we've been doing a lot of work on our end with Kols on specifically on <unk> and I'm wondering from.

The market research that perhaps.

You have done the company has done.

Have you been able to get a sense from your clinical advisors on whether theyre seeing a meaningful difference between what an M. One and <unk> four compound offers versus for selective compound at the end of the day.

Also wondering if you've gotten any feedback on.

At least on the Pan score, especially ahead of the phase III <unk> readout like what really is clinically meaningful in terms of what doctors want to see from a muscarinic based agent in terms of the placebo adjustment on pads.

That's question is really around kind of what you are hearing from.

Clinicians and then secondly, it was wondering if you could offer just your thoughts.

On what.

What we might be able to see from the phase III data for Corona and what that might mean for <unk> and then my last question just on the ADP program for <unk> and I'm wondering if there are any less.

The lessons learned or key takeaways that you've gotten either from looking at the Acadia.

Spirits or how Corona is running there.

ADP program. Thanks, so much.

Okay.

But because it's come up.

On our call.

On recession, Jarrod I think it would be useful to go through the four versus versus the import him. One thesis that we're operating with and what you think the relative contributions I know that you've said that you think that it's largely the antipsychotic effect is driven by the M. Four but there might be some additional clarification.

I know that we're always engaged with our strategic thought leaders in a variety of conversations, but I thought we'd start with the ground truth.

What the science has for us and what science tells US and then Ray will lateral to you to talk a little bit about the pan score, but Jerry if you take that first piece that would be great.

Sure, Tony.

Sure Thanks, Tony and thanks, Gregg for the question yes.

Yes.

Thank you.

As you know Greg the history here has been the approach was anomaly is really one that's gone after the muscular <unk> and as you know.

So one of the things that we reflect on is the Parkinson's patient, population, as Ray outlined, continues to have significant unmet need.

And when we look at the history and really kind of the recent launches of Parkinson's therapies, a couple of things really come forward for us.

With the nonselective compounds are normally Lilly was able to show benefits in both the.

One is, as Ray mentioned, there hasn't been much innovation. There has not been novel mechanisms, actions introduced to this patient population.

And ultimately, you know, those profiles really haven't led to a strong commercial presence of, most recent therapies that have been launched in the Parkinson's space.

All timers population, where I mentioned before that they saw.

Specifically impacts on the <unk>.

In that study they were looking at the impact on the psychosis measurements and so in that population they were particularly interested in things like localization and outburst paranoia things.

Things that have to do with.

What we understand to be related to hybrid dopaminergic activity and as you know in that study, even though it was not well tolerated the patients that were able to complete that study.

When we step back and we look at tavapidon, we see a novel mechanism of action that we think can offer a lot of benefit to patients, but also a very robust data package that really supports, as Ray said, tavapidon potentially being a backbone of therapy across the spectrum of Parkinson's disease.

Early initiation, but also really supporting patients through late-stage Parkinson's as well, which we think will really set us up well for, I think, a strong commercial presentation as we think about tavapidon.

Great.

<unk> benefited in a dose dependent manner. So also in the schizophrenia study.

Younger population. They also showed benefits in this the psychiatric schizophrenia symptoms that are related more towards the pan score. So.

What we were able to do with our data which was the first compound that is actually enforce selective.

What you saw was a very similar results to what we've seen with the Corona component. So with it to me what that validates. The fact that imports selectivity confers the NSA kotick benefit that was demonstrated by the <unk> and what we're able to deal with the main course selected compound also was.

<unk> decided effects that cause intolerable side effects that we're seeing with the non selective compound and so really what we're talking about is looking for the benefit of the muscular <unk> and treating symptoms related to schizophrenia or psychosis.

As we know this is related to the increase in dopamine levels and so if you look at where in one is expressed in the brain where employers expressed in Florida is really on the neurons.

Provide input into the dopaminergic system.

One is much more broadly expressed in there has been a target of interest for cognition.

The indications that we're looking at are really around the diseases, where psychotic symptoms as measured by the pain score or whether it was measured by the earlier study that Lilly did where theyre looking at specific features and psychosis and alzheimers patients those seem to be more related to dopamine and we know that the <unk> four receptor is selectively expressed.

And that.

Highly expressed in Australia, much more selectively expressed at high levels in that area of the brain that controls dopaminergic activity that can drive the psychiatric symptoms that had been seen in the populations that we're talking about today. So.

