Q3 2021 Praxis Precision Medicines Inc Earnings Call

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Operator: Good morning, and welcome to Praxis' third quarter 2021 update call. As a reminder, this call may be recorded. I would now like to turn the call over to Alex Kane, Vice President of Investor Relations and Corporate Communications. Thank you. Good morning, everyone.

Ladies and gentlemen, your conference is scheduled to begin momentarily. Please continue to standby and thank you for your patience.

[music].

Alex Kane: And thank you for joining us today to discuss Praxis's third quarter 2021 corporate update. With me on today's call is our President and Chief Executive Officer Marcio Souza, our Chief Medical Officer Bernard Ravino, and our Chief Financial Officer Tim Kelly. Please note that today's prepared remarks will focus on recent business and pipeline progress along with a brief update on our third quarter 2021 financial results. We will be referring to accompanying slides throughout today's prepared remarks, which are posted on the events and presentation section of our Investor Relations website. So please access them now if you have not already done so.

Yeah.

Good day and welcome to practice third quarter 2021 update call as a reminder, this call maybe recorded.

Alex Kane: Before we proceed, I would like to remind you that during today's call, we will be making certain statements that are beliefs, forward-looking, and subject to various risks and uncertainties. Any statements made during this call that are not statements of historical or current facts are intended to be forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. We want to emphasize that such forward-looking statements reflect our current expectations, assumptions, and currently available data regarding, among other things, our business operations, development efforts, and regulatory strategy, and are neither predictions nor guarantees of future events. However, actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with our business.

I'd now like to turn the call over to Alex Kane, Vice President of Investor Relations and corporate communications.

Thank you and good morning, everyone and thank you for joining us today to discuss practices third quarter 2021, corporate update with me on today's call is our president and Chief Executive Officer, Marcio Souza, Chief Medical Officer, Bernard Rubino, and our Chief Financial Officer, Jim Kelly.

Please note that today's prepared remarks will focus on recent business and pipeline progress along with a brief update on our third quarter 2021 financial results we.

We will be referring to supplement slides throughout today's prepared remarks, which are posted on the events and presentations section of our Investor Relations website. So please ask them now if you have not already done so.

Before we proceed I would like to remind you that during today's call, we will be making certain statements that are beliefs forward looking and subject to various risks and uncertainties and.

Any statements made during this call that are not statements of historical or current facts are intended to be forward looking statements pursuant to the safe Harbor provisions of the private Securities Litigation Reform Act of 1995.

I want to emphasize that such forward looking statements reflect our current expectations assumptions and currently available data regarding among other things our business operations development efforts and regulatory strategy and are neither predictions nor guarantees of future events.

Actual results could differ materially from those stated or implied by these forward looking statements due to risks and uncertainties associated with our business.

Alex Kane: For additional detail on the risk factors associated with our business, I encourage you to consult the detailed forward-looking statement and disclaimer on slide two of the supplement slides, as well as our SEC filing. I will now turn the call over to Marcio.

For additional detail in the risk factors associated with their business I encourage you to consult the detailed forward looking statements disclaimer on slide two of the supplemental slides as well as our SEC filings.

Marcio Souza: Hey, thank you, Alex. And good morning, everyone. Thanks for joining the call today. It's great to be here, and we're glad to share our recent progress and what's to come with all of you. Last month Praxis celebrated its one-year anniversary as a public company on the Nasdaq Stock Exchange. Looking back at where we were a year ago, it's natural to take inventory of how far we've come.

I'll now turn the call over to Marcia Marcia.

Hey, Thank you Alex and good morning, everyone.

Thanks for joining the call today.

It's great to be here and we are glad to share our recent progress and what's to come with follow up here.

Last month <unk> celebrated its one year anniversary as a public company on the NASDAQ stock exchange.

Looking back at where we were a year ago, it's natural to take inventory or how far would come.

Marcio Souza: As a company, we've been able to make significant progress towards the goal of bringing a number of CNS drugs to people in need and have positioned Praxis to do it over and over again. We have a saying here at Praxis, and one that you'll hear more and more in the coming months, "There for more." While we are proud of how far we've come in the past year, we dare for more in every aspect of what we do, from ourselves in our everyday work, to the patients we're working so hard for, and across the portfolio we are building and advancing every day.

As a company we've been able to make significant progress towards the goal of bringing a number of CNS drugs to people needs and have positioned practices to be able to do it over and over again.

We have a saying here practice and one that you'll hear more and more in the coming months.

For more.

While we are proud of how far we've come in the past year.

Dan or more in every aspect of what we do.

From our sales and our <unk>.

Everyday work.

For the patients we are working so hard for.

Marcio Souza: Praxis' foundational approach to drug development is the key to our ability to advance multiple programs so efficiently. This foundational approach is based on four pillars, which you will see on slide three, and they underlie each one of our programs.

And across the portfolio, we are building and advancing every day.

Practice foundational approach to drug development is the key to our ability to advance multiple programs so efficiently.

This foundation approach is based on four pillars.

Which you will see on slide three.

And date underlie each one of our progress.

Marcio Souza: First, we validate targets through genetics. While these principles apply to all our programs, our Lead Preclinical Program and ASO Candidates for Praxis 222 provide an ideal example. Praxis 222 targets mutations in the SCN2A gene, which can cause a rare and devastating epileptic encephalopathy.

First we validate targets through genetics.

While these principles apply to all of our progress.

Our lead preclinical product and they are so candidates for practices to two two.

Provides an ideal example.

Proxies to tier two targets mutations in the <unk> gene, which can cause a rare and devastating epileptic encephalopathy.

Marcio Souza: The second pillar draws upon genetic findings and leveraged translational tools, such as the Latin Cephalogram, or EG, which help inform development by, for example, supporting dose selection and indicating whether the drug is reaching its target. Bernardo highlights this more in depth later when he reviews the initial EEG findings from our Praxis 562 program. The third pillar leverages these learnings and applies them to rigorous and efficiently executed development paths to prove the concept.

The second pillar draws upon the genetic findings and leverage translational too such as of last week I apologize.

G, which help inform developments by for example, supporting dose selection and indicating whether that drug is reaching its targets.

Bernard just highlight is more in depth later when he reviews. The initial EG findings from our <unk> progress.

The third pillar leverage these learnings and apply them to rigorous and efficiently executed development paths to proof of concept.

Marcio Souza: The recent positive trial results for Prax114 provide a strength signal in perimenopause depression, or PMD, supporting our decision to move forward with the phase to be studying women with menopausal and mood symptoms. Finally, the fourth pillar is about implementing patient-guided development strategies. Ultimately, this encompasses everything we do at Praxis, from early-stage research into late-stage developments and eventually commercialization. Patient-guided developments are particularly evident in our lead programs, Praxis 114 in MDG and Praxis 944 in essential trauma, which could both address significant unmet needs for people living with this disorder.

The recent positive trial results, while <unk> one room for provide this strength signal impair mental Paul's depression or PMT.

Watching our decision to move forward with the phase <unk> study in women with menopausal symptoms.

Finally, the fourth dealers about implementing patient guided development strategies.

Ultimately it does encompass everything we do our practice so in early stage research into late stage developments and eventually commercialization.

Patient guided developments, particularly evident in our lead programs <unk>, one for <unk> and <unk> four in essential tremor.

Which could both address significant unmet needs for people living with this <unk>.

Marcio Souza: For Prax114, the potential of a fast-acting antidepressant that takes days, not weeks or months, to show its effects, combined with improved tolerability relative to the existing therapies, would certainly be meaningful for people suffering from depression. For Prax 944, the potential of a new treatment option, ideally developed to be given at daytime when tremor impacts patients' activities the most, holds significant promise.

For <unk>, one for the potential of a fast acting antidepressant that takes days not weeks or months to show the effects combined with improved tolerability relative to the existing therapies would certainly be meaningful for people suffering from depression.

So at <unk> 94 for the potential of a new treatment option.

Really developed to be given a daytime when tremor impacts patients active it's been most holds significant promise.

Marcio Souza: The foundation approach has led to a diverse pipeline that is quickly progressing and growing, as you can see on slide four. I'll point out that each of our three clinical problems is current in or soon to be in trials in multiple indications, which highlights the considerable expansion possibilities within our existing portfolio. In addition, our preclinical pipeline is advanced, and we anticipate the first inpatient trial of Praxis 222 to initiate in the first half of next year, which would add a fourth program to our portfolio. The status of the portfolio is well represented by the following slide, which shows how we expect to have six placebo-controlled trials active by the end of 2021.

