Q4 2023 Marinus Pharmaceuticals Inc Earnings Call

Ladies and gentlemen, greetings and welcome to Marinus Pharmaceuticals, fourth quarter and full year 2023 financial results and business update call.

Unknown Executive: Ladies and gentlemen, greetings and welcome to Marinus Pharmaceuticals' fourth quarter and full year 2023 financial results and business update call. Today's call is being recorded, and all lines have been placed on mute to prevent any background noise.

Today's call is being recorded in all lines have been placed on mute to prevent any background noise.

Unknown Executive: After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, simply press the star key followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one a second time. Thank you. And it is my pleasure to introduce your host, Sonya Weigle, Senior Vice President of Investor Relations, Human Resources, and Corporate Affairs. Ms. Weigle, you may begin. Thank you, and good afternoon.

After the Speakers' remarks, there will be a question and answer session. If you would like to ask a question during that time simply press. The star key followed by the number one on your telephone keypad.

If you would like to withdraw your question Press Star one a second time.

Thank you and it is my pleasure to introduce your host Sonya Weigel Senior Vice President of Investor Relations Human resources and corporate Affairs.

You may begin.

Thank you and good afternoon with me for Meredith with Doctor stopped <unk>, Chairman and Chief Executive Officer.

Sonya Weigle: With me for Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer, Christy Shafer, Chief Commercial Officer, Dr. Joe Hulihan, Chief Medical Officer, and Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements within the security blog. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development program, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Form 10-K, 10-Q, and 8-Q. I will now turn the call over to our CEO, Dr. Scott Braunstein. Thank you, Sonya.

Christy Schaefer, Chief commercial officer Dr.

Doctor, Joe Houlihan, Chief Medical Officer.

Defense deal Chief Financial Officer, and Chief operating Officer.

Before we begin I would like to remind everyone that some statements. We're making today are forward looking statements under the securities laws.

These forward looking statements involve substantial risks and uncertainties that could cause our clinical development programs future results performance or achievements to differ significantly from those expressed or implied by such forward looking statements.

These risks and uncertainty and risk associated with our business are described in the Companys reports filed with the Securities and Exchange Commission, including Form 10-K, 10-Q and 8-K.

Now I'll turn the call over to our CEO Dr. Scott Braunstein. Thank you Sonya Marin has concluded 2023 with a strong finish across all fronts commercial clinical and operational on today's call I'll provide a brief overview of some of the key areas before turning it over to our leadership team.

Scott Braunstein: Marinus concluded 2023 with a strong finish across all fronts, commercial, clinical, and operational. On today's call, I'll provide a brief overview of some of the key areas before turning it over to our leadership team. Starting with an update on Zotomi, we finished 2023 with another strong quarter of enrollment and robust quarterly growth. As a result of the progress made by our commercial team, we expect to achieve profitability on our Zotomi commercial investment by the second quarter of 2024, ahead of our previous two-year target. Christy will provide a summary of our revenue results in her remarks, as well as an update on our investments to continue to grow the CDD business and our launch plans as we prepare for two critical phase three data readouts in the second and fourth quarters of this year.

Starting with an update on the Tommy we finished 2023 with another strong quarter of enrollment and robust quarterly growth.

As a result of the progress made by our commercial team, we expect to achieve profitability on or is it totally commercial investment by the second quarter of 2024 ahead of our previous two year target.

Christine will provide a summary of our revenue results in her remarks as well as an update on our investments to continue to grow the <unk> business.

And our launch plans as we prepare for two critical phase III data readout in the second and fourth quarters of this year.

Our commercial partners in the EU, China, and Nida regions continue to make important progress to support the told me launches around the globe.

Scott Braunstein: Our commercial partners in the EU, China, and MENA regions continue to make important progress to support Zotomi launches around the globe. In China, the Tenacia team has been granted priority review of the NDA submission in PDD, as well as contributed to the enrollment of the TRUST-TSC trial. In Europe, Orion continues to plan for the launch of Ptolemy in select European countries in 2024.

In China. The tenacious team had been granted priority review of the NDA submission and TDD as well as contributing to the enrollment of the trust PSC trial.

In Europe <unk>.