The selectivity question that we've been able to answer with our compound is that <unk> by itself can drive an antipsychotic benefit in this study that we reported and it can avoid the side effects that are seen commonly with compounds that antagonize. The muscarinic M ones for instance, or other other muscular <unk>.

<unk>.

I think that.

What the data supports today from our point of view is that enforce selectivity is able to provide the managed psychotic benefit we don't believe that the data that was generated by a nonselective compounds in the Pan score was different from our compounds selective, but what we did see that was different between the two types of compounds was it the important selective.

He did confer a better tolerability profile, we did not see the Gi related issues. We did not see the dropouts were seeing previously was anomaly. So really our belief is it's really in four is important in driving the antipsychotic benefit has been demonstrated in four different studies by by three different sponsors to date.

And so we have a lot of confidence in this mechanism. We think we understand the neural network and the circuitry that drives the psychosis and we believe that we understand how the pharmacology of important receptor can drive that benefit so.

Thank you, Abe.

With that, Operator, let's take the next question.

Thank you.

With that I'll turn it over to Ray.

Okay great.

Yes, I'm sorry, if you could I was just thinking about the bridge to <unk> answer.

I know you talked to thought leaders are quite a bit you and your team can you just talk a little bit about how well you think both prescribing physicians and thought leaders will appreciate.

The distinction Jr. Just made that is mainly about enforce selectivity and how they might actually view that.

Pan score standard if you will for what a good clinical efficacy might be and then we'll come back to the other two questions that Greg has saw ads and then operator I think we will be out of time. So this will be our last question.

Our next question comes from Paul Matteis with Spiefel.

Absolutely good morning, Greg So Greg as you know historically on average.

Your line is now open.

Hey, thanks so much.

Absolute total pans reduction.

For any psychotics existing any psychotics has been somewhere between 10 and 15 points placebo adjusted about 5% to 10 points.

I have one MRAC-Libyan question and then one question on the CAPA, compound.

On the ambulatory blood pressure monitoring study that you're going to disclose data from by the end of this year, can you walk a little bit through your thought process around the math regarding the primary goal of that study?

And so we have therapies for any therapy, obviously, we're going to look at that absolute pans reduction as the placebo response.

And the variability introducing these trials, especially is even larger than that.

Definitely increases in it waxes and wanes over time, depending on how many trials you conduct but I think to Tony's point that there is definitely a need in the landscape for therapies that have a robust antipsychotic effect, but more importantly have a side effect of our tolerability profile.

In terms of metabolic issues in terms of extra pyramidal side effects and so forth that are fairly benign and what we're seeing at least in the data. That's been generated to date is that this is a pathway there.

That can actually have a very impressive side effect profile and much more better tolerated to existing therapies.

I think you've said you're hoping to rule out statistically a 3-millimeter mercury increase in blood pressure.

Understanding that the error bars are reflecting a small sample size in the Phase 1b, I think they were pretty wide, and the upper bound there is above 3.

But in terms of the efficacy provided that.

We're hoping that the efficacy will be as good if not better than than what we've seen historically and I think the selectivity of this mechanism.

<unk> as well as the once a day and no need for titration.

Characteristics of this therapy, I think speak to the compliance issues and the reset of isn't that you see in this patient population because of multiple dosing because of the need for titration and so forth. So we're overall extremely confident not only with the mechanism, but also with what the data can support and the benefits it will be.

Maybe you could just kind of comment on why you're confident that this study is likely to meet its statistical goal and if we're kind of mismatching time points in comparing.

Moving to the landscape.

I think I would just say thank you write that side of it was very good and very clear I think what I would do it I'll, probably just end with the following notion that obviously, we don't make a practice of commenting on other companies and we certainly won't speculate about what other companies might be.

And then on the CAPA compound, I was curious if you have direct plans there yet or might soon to study that in major depressive disorder, given the J&J data that have flown somewhat under the radar.

Thanks so much.

Yeah.

Good morning, Paul, and thank you for that.

There are probably a couple of things to level set from your question, notably the 3 millimeters, of mercury aspect of your question and the primary goal of the study.

Our perspective is that if we have a success because there's another therapeutic that shows benefits on patients than we all win and on that basis, we will learn as the field evolves, but are really focused not just on your <unk>, but all of the other things that we have ongoing dirt about in panic.