The foundation approach has led to a diverse pipeline that is quickly progressing and growing as you can see on slide four.

I would point out each of our three clinical programs with <unk> and our soon to be in trials in multiple indications.

Which highlights the considerably expansion possibilities within our existing portfolio.

In addition.

Our preclinical pipeline is that benzene.

And we anticipate the first in patient trial of <unk> should you choose to initiate in the first half of next year.

Which would add a fourth program to our portfolio.

The maturation of the portfolio is well represented by the following slides.

Which shows how we expect to have six placebo controlled trials active by the end of 2021.

Marcio Souza: This includes the ongoing PRAXIS 114 registration trial area in monotherapy MDD and the dose-ranging a capella study, and Praxis 944 Essential 1 study in ET that has recently initiated. This quarter, we expect to initiate Phase 3 studies for Praxis 1 on 4 in Essential Tremor and PTSD, as well as phase two forcing patient studies for our third clinical progress. Praxis 562, which will focus on rare adult pathology. Slide 6 clearly illustrates what this foundational approach has led to, catalyst-rich periods, which readout upcoming for each of our clinical stage programs in the coming year. Bernard will discuss these trials in depth momentarily.

This includes the ongoing tracks one for registration trial area in monotherapy MTG.

And the dose ranging of Capelli study.

And perhaps 94 essential wanted study in ETE.

Recently initiated.

This quarter, we expect to initiate phase III studies for <unk>, one on Florida in essential tremor and PTSD.

As well as phase two forcing patient studies for our third clinical program.

<unk> hundred 60, <unk>, which will focus in rare adults apologists.

Slide six clearly illustrates why this foundation approach has led to.

Our catalyst reach periods, which readouts upcoming for each of our clinical stage programs in the coming year.

Marcio Souza: Prior to passing the call to Bernard, I want to share that we'll be hosting a Movement Disorders Day in New York City on Friday, December 17. As you can imagine, with multiple programs and trials ongoing in Essential Tremor, the focus will be on our efforts there. We're also going to highlight the opportunities for Praxis 944 as a non-dopaminergic treatment for the motor symptoms of Parkinson's disease and discuss why this is just the beginning for the movement disorders franchise. For E.T., you can expect a comprehensive view of our clinical results today and a look into our market assessment. You'll hear more about the burden faced by people living with potential tremor.

Bernard will discuss this driving that momentarily.

Prior to passing the call to Bernard I want to share that we will be hosting a movement disorders day in New York City on Friday December 17.

As you can imagine with multiple programs and trials ongoing in essential tremor, the focus will be on our efforts there.

We're also going to highlight the opportunity for practice was $9 four as a known dopaminergic treatments for the motor symptoms in Parkinson's disease.

And discuss why this is just the beginning for movement disorders franchise.

Sure.

You can expect a comprehensive deal of our clinical results to date.

And a look into our market assessments.

Marcio Souza: And you'll also provide updates on the developments and regulatory paths for ongoing efforts with both Praxis 944 and 114. We're excited to be making the first advance in pharmacological treatment for essential tremor in over 50 years. Following our Movement Disorders Day in December, we'll be hosting Aware Disease Day and Psychiatry Day in the first half of next year. While there is much to look forward to in the remainder of this year.

Youll hear more about the burdens faced by people living with essential tremor.

And you also provide updates on the developments and regulatory paths for ongoing efforts with both <unk> 94, and one four.

We're excited to be meeting the first advance and pharmacological treatment for essential tremor in over 50 years.

Following our movement disorders day in December we'll be hosting a rare disease day and psychiatry dates.

In the first half of next year.

Marcio Souza: 2022 is all shaping up quite nicely to deliver on our promise to patients and all stakeholders. In the first half of the year, we expect top-line readouts from our ongoing Praxis 114 trials in depression and anticipate starting a phase three study in MDD later next year. We will also share top-line results in the first half of 2022 for the Praxis 562-ASSR biomarker study, which is currently being administered in the United States. Furthermore, in the first half of 2022, we plan to initiate a phase 2 study for Praxis 944 in Parkinson's disease and a phase II trial for Praxis 562 in DE, marking the second indication for each one of those programs.

While there is much to look forward to in the reminder of this year.

2022 results shaping up quite nicely to deliver on our promise to patients and all stakeholders.

In the first half of the year, we expect top line Readouts for.

Our ongoing practice 114 trials in depression.

And anticipate starting a phase III study in Mg.

Later next year.

We also share top line results in the first half of 2020 Q4, the <unk> slide six two asset sorry, biomarker study, which is currently dosing in the United States.

Furthermore, in the first half of 'twenty, two we plan to initiate a phase III study.

Nine four in Parkinson's disease.

In our phase III trial for <unk> six to <unk>.

This marks the second indication for each one of those programs.

Marcio Souza: Finally, we expect to start a Phase 1-2 trial for Praxis 2-2-2 in the first half of next year, which will be the first inpatient study for this program and will be the first ASO in Praxis's portfolio to reach the clinical stage. In the second half of 2022, we can expect stop-line readouts from Praxis 114 in PTSD and ET. Also, we plan to provide top-line results from our ongoing PRAXIS-944 Essential 1 study in ET, which would allow us to initiate a PRAXIS-944 Phase 3 trial in ET before the end of 2022.

Finally, we expect to restart our phase <unk> trial for <unk> Q2, two in the first half of next year, which would be the first in patient study for this program and will be the first ASO in practice portfolio to reach the clinical stage.

In the second half of 2022, we can expect top line Readouts from <unk> 140, PTSD ADT.

Also we plan to provide top line results from our ongoing <unk> nine port for essential one study in each C, which would allow us to initiate a practice nine for phase III trial in <unk>.

Marcio Souza: As you can see, we fully intend to keep up the pace to progress throughout our portfolio. I'll now pass the call over to Dr. Ravina to walk you through our ongoing and upcoming studies, as well as provide a look at Praxis 562 Phase 1 Health Volunteer data, which we just completed. Thanks, Marcio.

Before the end of 2022.

As you can see we fully intend to keep up the pace to progress throughout our portfolio.

I will now pass the call over to Dr. <unk> to walk you through our ongoing and upcoming studies as well as provides a look into the <unk> 560, <unk> phase one how volunteer data, which we just completed.

We're not.

Thanks Marcio.

To Echo Marseilles comments, it's great to be here with you and I'm looking forward to providing more perspective on our clinical studies and the progress we've made this quarter.

Bernard Ravino: To echo Marcio's comments, it's great to be here with you. I'm looking forward to providing more perspective on our clinical studies and the progress we've made this quarter. On slides 8 and 9, we've included the trial designs for the ongoing Prax114 ARIA and Acapellas trials. Both trials are currently enrolling patients, and we're confident in delivering top-line results in the first half of next year. Most of you have seen these slides before, so instead of reviewing all the details, I wanted to briefly call out an important aspect of the trial design for both studies. As you can see, the primary endpoint for these trials is after two weeks, but the blinded treatment period continues out for four. This is critical for two reasons.

On slides eight and nine we concluded the trial designs for the ongoing <unk>, one one for ARIA and Acapella studies.

Both trials are currently enrolling and we're confident in delivering top line results in the first half of next year.

Most of you have seen these slides before so instead of reviewing all the details I wanted to briefly call out an important aspect of the trial design for both studies.

As you can see the primary endpoint for these trials is after two weeks, but the blinded treatment period continues out for four weeks.

This is critical for two reasons.

First we believe that 114 will work rapidly to resolve depressive symptoms.

And that patients need to be treated through an episode of depression to ensure resolution and prevent relapse.

Whether that episode of several weeks or several months.

The design was completed in consultation with the FDA and we believe would allow for demonstration of both fast onset.

And support longer term treatment with <unk> 114.

Second this design is expected to dampen the placebo effect and thereby help separate signal from noise placebo effect tends to be maximal towards the end of the treatment period and in the case of the Orient Acapella studies at the end of the treatment period is two weeks after the <unk>.