<unk> continues to plan for the launch of the Ptolemy and select European countries in 2024.

Scott Braunstein: Finally, in the MENA region, we are targeting that our partner biologics will begin their distribution strategy in the second half of this year. Concurrently, we are expanding our manufacturing investments to ensure that we can adequately supply not only our global partners but the broader market opportunities for Zotomi over the coming year. Turning to our clinical pipeline, I'll first share an update on our Phase 3 RAISE trial of ibogainaxolone in refractory staticephalopathy. As we announced in our press release this afternoon, we are pleased to report that we have met the enrollment criteria for the interim analysis and now have more than 90 patients enrolled in the trial. We expect to deliver the interim results to the Data Monitoring Committee over the coming weeks and plan to announce the outcome within the first half of the second quarter.

Finally in the Mena region, we are targeting that our partner biologics will begin their distribution strategy in the second half of this year.

Concurrently we are expanding our manufacturing investments to ensure that we can adequately supply not only our global partners, but the broader market opportunities for the Tommy over the coming years.

Turning to our clinical pipeline I'll first share an update on our phase three ways trial of IV <unk> in refractory status epilepticus.

As we announced in our press release. This afternoon. We are pleased to report that we have met the enrollment criteria for the interim analysis and now have more than 90 patients enrolled in the trial.

We expect to deliver the interim results to the data monitoring committee over the coming weeks and plan to announce the outcome within the first half of the second quarter.

Scott Braunstein: Based on continued strong enrollment seen over the past six months, we project approximately 100 patients to be included in the secondary endpoint analysis. This growing data set should drive a robust package for both the FDA filing and our health economic outcomes. We expect to have the comprehensive trial results over the summer and to present this data at a series of medical meetings in the fourth quarter. We are currently planning for an NDA submission in the first quarter of 2025 and are expecting a priority review. We see the recent uptick in enrollment as a strong reflection of the potential market opportunity for the IB franchise.

Based on continued strong enrollment seen over the past six months, we project approximately 100 patients to be included in the secondary endpoint analyses.

This growing data set should drive a robust package for both the FDA filing and our health economic outcomes.

We expect to have the comprehensive trial results over the summer.

This data at a series of medical meetings in the fourth quarter.

We are currently planning for an NDA submission in the first quarter of 2025 and are expecting a priority review.

We see the recent uptick in enrollment as a strong reflection of the potential market opportunity for the IV franchise.

Scott Braunstein: Domestically, we believe the addressable market for RSC is approximately 35,000 patients per year, and we have the unique opportunity to bring a novel therapy to physicians. We plan to build our leadership in hospitals by continuing to invest in future status epilepticus research while making the appropriate commercial investments with the goal of ascertaining value-based pricing and broad physician adoption. Let me move to an update on our oral pipeline. Approximately 85% of the patients have been enrolled in our TRUST-TSC trial, and the discontinuation rate is below 7%. Due to some minor delays in screening, we expect to complete enrollment in the Trust TSC trial during the first half of the second quarter. As a result, we now anticipate our top line Phase 3 results in the first half of the fourth quarter of this year, rather than the end of Q3.

<unk>, we believe the addressable market for RSV is approximately 35000 patients per year, and we have the unique opportunity to bring a novel therapy to physicians.

We plan to build our leadership in the hospital by continuing to invest in the future status Epilepticus research, while making the appropriate commercial investments with the goal of ascertaining value based pricing and broader physician adoption.

Let me move to an update on our oral pipeline.

<unk>, 85% of the patients have been enrolled in our trust PST trial and the discontinuation rate is below 7%.

Due to some minor delays in screening we expect to complete enrollment in the trust PSC trial during the first half of the second quarter.

As a result, we now anticipate our top line phase three results in the first half of the fourth quarter of this year rather than the end of Q3.

We could not be more pleased with the baseline demographics of the patients enrolled the high percentage of patients rolling over into the open label portion of the study and the low overall discontinuation rates, which are substantially different than what we saw on phase two.

Scott Braunstein: We could not be more pleased with the baseline demographics of the patients enrolled, the high percentage of patients rolling over to the open-label portion of the study, and the low overall discontinuation rates, which are substantially different than what we saw in phase two. We believe the quality of this data set will support a compelling pricing strategy, consistent with what we've seen to date for the Tome.