Ray, why don't we just provide the context for everyone so we have a good understanding for thinking about this particular study as a Phase 1 requirement from the FDA?

Right.

So, good morning, Paul.

And as you know, as I mentioned earlier, that this is a Phase 1 trial that, per guidance, is required for agents that have shown a pressure effect in their development.

And so, it's another Phase 1 trial, like any other Phase 1 trial, that's required for registration, really, to inform the labeling, but it's not gating to approval.

And what we're really trying to understand here is not the absolute, as you know, the absolute, you know, pressure effect at any given time, but really, over the 8 weeks, is there a sustained systolic blood pressure effect over those 8 weeks?

And so, the goal here is really to look at the 2 doses of 10 milligrams and 30 milligrams, so a low dose and a high dose, and to understand, as you mentioned correctly, is there a greater than 3 millimeter of mercury sustained effect over time?

And that really, it's powered, 90 percent powered, to show a probability of a 95 percent confidence interval for change from baseline, for 24-hour baseline mean, to ambulatory or systolic blood pressure at Week 8.

And so, understanding that dynamic and looking at the upper bound of the confidence interval is what we'll be looking for, what the agency will be looking for, and understanding, you know, what that outcome is.

But again, this is really more informative for labeling than it is for approval, but it's needed for registration.

Ray, I think it's fair just to add that this really is about sustained increases in blood, pressure.

No.

I know you said that, but I want to draw everyone's attention to that, because I think one of, the points in the question asked was, you know, did we have episodic increases in blood pressure above three millimeters in mercury?

I think, you know, what we're looking at is really 24-hour blood pressure monitoring and, you know, using at the week eight versus the baseline, and so understanding the average during that 24-hour measurement is really what's important, but if we look at the week six average in the phase 1B trial, that it gives us confidence that we'll be able to really describe the benefits of imraclidine without concerns of a pressure effect overall, but in case the data suggests differently, that we will then inform labeling, but we still are confident that imraclidine has great benefit for the patients who need it.

That is, of course, not the point of this particular study, because what the agency, cares about is the sustained elevation of blood pressure, but I don't know if you had any more that you wanted to add beyond that clarification and that not-so-subtle distinction.

Yep.

Coming epilepsy data readout to wrap it on in Parkinson's that really exciting programs for M. D. D. The dementia related apps and we have so many things to focus on so we will stay abreast of all of these things as to learnings in terms of Alzheimers dementia psychosis I think we have watched how the agency has responded to other companies who have.

Okay.

By the way, if I could just clarify, in the 1B study, the data you've shown so far, what, time point was that taken, and was that closer to C-max versus, I think, this study of 24 hours, just trying to understand the context around the six-week data that we saw in the 1B?

Right. So, it was, you know, the measurements were taken at several points, but they were taken, in two hours post-dose, so closer to C-max.

The data that we showed was the seven-day average of the daily measurements at week, six, and so that's closer to what ultimately we will want to show because it really shows the average over time, which is what we'll see in a 24-hour period, Paul, and so that's the difference in that it speaks to the sustainability of the effect and not just an acute effect at any given time point.

Jayar, I know that your team was involved in leading that phase one study.

Any additional comments on the C-max aspect of the question, just to complement what Ray, has offered, and maybe if you would lateral from that into the answers around our intentions for the CORA program and MVD?

Sure.

Thanks, Tony, and thanks, Paul, for the question.

Yeah, so the data that was reported for six weeks was at the two-hour time point, and, so that is what we estimate to be C-max based on average pharmacokinetics, what we've seen, and so what you're looking at really is what is the worst deviation that you would expect to see based on what we know about when we did see the transient increases, which maximize it at the C-max, and so what you saw was the worst that we could see, and then what you have to consider is if you take the fact that there's a transient effect, even on the first days of dosing, that transient effect goes away over time, and so if you're averaging over a 24-hour time period and this, you know, what you've seen is the worst that it could be, we don't anticipate that we'll be in an area where we'll have to worry about the three millimeters at this point, but we're doing the study to confirm that, but the data reported was at around the estimated C-max point.

To your second point, Paul, around CORA, so yeah, we're really very excited about our molecules.

So, as you know, J&J has reported positive data in a Phase II design study in depression.

We do know that there are additional studies with their molecule around GI tolerabilities have been reported on clinicaltrials.gov.

Appreciate it.