Bernard Ravino: First, we believe that 114 will work rapidly to resolve depressive symptoms, and that patients need to be treated through an episode of depression to ensure resolution and prevent relapse, whether that episode is several weeks or several months. The design was completed in consultation with the FDA and we believe would allow for demonstration of both fast onset and support longer-term treatment with Prax114. Second, this design is expected to dampen the placebo effect and thereby help separate signal from noise.

Mary endpoint.

Moving on to slide 10, consistent with our focus on psychiatry, we anticipate starting a phase II proof of concept study of <unk> 114 for the treatment of PTSD in the fourth quarter of 'twenty, one with topline data to come in the second half of 'twenty two.

PTSD impacts an estimated 11 million adults in the U S alone.

There is a marked and growing need that we believe could be addressed by 114.

There's a strong rationale for 114 in this indication based on its mechanism of action and the clinical profile, we've seen to date.

Bernard Ravino: The placebo effect tends to be maximal toward the end of the treatment period, and in the case of the ARIA and Acapella studies, the end of the treatment period is two weeks after the primary endpoint. Moving on to slide 10.

And while we are well aware of the historical challenges in developing treatments for PTSD, we're confident in our approach here.

A natural role of neuro active steroids light cracks 114 is immediately <unk>.

Spots distress.

Deficits and Gaba and narrow active steroids have been documented in patients with PTSD and correlate with clinical symptom severity.

Bernard Ravino: Consistent with our focus on psychiatry, we anticipate starting a phase two proof-of-concept study of PRAX114 for the treatment of PTSD in the fourth quarter of 21, with top-line data to come in the second half of 22. PTSD impacts an estimated 11 million adults in the U.S. alone, and there is a marked and growing need that we believe could be addressed by 114. There's a strong rationale for 114 in this indication, based on its mechanism of action and the clinical profile we've seen to date.

Also <unk> four has shown benefits and stress induced preclinical models of depression and PTSD.

Finally, the rapid onset anti depressant, an anxiolytic effects as well as the improvement in sleep CMO with one four in depression would be clinically very important if replicated in PTSD.

Next I'd like to discuss our practice one one for essential tremor study.

We believe that people with ETE need a medication that is well tolerated. So they can function throughout the day. The goal of this trial is to determine if 114 can improved tremor without tolerability issues when taken during the day.

Our preclinical data and the harmful and model of tremor and EG measures in humans suggests that exposures that correspond to human doses of 10, and 20 milligrams may be effective for tremor.

Bernard Ravino: And while we're well aware of the historical challenges in developing treatments for PTSD, we're confident in our approach. A natural role of neuroactive steroids, like Prax114, is in mediating the response to stress. Deficits in GABA and neuroactive steroids have been documented in patients with PTSD and correlate with clinical symptom severity.

It is important to note that this dose range was well tolerated during the day and previous healthy volunteer studies.

This trial is designed as a three way crossover of a single dose of 10 or 20 milligrams of 114 or placebo and this study will allow us to select the dose and regimen of 114 for subsequent trials.

We're fortunate to have two distinct mechanisms to address the large population, which has a range of treatment needs.

Bernard Ravino: Also, PRAX114 has shown benefits in stress-induced preclinical models of depression and PTSD. Finally, the rapid-onset antidepressant and anxiolytic effects, as well as the improvement in sleep seen with PRAX114 in depression, would be clinically very important if replicated in PTSD. Next, I'd like to discuss our Prax114 Essential Tremors Study. We believe that people with ET need a medication that is well-tolerated so they can function throughout the day. The goal of this trial is to determine if 114 can improve tremor without tolerability issues when taken during the day. Preclinical data in the Harmelin model of tremor and EEG measures in humans suggest that exposures that correspond to human doses of 10 and 20 milligrams may be effective for tremor.

And our lead movement disorders program <unk> 904, four we've made good progress across three clinical trials for <unk>.

We previously reported dose related pharmacodynamic effects of 94, four on EG from about five to 120 milligrams, suggesting a broad therapeutic range.

In part a of our phase Iia <unk> study in <unk> patients, which SaaS doses of 20, and 40 milligrams, we saw reduction in tremor amplitude and the arms of over 40%.

We will report preliminary open label data from part B later this year assessing doses of up to 120 milligrams titrated over about four weeks.

Complete data from the open label and the randomized withdrawal period of part B will be released in the first half of 'twenty two.

In parallel to these studies, we've assessed the safety and Tolerability of up to 120 milligrams.

<unk> 94 for in a faster turn date titration regimen in healthy volunteers in the phase one study.

This faster titration regimen confirmed the previously reported safety profile with no SaaS or dose limiting toxicities.

And we believe the results of this study will support flexibility in dosing for patients going forward.

Bernard Ravino: It's important to note that this dose range was well tolerated during the day in previous Healthy Volunteer studies. This trial is designed as a three-way crossover of a single dose of 10 or 20 milligrams of 114 or placebo. In this study, we'll allow us to select the dose and regimen of 114 for subsequent trials. We're fortunate to have two distinct mechanisms to address the large ET population, which has a range of treatment needs. In our LEAD Movement Disorders Program, PRAX 944, we've made good progress across three clinical trials for E.T. We previously reported dose-related pharmacodynamic effects of PRAX 944 on EEG from about 5 to 120 mg.

Based on the overall safety profile pharmacodynamic effects and encouraging preliminary efficacy we've initiated the essential one phase two b trial Sn.

Essential one is a randomized double blind placebo controlled dose ranging trial that will assess the safety tolerability and efficacy of 2016, and 120 milligrams of $90 four in patients with moderate to severe <unk>.

We expect top line data from this study in the second half of next year, which will support the design of our phase III trials expected to start before the end of 'twenty two.

Moving on to our rare disease portfolio, we have completed the phase one sad mad and food effects studies for <unk> $5 62.

Consistent with the mechanism of action and our preclinical data <unk> two was well tolerated.

Over 14 days of dosing there were no drug related aes or severe aes.

Over 90% of the treatment emergent adverse events were mild and they were generally transient around the time of C. Max.

<unk> 562 showed generally dose proportional PK peak concentrations were seeing two to three hours after dosing.

The half life of four to five days with no appreciable food effect.

The highest single dose of 560 <unk> studied was 150 milligrams and the highest multiple dose was 120 milligrams for 14 days.

Bernard Ravino: Suggesting a broad therapeutic range, in Part A of our Phase 2a PRAX 944 study in ET patients, which assessed doses of 20 and 40 milligrams, we saw a reduction in tremor amplitude in the arms of over 40 percent. We will report preliminary open-label ET data from Part B later this year, assessing doses of up to 120 milligrams, titrated over about four weeks. Complete data from the open label and the randomized withdrawal period of Part B will be released in the first half of 2022.

Importantly, we achieved exposures that are well in excess of those needed for efficacy based on the preclinical data in epilepsy models.

Additionally, we saw a dose related trend and over 50% reduction at the highest dose of <unk> on our exploratory biomarker of auditory steady state response.

As with our other programs, we've used EEG to measure effects on iron channels and in this paradigm, we measured the EEG in response to an auditory stimulus.

Bernard Ravino: In parallel to these studies, we assessed the safety and tolerability of up to 120 milligrams of Prax944 in a faster 10-day titration regimen in healthy volunteers in a Phase I study. This faster titration regimen confirmed a previously reported safety profile with no SAEs or dose-limiting toxicity.

These clinical findings on SSR are consistent with our preclinical data where assets are changes tended to occur at exposures well above the EC 50 in epilepsy models.

We've started a follow up healthy volunteer study in the U S intended to confirm and extend the SSR pharmacodynamic bindings over four weeks of dosing, which will approach steady state concentrations or $5 62.

Bernard Ravino: And we believe the results of this study will support flexibility in dosing for ET patients going forward. Based on the overall safety profile, pharmacodynamic effects, and encouraging preliminary efficacy, we've initiated the Essential 1 Phase 2B trial. Essential One is a randomized, double-blind, placebo-controlled, dose-ranging trial that will assess the safety, tolerability, and efficacy of 20, 60, and 120 milligrams of 944 in patients with moderate to severe ET.

We expect to report topline results from this trial in the first half of 'twenty two.

The phase one data and the ongoing follow up studies give us confidence in the safety and Tolerability profile of $5 62.

What we believe is a therapeutic dose range.