Our molecule from a tolerability and safety perspective based on preclinical toxin and what we've seen to date in the clinic is very promising.

And so the data that we're getting back shows that it's very well tolerated within a SAD study.

So I think what we're looking forward to is being able to take the next steps once we've completed the SAD and MAD portion.

Obviously, we're very engaged in planning what those next steps look like to maximize the understanding of the molecule and giving us options for our next indications.

But we are considering how those trials will be dosed and designed based on what we're seeing as far as feedback and data that we're getting in the clinical study.

Thanks.

Thank you.

Okay.

Thank you for all the work.

<unk> explored that potential indication and obviously are incorporating those learnings into our designs and plans.

Operator, we'll take the next question.

Our next question comes from Tiffany Sun with J.P. Morgan.

Your line is open.

Hey, guys.

Good morning.

Thanks for the question.

So, let's let's stay abreast, let's stay tuned we'll certainly keep you guys informed as we know more operator. Thank you all for assisting US today. Thank you team for the excellent work and thank you each for listening to US. We're just past the hour. We appreciate your time and your support and we will look forward to future.

Can you provide some more color on the key next steps for immorality?

And you mentioned prioritizing moving forward, so the non-clinical CFC pharmacology studies, CMC manufacturing, scale-up, et cetera.

And what's the expected timeline for these?

Thank you, Tiffany, for the question.

And more broadly, what do you expect to be, you know, the gatekeeper for approval, one of these, or the 52-week safety trial?

J.R. and Ray, I think I'll ask the two of you to respond.

Thanks.

J.R. largely on the product development and CMC side.

Great.

But, Ray, if you don't mind providing an overview of the Phase 2 program that we've been talking about, that'd be terrific.

And I think we'll be able to answer Tiffany's questions.

Yeah.

Good morning, Tiffany.

Thank you, John.

Yes.

Sure.

So, as you know, as we mentioned, that we are conducting a robust Phase 2 program that consists of two 6-week trials of 372 individuals living with schizophrenia each, as well as the 52-week open label, which is slated to start soon, since these individuals then have the opportunity to roll over into the open label extension.

Thank you, Ray, and thanks, Tiffany.

We will also be adding de novo patients in the future to ensure that, in fact, the open label extension does not become rate limiting to our being able to file, if, indeed, the data supports, both trials' data supports potential for registration. But we've started dosing in both trials.

So, yeah, so from a tech ops perspective, we are being very aggressive about being able to bring forward a registrational package so that we have done all of the tech ops work on the manufacturing and the quality controls, et cetera, and all the qualification and stability work that will be necessary to support that successful NDA filing if the data comes back positive.

They are being conducted in the U.S., in Bulgaria, Serbia, and Hungary.

From preclinical work, as you know, one of the things that usually takes a lot of time is the CARSI work.

The countries have been separated between the two trials.

The CARSI work will be done in time to support an NDA submission around the time that we're getting the other key data points, and so that has been initiated. It's on track to deliver the necessary NDA submission package in the timeframe that we expect the other studies to complete, including the OLE.

So, from that perspective, you know, we're meeting what we believe the agency is looking for, which is, of course, the long-term safety data, but as well as understanding and characterizing the full dose range, which we're doing, and then, of course, showing statistical separation from placebo.

I think with your question about extra indications, you know, we've had a very constructive meeting with the FDA around our plan for going into the elderly population.

There's a lot of other – a lot of work that's being conducted in terms of technical operations and preclinical work and pharmacokinetic work and so forth that John can outline, but our hope is that, if the data reads out as we hope it will, that we will have a package that can be provided to the agency and, with their support, try to get emeraclid into patients as soon as possible.

As Ray mentioned, the same doses that we've covered in the younger, healthy population, will be carried forward, and so we'll be including from 2 milligrams up to the highest dose that we think that we need to achieve, which is the 30 milligram dose in that study that we've announced today, and so we're excited to get that safety and tolerability data in the elderly population to support our lifecycle management opportunities in ADP.

So, we do have vendor selection to support all the compound manufacturing to support this on a commercial scale, and so we're getting ready to have successful follow-up work once we have the positive data from the Phase 2 studies.

I hope that helps.

So, thank you guys for that.

Tony?

Operator, next question.

This concludes today's conference call.

Yeah, no, that's perfect.

Our next question comes from Douglas Tsao with H.C. Wainwright.