Based on these encouraging data before the end of this year, we plan to initiate a phase II trial in adult <unk> with a cohort of selling and soon a patients.

Cohort of trigeminal neuralgia patients.

We also plan to start a practice <unk> phase II trial for the treatment of developmental epileptic encephalopathy or <unk> in the first half of 'twenty two.

As you've heard there's been tremendous progress across our portfolio.

Bernard Ravino: We expect top-line data from this study in the second half of next year, which will support the design of our phase three trials expected to start before the end of 2020. Moving on to our rare disease portfolio, we've completed phase one SAD, MAD, and food effect studies for PRAX562. Consistent with the mechanism of action and our preclinical data, 5.6.2 was well tolerated. For example, over 14 days of dosing, there were no drug-related SAEs or severe AEs.

We're excited to report our continued progress in the coming months as we've read out a number of these trials.

I'll now turn the call over to Tim for an update on the financials for the quarter Tim.

Thanks, Bernard and good morning, everybody I'm glad to join you all today.

We'll focus on the key financial updates for the third quarter and would refer you to this morning's press release and our 10-Q on file with the SEC for a comprehensive review of the third quarter financial results.

As of the end of the third quarter practice had $314 million in cash and investments, which.

Which is expected to fund operations into the second quarter of 2023 and through the trials and data Readouts discussed on today's call.

This compares to $339 million as at the end of the second quarter of 2021 quarter over quarter decrease.

Bernard Ravino: Over 90% of the treatment-emergent adverse events were mild, and they were generally transient around the time of CMAC. Praxis 5.6.2 showed generally dose-proportional PK. Peak concentrations were seen two to three hours after dosing. We observed a half-life of four to five days with no appreciable food effects.

Of approximately $25 million.

With the breadth of portfolio that practice has developed one way that we dare for more.

Two leveraging our strong cash position efficiently and effectively.

Advanced a quickly growing pipeline.

Operating expenses for the third quarter were approximately $44 $8 million, an increase of roughly $8 $3 million from the prior quarter, which is in line with our internal assumptions on expense growth as our portfolio advances.

Bernard Ravino: The highest single dose of 5, 6, 2 studied was 150 milligrams, and the highest multiple dose was 120 milligrams for 14 days. Importantly, we achieved exposures that are well in excess of those needed for efficacy based on preclinical data in epilepsy models. Additionally, we saw a dose-related trend of over 50% reduction at the highest dose of 5.62 on our exploratory biomarker of auditory steady-state response. As with our other programs, we've used EEG to measure effects on ion channels, and in this paradigm, we measured the EEG response to an auditory stimulus. These clinical findings on ASSR are consistent with our preclinical data, where ASSR changes tended to occur at exposures well above the EC50 in an epilepsy model.

The quarter over quarter increase in operating expenses was primarily driven by higher R&D expenses during the third quarter.

Related to ongoing and soon to be initiated clinical trials.

These R&D expenses comprise roughly 75% of third quarter operating expense.

And approximately 89% of the growth from the second quarter with.

With the remainder being G&A expenses.

The difference in operating expenses and cash and investments.

Over quarter was primarily due to an increase in R&D accruals as well as noncash charges for stock based compensation expense.

I'll now turn the call back to Alex to cover Q&A with the operator.

Thanks, Pam and thank you to everyone today.

For the Q&A session, we would ask that you limit yourself to one question. Initially you have follow up questions. Please feel free to return to the queue.

With that operator, please feel free to open up the line for questions.

Thank you as a reminder to ask a question Thats Star one.

First question comes from <unk> <unk> with Cowen Your line is open.

Good morning, guys. Thanks for taking the question.

Talk about how youre looking at some of the other endpoint from the ARIA Acapella study.

Bernard Ravino: We started a follow-up healthy volunteer study in the U.S. intended to confirm and extend the ASSR pharmacodynamic bindings over four weeks of dosing, which will approach steady-state concentrations for 5-6-2. We expect to report top-line results from this trial in the first half of 2020. The Phase I data and the ongoing follow-up study give us confidence in the safety and tolerability profile of 5-6-2 at what we believe is a therapeutic dose rate. Based on these encouraging data, before the end of this year, we plan to initiate a phase 2 trial in adult cephalgias with a cohort of sunken insuna patients and a cohort of trigeminal neuralgia.

You guys could walk us through why you're anticipating placebo again.

Mitigated.

But one of the other Gaba agents have decided.

Different trial design to elevate suite as well are you going to be considering.

Elevating day, three does that make sense given the chronic treatment paradigm in these two studies.

How do you think about that sort of ultra SaaS.

Lead time points.

Alright. Thank you. Thank you Richard Thank you so much for the question and.

It should be up from here.

So.

Maybe go back and remind everyone about what's the expectation here right four largest trials from our perspective would be pretty cost expense.

The development of Gaba.

Agents for depression, so quick.

We expect them to start acting fairly fast.

So in that regard to make sense just see as we discussed on the prepared remarks, just the action pretty fast like enough in a matter of days.

But we do expect that effect to maximize anywhere around like seven to 10 days or so as we've seen before.

Bernard Ravino: We also plan to start a PRACT-562 Phase 2 trial for the treatment of developmental epileptic encephalopathies, or DEEs, in the first half of 2022. As you've heard, there's been tremendous progress across our portfolio. We're excited to report continued progress in the coming months as we read out a number of these trials. I'll now turn the call over to Tim for an update on the financials for the quarter. Tim?

But quite importantly.

The fact that patients will only benefit certainly benefits our holistically benefit if I may if we kept been on drug for longer.

And Thats, what Bernard discussed a little bit on his part of the of the script today in terms of going for four.

Four weeks of our trial and that would allow us directly those have already been longer and.

In the commercial setting for Abra gap, there hopefully well.

So we don't have any plans for maintenance should be a little bit more pointed on your question. We don't have any plans to change the endpoints right now those war based on the preclinical and clinical data, we have and on the treatment rationale they were well discuss.

With the FDA and we're going to go the right way to treat depression, we're not we're not trying to salvage the dry or tried to gas Beth.

Tim Kelly: Thanks, Bernard. And good morning, everybody. I'm glad to join you all today.

You could be registrational and youll help patients needs.

Got it thanks for taking the question I'll hop back in the queue.

Tim Kelly: I will focus on the key financial updates for the third quarter and would refer you to this morning's press release and our 10Q1 file with the SEC for a comprehensive review of the third quarter financial results. As of the end of the third quarter, Praxis had $314 million in cash and investment, which is expected to fund operations into the second quarter of 2023 and through the trials and data readouts discussed on today's call.

Thank you. Thank you.

Our next question comes from Yasmin Rahimi with Piper Sandler Your line is open.

Hi team. Thank you so much for hosting the call and thank you for taking my questions.

Team maybe.

Tim Kelly: This compares to $339 million as of the end of the second quarter of 2021, of approximately $25 million. With the breadth of the portfolio that Praxis has developed, one way that we dare for more is through leveraging our strong cash position efficiently and effectively to advance the quickly growing pipeline. Operating expenses for the third quarter were approximately $44.8 million, an increase of roughly $8.3 million from the prior quarter, which is in line with our internal assumptions on expense growth as our portfolio advances.

Synaptic Gaba a receptors versus synaptic we really have not seen anything like next day somnolence.

In our depression population or in the healthy volunteers, who were dose. So it's been very well tolerated across the board there is a little bit of a hypnotic effect at night time, which is desirable, but it's short lived around C. Max in terms of where it occurs with respect to dosing.

Tim Kelly: A quarter-over-quarter increase in operating expenses was primarily driven by higher R&D expenses during the third quarter related to ongoing and soon to be initiated clinical trials. These R&D expenses comprise roughly 75% of third quarter operating expenses and approximately 89% of the growth from the second quarter, with the remainder being G&A expenses. The difference in operating expenses in cash and investments, quarter over quarter, was primarily due to an increase in R&D accruals, as well as non-cash charges for stock-based compensation expenses.

And our goal.

As variable in general we tended to see people experiencing solid months, if they were going to upfront, but it can occur overnight. So.

We don't see any tolerance Asian to treatment effects. So again it generally occurs upfront if people are going to have.

That side effect, but it can less glass through the dosing period, we certainly have not seen any pattern.

Cumulation or worsening as people continue to take it.

Thank you Bernard and then I apologize just a quick follow up in your guidance.

Coming.

Open label cohort from 94 four.

Alex Kane: I'll now turn the call back to Alex to cover Q&A with the operator. Thanks, Tim. And thank you to everyone today. For the Q&A session, we would ask that you limit yourself to one question initially. If you have follow-up questions, please feel free to return to the queue. With that, operator, please feel free to open up the line for questions. Thank you.

That's expected in this quarter is just kind of remind us like how many piece.

Patients what type of data should we be seeing what.

Yes.

How should we be how should we be looking at this upcoming dataset or are we looking for consistency versus the six patient data that we have seen so far can you. Just orient ahead of this catalyst could be very helpful for us. Thank you.

Yes.

Thanks, a lot. So we will be presenting data from the open label portion of part B, So up to a 120 milligram and then.

Operator: Thank you. As a reminder to ask a question, that's star number one.

Ritu Subhalaksmi Baral: Our first question comes from Ritu Baral on behalf of Cowan. Your line is open. Good morning, guys. Thanks for taking the question. I wanted to ask you about how you look.

In the first half of next year, we'll have the complete data set of the randomized withdrawal. So there'll be some placebo comparator there what we'll be looking for what we'll be presenting is really the same kind of data you saw from part a with a focus on upper limb tremor, we think thats. The most important aspect of tremor and the most of it.

Wisely measured in terms of.

What we are looking for out of the data and this was really overall, Matt has a safety check for us in terms of titration of higher doses. We have seen what we have seen at 40 milligrams was really very robust improvement.

Ritu Subhalaksmi Baral: at some of the other endpoints in the ARIA and Acapella study. You guys did walk us through why you're anticipating placebo being mitigated. But one of the other GABA agents has decided in a different trial design to elevate day three as well. Are you going to be considering elevating day three?

Tremor control in the hands just over 40%.

We may or may not.

See more than that in the small cohort like this.

But certainly 40% or in that ballpark similar to what we saw with 40 milligrams would be very consistent.

Ritu Subhalaksmi Baral: Studies. How do you think about this sort of ultra-fashion? Early Time Points.

And certainly enough to move forward with.

Marcio Souza: Thank you. Thank you, Ritu.

And maybe just to add smaller market from a question about the patient numbers that we expect so as we mentioned.

Marcio Souza: Thank you so much for the question and it's nice to hear from you. So let's maybe go back and remind everyone about what's the expectation here, right, for these trials. From our perspective, we've been pretty consistent in how we see the development of GABA agents for depression. We expect them to start acting fairly fast, so in that regard, it makes sense to see, as we discussed in the prepared remarks, action pretty fast, like in a matter of days.

We expect that you roll 12 patients in this cohort.

Mike, It's probably obvious that we can.

We're like moving dissipation along.

Later in daycare to discuss on one November December I apologize for that September 17, New York I'm going to give a comprehensive policy the program, including any other data that we might have at that point in time some form.

Just wanted to call that part of the question staying incredibly pumped about this supra.

Cited about nine performed to potentially has.

Great. Thank you so much for taking my questions. We're looking forward at CBOE.

Likewise.

Marcio Souza: But we do expect that effect to maximize anywhere around 7 to 10 days or so, as we've seen before. But, quite importantly, we also expect that patients will only benefit, truly benefit, or holistically benefit, if I may, if we keep them on drugs for longer. And that's what Bernard discussed a little bit on his part of the script today, in terms of going for these four weeks as our trial, and that would allow us to actually do those things for even longer in the commercial setting, if we ever get there. Hopefully, we will.

Thank you.

Question comes from Laura Chico with Wedbush Securities. Your line is open.

Hey, good morning, guys. Thanks, very much for taking the question.

I guess I'll stay on the one on <unk>.

One question for you on the Acapella study and I apologize if I missed this in the opening remarks, but could you remind us kind of.

More about the powering assumptions here and what would be a positive outcome from acapella.

<unk>.

So I can tell it's not powered for efficacy and I want to be clear about that and maybe we're not that clear into SaaS right. So the way. We're looking through this program maybe to give a general overview.

ARIA is a phase III registrational.

Registrational trial, when we talk to the FDA. They didn't agree with funds that we could explore and lower dose in a different trial.

Marcio Souza: So we don't have any plans to maybe be a little bit more pointed on your question. We don't have any plans to change the endpoints right now. Those were based on the preclinical and clinical data we have, and on the treatment rationale. They were well discussed with the FDA, and we believe they're the right way to treat depression. We're not trying to salvage this trial.

And Thats, what we are doing.

And basically the going assumption there is that the.

Might be a lower dose of 40 milligrams per day or approximately one four that generate similar or the same effects, but with lower side effects and thats kind of the going assumption there. So I'm looking for trends in terms of adults our LNG.

More typical phase II dose ranging.

Study, obviously, we're putting all the controls in place on the quality measures, we're using like conversion benefits verification and so on so we shouldnt be able to trust. The data comes out of that but the real I'll say efficacy Bath is on Q1, three our ARIA that is coming up starting the year.

Marcio Souza: We're trying to get that to be registerable and to help patients in need. Got it. Thanks for taking the question. I'll hop back in the queue.

Thanks Marcia.

Cox.

Thank you. Our next question comes from Myles Minter with William Blair. Your line is open.

Yasmeen Rahimi: Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Hi, team. Thank you so much for hosting the call. And thank you for taking my questions. Team, maybe a good place to start would be just to understand

Hey, guys. Thanks for taking the question just on non full floor in the sausage pricing price one study conducted.

Can you just sort of frame for us what the nausea.

Rates were and whether there was sort of <unk> limited.

Relative to the titration schedule that you're using in the upcoming <unk> data that you're going to disclose.

Yasmeen Rahimi: What, as you pointed out in the RES study, your...

And are you using as fast the titration schedule in the essential one phase two trial.

<unk>.

Good models, and I'll start and I'll hand over to Bernard So.

Yasmeen Rahimi: Key secondary endpoints are going to be at the 29 as well, so patients have been dosed for over a month. I guess, you know, what do we know about sort of the cadence of somnolence and sedation when we look between

As part of the question is no we are not using the scaffold the way Youre looking to the fast migration study that are exempt.

When you are planning for a like blockbuster type of drug as we are thinking about $9 four to be kind of like look I had several years and ask how physicians are going to use what is the expectation in terms of a patient shows up to the clinic or what it's going to be important for them and thats why the SaaS by tradition.

Yasmeen Rahimi: you know, treatment duration at week two versus continued duration over to one month. And I think that's going to be really important because a lot

<unk> for US you have a younger cohorts in an older cohort.

Yasmeen Rahimi: Marketing, Kambiz Pashneh, Daniel Friedman, Asim Rahimi, Alex Kane, Marcio Souza, Joon Lee, Steven Petrou, Kambiz Pashneh, Daniel Friedman, Asim Rahimi, Alex Kane, Marcio Souza,

That study is for younger and older than 50 years of <unk>.

And we've seen very comparable safety, we're able to dose up to 120 on both cohorts.

On the SaaS so in that regard check all the marks.

You wanted there.

Essential one had started.

As you know we're trying to run this broadening farnell out like and accelerate as much as possible should be clear from all of our press release, but we do have that try to stop in the Midwest. We do have patients enrolled on that trial. So it's moving quite nicely. So we don't expect to slow that down or the new penetration now we.

Bernard Ravino: Absolutely, and I'm going to ask Bernard to discuss the state's profile that we see on 1.1.4 and address your question. Yeah, thanks for the question, Ed.

Bernard Ravino: As you've seen before, we have a very well tolerated profile overall, and we believe that due to the relative preference for extra synaptic GABA receptors versus synaptic, we really have not seen anything like next-day somnolence. In our depression population or in the healthy volunteers who were dosed, so it's been very well tolerated across the board. There is a little bit of a hypnotic effect at nighttime, which is desirable, but it's short lived around C-max.

<unk> come back already been part of phase III that we expect to initiate next year and implement that but not for essential one right now I'll now hand over to Bernard talk a little bit about the tax profile in general.

The safety profile with some of the SaaS or titration was really very similar to what we saw with the original titration 94, four 105 study where are we titrated up over about a month.

What is overall tells us is that.