Updates thank you guys.

I think the thrust is we are doing everything we can in parallel to ensure that when the clinical data are ready, we're ready with everything else.

Your line is now open.

Hi.

This concludes today's conference call. Thank you for participating you may now disconnect.

Good morning.

Thanks for taking the question.

This is the first on Dorjabat and acute panic, disorder.

I'm just curious, do you have a sense, I think in the earlier study with 8K endpoint, the duration of dosing in the primary endpoint for the Phase 2 study?

Doug, let me just make sure I got the question because you broke up a little bit. You're asking, about duration of dosing in which study? For the Dorjabat, the panic disorder study.

Yes, okay.

Ray, do you want to, we haven't finished with all the details there.

Ray's, indicated we're going to talk to the agency, but Ray, what can you say?

Sure.

So, Doug, as you know, there hasn't been a drug approved for the treatment of panic disorder since 2005, so 17 years ago. The duration of trials historically in terms of precedent have been anywhere from 8 to 12 weeks. We are currently finalizing our proposal for a proof of concept trial in patients with panic, disorder, and we will be going to the agency this fall to align, to ensure that there hasn't been any change of thought within the agency, given that it's been a long time, a lot of changes within the FDA, and so we want to make sure we're aligned, but obviously our construct for that program is really based on precedent, and we just want to make sure that precedent still upholds currently.

Okay, great, thank you.

And then just a follow-up in terms of the Miraclidene study in dementia-related, psychosis.

The conference will begin shortly to raise Johan during Q&A, you can dial star one one.

Just curious, I think you, John just mentioned that you were testing doses as low as two milligrams.

I'm just curious, do you anticipate, or how are you thinking about that study and the readout and what you'll get in terms of potential dosing for a patient-driven study?

I mean, do you think the dosing will differ significantly from what you've seen for schizophrenia?

Thank you.

Dr. John Reneau, Chair, your team's going to be conducting that particular program.

Why don't you start with the answer to Doug's question?

Dr. John Reneau Sure, thanks, Tony.

[music].

Thanks, Doug.

Yeah, so, as you know, we've had to date a very well-tolerated profile in both patients and healthies.

We need to confirm that as the next step before we go into the ADP study.

So we are covering the full dose range in the multiple dose study that we've announced.

We don't expect the elderly to have a shift in their dose response based on what we know about how the drug is metabolized and the things that can impact metabolism in the elderly.

And so what we anticipate is based on the side effect profile that we've seen to date, based on what we know about how the drug is cleared, we don't expect to see differences in GK or expect a need for a dose adjustment.

Yeah.

But obviously, we'll get the data and determine whether that's the case.

But that's the plan going in.

Okay.

Dr. Tony Fauci Okay, John.

[music].

And so just to confirm, so it, sounds like this is more sort of confirmatory rather than sort of an exploratory study.

Dr. John Aucott Well, I mean, we have to get the data.

So, we'll be making sure that what we've seen to date is extended into the elderly population before we go into the patient population.

But based on what we know to date, we don't expect to see something that we would forecast that we would need to do a dose adjustment in the elderly.

But again, we have to get the data first.

Dr. Tony Fauci Yep, great.

Thank you so much.

Okay, thank you, Dob.

Thanks for the question.

Operator, we'll take the next question.

Okay.

Operator Our next question comes from Madhu Kumar with, Goldman Sachs.

[music].

Your line is now open.

Madhu Kumar Hey, thanks for taking my question.

This is, Rob on for Madhu.

I was just wondering, for Darigabat and panic disorder, how do you think about the target population?

Is that patients already on benzodiazepines, refractory, or something broader?

Dr. Tony Fauci Okay, good.

Ray, what can we say, given our, upcoming planned discussions and our further work?

Dr. Ray Pazin Right, right.

Thank you, Madhu.

So the plan, is really to enroll patients who are suffering from panic disorder, meaning they have panic attacks.

And the frequency, of course, is something that we'll have to understand better in terms of what that threshold is, because the patient profile, as you know, is critical and drives the success outcomes of trials.

We're still looking at that internally, but we'll be making that proposal based on historical precedent.

So we'll stay tuned for those details as soon as we align with the agency.

Okay, thanks, and then just one other quick question on um, on umraclidine.

Are you thinking of any drug-drug interactions with elderly populations that might differ, from previous populations?

Jared, do you want to hit that one quickly?

Sure, so there, there is, as you can see from clinicaltrials.gov, we've excluded some of, the strong SIP compounds, and so whether they're inducers or inhibitors, and so there's a potential for that.

We have, we have data to collect yet to inform that, but that's, that's the, that's what, we'll be looking for, but I think that, you know, this is not something that's unusual in this, in this population, and so there is the ability, obviously, to inform physicians about that should it occur, but we'll get that data as well.

But you don't, you don't expect anything out of the ordinary just because it's an elderly, population.

I think that was the second part of the question.

No.

No, the answer is no.

No.

Good, thank you.

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

Thank you.

As a reminder, to ask a question, please press star 1-1.

Our next question comes from Greg Savinovich with Mizuho.

Your line is open.

Greg, your line is open.

Please check your mute button.

Hi.

Can you hear me?

Yes.

Now we've got you, Greg.

Go ahead.

Okay.

Thanks so much.

Thanks for taking the questions.

Tony, I was wondering, you know, we've been doing a lot of work on our end with KOLs.

Specifically on amraclidine.

And I'm wondering from the market research that perhaps you have done or the company, has done, have you been able to get a sense from your clinical advisors on whether they're seeing a meaningful difference between what an M1 and M4 compound offers versus an M4 selective compound at the end of the day?

And I'm also wondering if you've gotten any feedback on, at least on the PANS score, especially, ahead of the phase 3 CAR XT readout, like what really is clinically meaningful in terms of what doctors want to see from a muscarinic-based agent in terms of the placebo adjustment on, PANS?

So that question is really around kind of what you're hearing from, you know, clinicians.

And then secondly, I was wondering if you could offer just your thoughts on what we, might be able to see from the phase 3 data for Karuna and what that might mean for amraclidine.

And then my last question just is on the ADP program for amraclidine.

I'm wondering if there are any lessons learned or key takeaways that you've gotten either, from looking at the Acadia experience or how Karuna is running their ADP program.

Thanks so much.

Because it's come up a couple of times in our conversation, JR, I think it'd be useful, to go through the M4 versus the M4, M1 thesis that we're operating with and what you think the relative contribution is.

I know that you've said that you think that it's largely the antipsychotic effect is driven, by the M4, but there might be some additional clarification.

I know that we're always engaged with our strategic thought leaders in a variety of, conversations, but I thought we'd start with the ground truth of what the science has for us and what the science tells us.

And then Ray, we'll lateral to you to talk a little bit about the PAN score.

But JR, if you take that first piece, that'd be great.

Sure.

Thanks, Tony.

And thanks, Greg, for the question.

Yeah, I mean, as you know, Greg, the history here has been that the approach with zanomalene is really one that's gone after the muscarinics.

And as you know, with the non-selective compounds in zanomalene, Lilly was able to show benefits in both the Alzheimer's population, where I mentioned, before that they saw specifically impacts on the, in that study, they were looking at the impact on the psychosis measurements.

And so in that population, they were particularly interested in things like vocalization, outbursts, paranoia, things that have to do with what we understand to be related to hyperdopaminergic activity.

And as you know, in that study, even though it was not well tolerated, the patients that were able to complete that study were benefited in a dose-dependent manner.

So also in the schizophrenia study in a younger population, they also showed benefits in this, you know, the psychiatric, the schizophrenia symptoms that are related more towards the PAM score.

So, you know, what we, what we were able to do with our data, which was the first compound that is actually M4 selective, what you saw was a very similar result to what was seen with the corona compound.

And so with that, to me, what that validates is the fact that M4 selectivity confers the antipsychotic benefit that was demonstrated by xenamoline.

And what we were able to do with an M4 selective compound also was avoid the side effects that caused intolerable side effects that were seen with a non-selective compound.

And so really what we're talking about is looking for the benefit of the muscarinics in treating symptoms that are related to schizophrenia or psychosis.

And as we know, this is related to, you know, the increase in dopamine levels.

And so if you look at where M1 is expressed in the brain, where M4 is expressed, M4 is, really on the neurons that provide input into the dopaminergic system.

M1 is much more broadly expressed and has been a target of interest for cognition.

But the indications that we're looking at are really around the diseases where psychotic symptoms, you know, whether it's measured by the PAN score or whether it was measured by, you know, the earlier study that Lily did where they're looking at specific features in psychosis in Alzheimer's patients, those seem to be more related to dopamine.