We've said before it people tend to have knowledgeable business when they start out.

And then they don't seem to really have issues as they titrated up.

Bernard Ravino: In terms of where it occurs with respect to the dosing interval, it's variable. In general, you know, we tended to see people experiencing somnolence if they were going to take it upfront, but it can recur overnight. So we don't see any tolerance to treatment effects. So again, it generally occurs up front if people are going to have that side effect, but it can last throughout the dosing period. We certainly have not seen any pattern of accumulation or worsening as people continue.

So we'll enhance those data a bit more the movement Sowders day in December but overall the profiles are looking the same with the longer or shorter titration. So the big picture like Marcio was getting at is it's going to allow people flexibility for how quickly they want to or need to get up to higher doses.

Yeah.

Yeah.

Makes sense, thanks, I'll hop back in the queue.

Thank you. Thank you.

I have a follow up with <unk> with Cowen Your line is open.

Hi, guys. Thanks for taking the follow up.

Got it.

You can move to.

PTSD.

And the rationale.

Four.

For one for AEP, PSB, especially marci.

Marcio.

And Bernard you were talking about anxiety.

Yasmeen Rahimi: Thank you, Bernard. And then, I apologize, just a quick follow-up in regards to the upcoming open label cohort from 944 that's expected this quarter.

Is the how is anxiety sort of moving into the caps five.

I know there's various domains.

But it's not I.

I feel like there is.

And variety components to certain questions in certain sub domains and not others I'm just wondering if there are certain sub domain.

Yasmeen Rahimi: Just kind of reminds us.

Yasmeen Rahimi: Patients. What type of data should we be seeing? What?

I think one four could improve the most within the cap spot.

Yasmeen Rahimi: How should we be looking at this upcoming data set? Are we looking for consistency versus the six patient data that we have seen so far? So if you could just orient us ahead of this catalyst, it could be very helpful for us. Thank you.

Yeah. So the.

Really excited about the just the rationale, particularly strong for a Gaba Pam.

Especially one with an extra synaptic preference.

Given that Benzos don't work, particularly well and Pts and a lot of people actually avoid them as part of the treatment regimen.

The overall rationale of those right.

Endogenous neuro active steroids like <unk> NAND alone are involved in modulating the response the stress modulate.

Bernard Ravino: So we'll be presenting data from the open-label portion of Part B, so up to 120 milligrams. And then in the first half of next year, we'll have the complete data set with the randomized withdrawal. So there'll be some placebo comparator there. What we'll be looking for, and what we'll be presenting is really the same kind of data you saw from Part A, with a focus on upper limb tremor. We think that's the most important aspect of tremor and the most reliably measured.

Access so there's really good experimental data.

And you get reduction in GAAP.

<unk> NAND alone.

In PTSD internationally correlates with clinical symptom severity in some studies.

So in terms of what we're expecting to see the caps five as the 30 items scale, it's actually pretty complicated in terms of the different factors that cut across there, but cutting across many of the items are.

Comment features of anxiety worry and avoidance.

As well as like just for Ya depressive symptoms.

And <unk>.

Bernard Ravino: In terms of what we are looking for out of the data, this was really meant as a safety check for us in terms of titrationing on higher doses. We had seen that what we had seen at 40 milligrams was really very robust improvement of tremor control in the hands, just over 40%. We may or may not, you know, see more than that in a small cohort like this. But certainly 40% or in that ballpark, similar to what we saw with 40 milligrams, would be very consistent and certainly enough to move forward with.

And so we're not focusing on any particular domain. We're looking at the overall caps. Five is this is phase two exploratory study. So we will learn if particular domains.

As they are captured in the caps five come out, but I expect it will.

Benefit, we'll see what kind of cut across the domains that will show up in the overall score the other factor in there is sleep.

There are a whole range of different kind of sleep impairments.

Just regular than some nightmares that might be improved 114. So we're looking broadly, but we expect to learn a lot from this drop.

Got it.

Bernard Ravino: And maybe just to ask part of your question about the patient numbers that we expect. So, as we mentioned before, we expected to enroll 12 patients in this cohort. Like, it's probably obvious that we did. And we're just moving this patient along.

The overall prevalence of sleep disorders.

Within within PTSD.

Any sort of.

Files of the sleep disorder that might for whatever reason.

Hunter you indicate on Gaba.

You mentioned that.

Not really.

Okay.

Could you could you go into why.

Yes, it's incredibly prevalent.

Return the <unk> equity interesting is while we have.

Yasmeen Rahimi: Great. Thank you so much for taking my questions. We're looking

One of our clinic clinicians banking companies.

Yasmeen Rahimi: Thank you so much for taking my questions. We're looking forward to seeing you in New York.

Hello, Paul MGH, we can have a power ship program, which then that focus on is lead.

Laura Kathryn Chico: Thank you. Our next question comes from Laura Chico with Red Bush Securities. Your line is open.

Eric.

<unk>, specifically, so it's something we've been looking quite closely.

And obviously the patterns change depending on the patient and so on but it's pretty dramatic impact it has and to the point that we always discuss is about all the conditions other mood disorders. This when it's least becomes primary to the condition versus secondary rights like are you like tier one all the time or heavy model.

Laura Kathryn Chico: Good morning, guys. Thanks very much for taking the question. I guess I'll stay on the 114 track. One question for you on the Acapella study, and I apologize if I missed this in the opening remarks, but could you remind us kind of more about the powering assumptions here and what would be a positive outcome from Acapella?

<unk> didn't sleep forces modestly because of that so that is central.

The condition in our deal.

Being able to really ease into it versus not feeling okay. All the time like and we're not mentioned Benzos here I think that's the biggest problem there.

Marcio Souza: Thank you. You are.

Marcio Souza: Hey Laura, so Acapella is not powered for advocacy. And I want to be clear about that. And maybe we weren't that clear in the past, right? So the way we're looking at this program, maybe to give a general overview as ARIA as a Phase 2-3 trial is our first registrational trial. When we talked to the FDA, they did agree with us that we could explore a lower dose in a different trial. And that's what we are doing in Acapela.

Just don't do okay at any time with it.

Seems to be quite important differentiator for us.

Go back to the preclinical models when you were talking about distinguishing fear just.

That is a huge rationale for us on this but we're not anything to add there just say that the sleep connection.

Kind of comorbid with depression stress disorders, like PTSD and conditions like Peri menopausal depression.

But it's very common.

A lot of people actually think the sleep disorder start first in our vulnerability.

But it would be something that would be a good thing for us to follow up on more and break it out in some more detail in terms of the different kinds of sleep disruption is going to be you can do that our psychiatry day.

Got it thanks for taking the follow up guys.

Alright anytime.

Marcio Souza: And basically, the going assumption there is that there might be a lower dose than 40 milligrams per day of PRAXIS-114 that generates similar or the same effects but with lower side effects. And that's kind of the going assumption there. So, we're looking for trends in terms of a dose-ranging, kind of a more typical Phase 2 dose-ranging study. Obviously, we are putting all the controls in place, all the quality measures. We're using, like, eligibility verification and so on. So, we should be able to trust the data that comes out of that. But the real, I would say, efficacy best is on Q13 or ARIA that is coming up.

Thank you. Our next question comes from <unk> Ahmad with Bank of America. Your line is open.

Hi, good morning, Thanks for taking my question.

Sorry, if this is part of this question has already been asked before but.

So as far as the Central Tremor study is concerned I think youre going to be releasing data in two tranches.

Talk a little bit about what can we expect for this quarter I'm.

I'm, assuming the bigger data released in the next year what additional data.

Should we expect to see in totality and what's going to be your far for what you think is good enough to move forward overall. Thank you.

Absolutely announced and so on.

I'll break it down like did see a what do we expect north as Bernard mentioned that is not a lot more to be done in terms of tremor reduction when you're welcome to amplitudes goes there is a floor in fact on the Paas risks so when you're looking to the 40% of our so that we had before.

We think that Thats like outstanding and if you work down on that ballpark that would be great.

Miles Menter: Thank you. Our next question comes from Miles Mentor with William Blair. Your line is open.

For the next 12 patients are more that are going to be showing up in the next few months.

For next year, we're looking for like a number of things right and this is would be earlier in the year. So one is the more complete datasets like as many patients that had completed the trial at that point in time the activities of daily living that we are also measuring we've been doing some work like exploring some.

Miles Menter: Hey guys, thanks for taking the question. Just on 944 and the faster titration phase 1 study you conducted, can you just sort of tell us what the nausea rates were and whether they were sort of titration limited there relative to the titration schedule that you're using in the upcoming open-label data that you're going to disclose? And are you using this faster titration schedule in the essential 1 phase 2 trial? Thanks. Good morning.

Like Biomarkers like digital Biomarkers, and who wants to talk a little bit more about that as well and how that would enable the phase III program.

Quite importantly, how much patients come back to baseline after discontinuation right and Thats the randomized withdrawal phase.

That's right and that's why we need to wait a little bit longer to wrap that up that part is blinded. So it requires a little bit different type of treatments and why we are going to be showing that at the beginning of the year, our going hypothesis is that.

It's going to be a relatively slow coming back because this is a more fundamental change to the network monitoring not simply reducing tremor, but again, we're going hypothesis.

Marcio Souza: I'll start, and I'll hand over to Bernard. So, the easiest part of the question is, "No, we are not using this schedule." The way to look into the fast titration study that we did is when you are planning for a blockbuster type of drug, as we are thinking about 944-2B, you've got to look ahead several years and ask how physicians are going to use it, what is the expectation in terms of a patient showing up to the clinic, what is going to be important for them, and that's what the fast titration study was for us.

That's the oscillations are being re <unk> modulator.

In sum our fundamental treatment for essential tremor is like probably module may I say.

In terms of how they bring as wires. So it might actually be that would create a more constant is states of reduction and thats why we are trying to explore on this.

This driver for the second one for essential one that we used to call non port <unk> and now the name is essential one that is a more typical parallel design. So we wouldn't be able to explore on that trial and thats. Why we were separating this June in terms of the learnings, but in the first quarter and the beginning of the year, we should be able to see.

First our second quarter and the first half of the year should be able to see this patient and how much they returns and.

Marcio Souza: It was a younger cohort and an older cohort in that study, so younger and older than 55 years of age, and we've seen very comparable safety. We're able to dose up to 120 in both cohorts fairly fast. So, in that regard, check all the marks that you wanted there.

We hope they didn't return much for the sake of the patients, but we do expect nice separation there.

I'll just add on the echo of the plays of ours, Jim mentioned, which is roughly.

Roughly 40% reduction we saw in cohort a 40 milligrams.

That was on top most people were taken propranolol. So we've been mostly studying as adjunctive, allowing people to comment on one medication, but the other key point is the floor effect in the Tetris because just.

It's almost impossible to get below a one where tremor is barely visible.

Marcio Souza: Essential One has started. As you know, we're trying to run this program in parallel, like, and accelerate it as much as possible. It should be clear from our press release, but we did have that trial started in May last. We do have patients enrolled in that trial, so it's moving quite nicely. So we don't expect to slow that down for the new titration. Now, we might come back, or even for the Phase 3 that we expect to initiate next year and implement, but not for Essential One right now.

So the only thing you can really do is you go up in dose is maybe up higher responder rates.

But on a patient by patient basis, you'd have to make tremor, basically invisible or go away, which so you run into these floor effects unless they have a better measure tremor.

Okay. That's helpful. Thank you.

Of course.

Thank you and I have a follow up with Myles Minter with William Blair. Your line is open.

Yeah, Hey, guys. Thanks for taking the follow up just on the.

The price to pay to the study.

Study does on what was the restaurant.

Doing that potentially what starts off one one for the patients but improved from the private pay rates versus just running a separate 16 Luke.

I think I think getting a few questions like we'd like the single payer since almost 60 mix just given the disclosure.

Peri menopausal depressing patient Hudson Isom at 60 minutes.

If you could just run me through the rationale for this specific right.

Bernard Ravino: Now, I hand over to Bernard to talk a little bit about the safety profile in general. Yeah, well, the safety profile we saw with the faster titration was really very similar to what we saw with the original titration, that 944105 study, where we titrated for about a month. So what this overall tells us is that, you know, as we said before, people tend to have nausea and a little dizziness when they start out, and then they don't seem to really have issues as they titrate up.

Yes, I will start with the last part of your question there so.

So the formulation that we're using right now is a lot tighter in terms of the exposures that are gaps so.

So we don't expect to have much variability there so that gives us a nice separation between 40 and 60, they have not really seen much before it varies a lot as we discussed on the previous formulations. So thats one.

Second what we're looking at you here one is the first slide suggested.

So want to make sure we understand than we looking to the actual PTSD patients and their domain and like how much they would solar rays like certain.

Bernard Ravino: So we'll unpack those data a bit more at the movement on Thursday in December, but overall, the profiles are looking the same with the longer or the shorter titration, so the big, makes sense, thanks for helping the kids.

Like exposures off a Gaba Pam or how much their brands would needs or their bodies with needs and thats why we thought that going on there either action.

Therefore, the ones that did not move too.

The 20% or so in the in the top five will allow for under the discretion to go up to 60.

Ritu Subhalaksmi Baral: And I have a follow-up with Ritu Baral on Cowan. Your line is open.

Ritu Subhalaksmi Baral: Hi guys. Thanks for taking the follow up. I wanted

Gifts.

Just kind of the best possible way to explore in this phase III trial, we do expect most of the patients who are not going to go up there.

Ritu Subhalaksmi Baral: I wanted to move to PTSD and the rationale for for 114 in PTSD, especially Marcio Souza.

But it gives us an extra understanding and then we will run we probably going to get these patients for a few more weeks after that as well as the current plan all of the feedback we got from all the sites, where the <unk> is to run an open label right after that and.

Bernard Ravino: and Bernard, you were talking about anxiety. How is the how is anxiety sort of woven into the CAPS-5? I know there are various domains, but it's not I feel like there's anxiety components to certain questions and certain subdomains and not others. I'm just wondering if there are certain subdomains that you think 114 could improve the most within the cap Yeah, so the you know, we're really excited about PTSD. I think that the rationale is particularly strong for a GABA APAM, especially one with an extra synaptic preference.

That's why we happened to docs being planned.

So we're going to have a very nice exposure response understand.

Stacy on this population and being able to hopefully discuss with the FDA, what a registrational path will look like afterwards.

Thanks.

Thank you and at this time Im showing no further questions in the queue I'd like to hand, the conference back over to Marcio for any closing comments.

Thank you so much and thanks again, everyone for joining and for all the questions then on behalf of the team here at practices that.

That was a lot of work and there was a lot that we reviewed today and were quite pleased to share the progress.

Bernard Ravino: Given that benzos don't work particularly well in PTSD, and a lot of people actually avoid them as part of the treatment regimen, the overall rationale, though, is that endogenous neuroactive steroids like allopregnanolone are involved in modulating the response to stress and modulating the HPA axis. There's really good experimental data, and you get reductions in GABA and allopregnanolone in PTSD, and it actually correlates with clinical symptom severity in some studies. So in terms of what we're expecting to see, the CAHPS-5 is a 30-item scale.

As you saw there was a lot going on in our portfolio and virtually everything advance quite nicely. So a busy year for us.

One year as a public company, we have events like basically average program to this stage, we wanted them to be true proof of concepts, we're bringing in our <unk>.

So to the clinic early next year as we discussed and that's for US It's Super exciting since we have a number of other hassles to come in the near future.

More than double the number of practices as we call. Our fellow colleagues here that work everyday to deliver these therapies to patients.

In the last 12 months as well we surpassed the 100 full time employees in the company. The last few months and we move to our new headquarters in Boston that people are not in Panama City, just next to me here.

Bernard Ravino: It's actually pretty complicated in terms of the different factors I cut across there, but cutting across many of the items are common features of anxiety, worry, and avoidance, as well as symptoms like dysphoria, depressive symptoms, and anhedonia.

Beautiful.

And Boston and finally, we have like all the personnel all the funding that is necessary to continue to tag along and to deliver on the steep growth trajectory.

Bernard Ravino: And so, we're not focusing on any particular domain. We're looking at the overall CAHPS V. This is, you know, a phase two exploratory study. So, we'll learn if particular domains, as they're captured in the CAHPS V, come out. But I expect the benefit we'll see will kind of cut across the domains. It'll show up in the overall score. The other factor in there is sleep. There is a whole range of different kinds of sleep impairments, from just regular insomnia to nightmares that might be improved with 114. So, we're looking broadly, but we expect to learn a lot from this trial.