And we know that the M4 receptor is selectively expressed in the, you know, highly expressed in the striatum, much more selectively expressed at high levels in that area of the brain that controls dopaminergic activity that can drive the psychiatric symptoms that have been seen in the populations that we're talking about today.

So, you know, I think that, you know, the selectivity question that we've been able to answer with our compound is that M4 by itself can drive an antipsychotic benefit in this study that we reported, and it can avoid the side effects that are seen commonly with compounds that antagonize the muscarinic M1s, for instance, or other muscarinics.

So, you know, I think that, you know, what the data supports today from our point of, view is that M4 selectivity is able to provide an antipsychotic benefit.

We don't believe that the data that was generated by a non-selective compound in the PAN score was different from a compound that's selective. But what we did see that was different between the two types of compounds was that the M4 selectivity did confer a better tolerability profile.

We did not see the GI-related issues.

We did not see the dropouts that were seen previously with zanomaline.

So, really, our belief is it's really M4 is important in driving the antipsychotic benefit.

It's been demonstrated in four different studies by three different sponsors to date, and so we have a lot of confidence in this mechanism.

We think we understand the neural network and the circuitry that drives the psychosis, and we believe that we understand how the pharmacology of the M4 receptor can drive that benefit.

So, with that, I'll turn it over to Ray.

Ray, I'm sorry.

If you could, I was just thinking about the bridge to JR's answer.

I know you, talked to thought leaders quite a bit, you and your team.

Can you just talk a little bit about how well you think both prescribing physicians and thought leaders will appreciate the distinction JR just made, that is mainly about M4 selectivity, and how they might actually view the PANS score standard, if you will, for what good clinical efficacy might be?

And then we'll come back to the other two questions that Greg has.

And then, Operator, I think we will be out of time, so this will be our last question.

Absolutely.

Good morning, Graig.

So, Graig, as you know, historically, on average, the, absolute total PANS reduction for any psychotics, existing any psychotics, has been somewhere between 10 and 15 points. Placebo adjusted about 5 to 10 points.

And so, you know, we have therapies, for any therapy, obviously, we're going to look at that absolute PANS reduction as the placebo response and the variability introduced in these trials, especially as you enlarge them, definitely increases, and it waxes and wanes over time, depending on how many trials you conduct.

But I think, to Tony's point, that there is definitely a need in the landscape for therapies that have a robust anti-psychotic effect, but more importantly, have a side effect or tolerability profile, in terms of metabolic issues, in terms of extrapyramidal side effects, and so forth, that are fairly benign.

And what we're seeing, at least in the data that's been generated to date, is that this is a pathway that can actually have a very impressive side effect profile and much more better tolerated than existing therapies.

But in terms of the efficacy provided that, you know, we're hoping that the efficacy will be as good as, if not better, than what we've seen historically.

And I think the selectivity of this mechanism for emraclidine, as well as the once a day, and no need for titration characteristics of this therapy, I think, speak to the compliance issues and the recidivism that you see in this patient population because of multiple dosing, because of the need for titration, and so forth.

So, we're overall extremely confident, not only with the mechanism, but also with what the data can support and the benefits it'll bring to the landscape.

I think I would just end.

Thank you, Ray.

That was very good and very clear.

I think what I would do, I'll probably just end with the following notion that, obviously, we don't make a practice of commenting on other companies, and we certainly won't speculate about what other companies might be.

Our perspective is that, if we have a success because there's another therapeutic that shows benefits in patients, then we all win.

And on that basis, we will learn as the field evolves, but are really focused not just on emraclidine, but all of the other things that we have ongoing, Darugabad and PANIC, the upcoming epilepsy data readout to Vapidon and Parkinson's, the really exciting program for MDD, the dementia-related apnea.

We have so many things to focus on.

So, we will stay abreast of all of these things.

As to learnings in terms of Alzheimer's, dementia, psychosis, I think we have watched how the agency has responded to other, companies who have explored that potential indication, and obviously, they're incorporating those learnings into our designs and plans.

So, let's stay abreast.

Let's stay tuned.

We'll keep you guys informed as we know more.

Operator, thank you for assisting us today.

Thank you, team, for the excellent work, and thank you each for listening to us.

We've just, passed the hour.

We appreciate your time and your support, and we will look forward to future updates.

Thank you, guys.