Practical and efficient manner, we're proud of how far we come no doubt whatsoever on that.

But we always say, we therefore more.

And we look forward to having all of your right along with us borrowing for the patients in need. So thanks again for the spark and enjoyed the wrap up the day.

This concludes today's conference call. Thank you for your participation you may now disconnect everyone have a wonderful day.

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Yeah.

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No.

Yes.

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Ritu Subhalaksmi Baral: Got it. And what is the overall prevalence of sleep disorders within within PTSD? And are

Yes.

Yes.

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Ritu Subhalaksmi Baral: There is any sort of.

Ritu Subhalaksmi Baral: of the Sleep Disorder that might, for whatever reason, contraindicate GABA. You mentioned that benzones aren't really used for PTSD, and could you go into why?

Okay.

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Yes.

Yes.

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Marcio Souza: Yeah, it's incredibly prevalent. Ritu and the PTSD are actually interesting as well. We have one of our clinicians in the company is a fellow from MGH.

Marcio Souza: We have a fellowship program with them that focuses on sleep or areas of sleep and PTSD specifically. So, it's something we've been looking quite closely at, and obviously, the patterns change depending on the patient and so on. But it's pretty dramatic, the impact it has.

Marcio Souza: And to the point that we always discuss this about other conditions, other mood disorders, that when sleep becomes primary to the condition versus secondary, right? Like, are you, like, tired all the time or having more of this fear because you didn't sleep versus not sleeping because of that? So, that is central to the condition in our view. And being able to really ease into it versus not feeling okay all the time, like Bernard mentioned benzos here, I think that's the biggest problem there, right?

Marcio Souza: That they just don't feel okay at any time with it. Seems to be a quite important differentiator for us. And I'll even go back to the preclinical models when you're talking about extinguishing fear. Just that is a huge rationale for us on this. Bernard, anything to add there?

Bernard Ravino: Yeah, I would just say that the sleep connection and is kind of comorbid with depression, stress disorders like PTSD, and conditions like perimenopausal depression, but it's very common. A lot of people actually think that sleep disorders start first and are a vulnerability. But it'd be something that would be a good thing for us to follow up on more and break it out in some more detail in terms of the different kinds of sleep disruptions. Maybe we can do that on our psychiatry day. Got it. Thanks for taking the follow up guide.

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Kazin Ahmad: Our next question comes from Kazin Ahmad with Bank of America. Your line is open. Hi, good morning. Thanks for taking my question. I'm sorry if this part of this question has already been asked before. But, Marcio, as far as the essential tremor study is concerned, I think you're going to be releasing data in two tranches. I think you spoke a little bit about what to expect for this.

Kazin Ahmad: this quarter, but for I'm assuming a bigger data release next year.

Kazin Ahmad: Here, what additional data should we expect to see in totality? And what's going to be your bar for what you think is good enough to move forward overall? Thank you. Absolutely not.

Marcio Souza: Absolutely, and thanks, Zin. So, I'll break it down like this here, what we expect. As Bernard mentioned, there is not a lot more to be done in terms of tremor reduction when you look into amplitudes because there is a floor effect on the tetris.

Marcio Souza: So, when you look into the 40% or so that we had before, I would think that that's outstanding, and if you were there at the ballpark, that would be great for the next 12 patients or more that are going to be showing up in the next few months. The – For next year, we're looking at a number of things, right, and this would be earlier in the year. So, one is the more complete data sets, like as many patients that have completed the trial at that point in time, and the activities of daily living that we're also measuring.

Marcio Souza: We've been doing some work, like exploring some biomarkers, like digital biomarkers, and we wanted to talk a little bit more about that as well and how that would enable the Phase III program. And, quite importantly, how much patients come back to baseline after discontinuation, right? And that's the randomized withdrawal phase of that trial, and that's why we need to wait a little bit longer to wrap that up. That part is blinded, so it requires a little bit of a different type of treatment, and why we're going to be showing that at the beginning of the year.

Marcio Souza: Our going hypothesis is that it's going to be a relatively slow coming back because these are more fundamental changes to the network, right? We're not simply reducing tremor, but again, our going hypothesis is that the oscillations are being re-modulated into more fundamental treatments for essential tremors, like primordial, may I say, in terms of how the brain is wired. So it might actually be that we create a more constant state of reduction, and that's why we're trying to explore on this trial. For the second one, Essential 1, which we used to call 944222, and now it's called Essential 1, that is a more typical parallel design, so we wouldn't be able to explore on that trial.

Bernard Ravino: And that's why we're separating these two in terms of learnings. But in the first quarter, at the beginning of the year, we should be able to see, in the first or second quarter, in the first half of the year, this patient and how much they returned. And we hope they didn't return much for the sake of the patients, but we do expect to see a nice separation there. And I'll just add to echo the point that Marcia mentioned, which is the roughly 40% reduction we saw in Cohort A at 40 milligrams. That was on top.

Kazin Ahmad: Most people were taking propranolol, so we've been mostly studying this as a junket, allowing people to come in on one medication. But the other key point is the floor effect in the Tetris, because it's almost impossible to get below a 1 where tremor is barely visible. So the only thing you can really do is go up in doses, maybe have higher responder rates. But, you know, on a patient by patient basis, you'd have to make tremor basically invisible or go away, which

Kazin Ahmad: Okay, that's helpful. Thank you. Thank you. And I have a follow-up with Miles Menter and William Blair. Your line is open. Yeah, hey guys, thanks. Thanks for the follow-up.

Miles Menter: Yeah, hey guys, thanks for taking the follow-up. Just on the Phase 2 PTSD study design, what was the rationale for doing a potentially flex dose of 1,1,4 for patients that don't improve on the CAFS-5 for two weeks versus just running a separate 60 MIG arm? I think I've been getting a few questions like we'd like to see more patients on the 60 MIG just given the disclosure that I think of perimenopausal depression patients had sedation at 60 MIG. If you could just run me through the rationale for this, that would be great.

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Marcio Souza: Yeah, I will start with the last part of your question there, Pais. So the formulation that we're using right now is a lot tighter in terms of the exposure that it gets, so we don't expect to have much variability there. So that gives us a nice separation between 40 and 60. So you're not really seeing much before it varies a lot, as we discussed with the previous formulation. So that's one.

Marcio Souza: The second one we're looking at here is the first-try PTSD, right? So we want to make sure we understand. Then we looked into the actual PTSD patients and the domains and, like, how much they would tolerate certain exposures of a GABA-APM or how much their brains would need or their bodies would need. And that's why we thought that if they were going on in the right direction... Therefore, the ones that did not move to the 20% or so in the Caps 5 would allow for, at discretion, that to go up to 60.

Marcio Souza: It's kind of the best possible way to explore in this phase two trial. We do expect most of the patients are not going to go up there, but it gives us extra understanding. And then we will run. We're probably going to keep these patients for a few more weeks after that, as well as the current plan. All the feedback we got from all the sites we've been talking to is that to run an open label right after that.

Marcio Souza: And that's what we have in the docs being planned. So we're going to have a very nice exposure response, understand the safety in this population, and be able to, hopefully, discuss with the FDA what our registrational path will look like afterwards.

Operator: Thank you. And at this time, I'm showing no further questions in the queue. I'd like to hand the conference back over to Marcio for any closing comments.

Marcio Souza: Thank you so much. And thanks again for everyone to join in for all the questions. And on behalf of the team here at Praxis, right, that's a lot of work. And there was a lot that we reviewed today. And we're quite pleased to share the progress. As you saw, there was a lot going on in our portfolio, and virtually everything advanced quite nicely. So this year for us, in just one year as a public company, we advanced basically every program to today's stage. We wanted them to be through proof of concepts.

Marcio Souza: We're bringing our first ASO to the clinic early next year, as we discussed, and for us, it's super exciting since we have a number of other ASOs to come in the near future. We have more than doubled the number of Praxins, as we call our fellow colleagues here that work every day to deliver these therapies to patients. In the last 12 months, as well, we surpassed the This concludes today's conference call. Thank you.

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Operator: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone have a wonderful day.

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