We believe the quality of this data that will support a compelling pricing strategy consistent with what we've seen to date for <unk>.

Scott Braunstein: The commercial team continues to make the appropriate investment and prepare for a potential launch in 2025, and we are eager to offer patients suffering from refractory TSC a novel anti-seizure therapy. Based on our market analysis, the addressable patient population for refractory TSC is projected to be about 10,000 patients in the United States. By leveraging our current commercial organization, we believe successful expansion of this opportunity will require a modest incremental investment.

The commercial team continues to make the appropriate investments to prepare for a potential launch in 2025, and we are eager to offer patients suffering from refractory GSE a novel anti seizure therapies.

Based on our market analysis, the addressable patient population of refractory GSC is projected to be about 10000 patients in the United States.

Leveraging our current commercial organization, we believe successful expansion of this opportunity will require a modest incremental investment.

Christy Shafer: As a result, our goal is to drive profitability for the entire Zotomi franchise within six to 12 months of the 2025 TSC law. 2024 will be a pivotal year for the company as we have built a solid foundation that has us well positioned to drive future growth. Together, the CDD, RSD, and TSC markets represent a multi-billion dollar opportunity where we believe we can take a firm leadership position for these disease states and other refractory epidemics, with an established commercial and clinical track. We look forward to building our momentum for Zotomi while also reporting on these key data milestones later this year. I'll now turn the call over to our Chief Commercial Officer, Christy Shafer. Thank you, Scott, and good afternoon, everyone. In my remarks today, I will share an update on our Zotel Milan, the progress we are making to grow our CBD franchise, and an update on our commercial readiness planning for potential launches into TSC and RS. Starting with Hitomi, in our first full year of launch, we generated net product revenue of $19.6 million for the full year 2023.

As a result, our goal to drive profitability for the entire that told me franchise within six to 12 months of the 2025 GSC launch.

2024 will be a pivotal year for the company as we have built a solid foundation that has us well positioned to drive future growth.

Together, the CDT RSC and TLC markets represent multibillion dollar opportunity, where we believe we can take a firm leadership position for these disease state and other refractory epilepsies.

With an established commercial and clinical track record, we look forward to building our momentum for the Tommy while also reporting on these key data milestones later this year.

I'll now turn the call over to our Chief commercial Officer Christy Shaper.

Thank you Scott and good afternoon, everyone. In my remarks today I will share an update on our the Tommy launch the progress we are making to grow our CDB franchise and an update on our commercial readiness planning for potential launches into TSA and RSC.

Starting with the Tommy and our first full year of launch we generated net product revenue of $19 $6 million for the full year 2023.

This solid performance is a result of our strategy to establish the Tony I think critical treatment and a comprehensive management of seizures associated with CEB.

Christy Shafer: This solid performance is a result of our strategy to establish Zytomy as a critical treatment in the comprehensive management of seizures associated with CDD and to ensure that patients have seamless access to Zytomy from prescription through fulfillment. We ended 2023 with more than 165 patients active on therapy. We continue to see swift payer approval, with time from enrollment to patient fill of approximately two weeks in the second half of 2023, representing a consistent improvement throughout the year and demonstrating payers' understanding of Zotomi's impact on patients in need. Additionally, payer approvals of CBD prescriptions remain at nearly 100%, indicating strong payer recognition of the value of Zotomi for these patients. To date, discontinuation rates are still well within our anticipated range. Looking ahead, we continue to expect full year 2024 U.S. economy net product revenues of between $32 and $34 million. The midpoint of this range represents growth of nearly 70% versus 2023.

And to ensure that patients have seamless access to the Tommy from prescription through fulfillment.

We ended 2023 and much more than 165 patients active on therapy, we continue to see Swift payer approval with time from enrollment to patients of approximately two weeks in the second half of 2023.

Representing a consistent improvement throughout the year and demonstrating payers understanding of the Tommy its impact on patients in need.

Additionally, payer approvals and CVD prescriptions remained at nearly 100%, indicating strong pay a recognition of the value of the Tommy for these patients.

To date discontinuation rates are still well within our anticipated expectation.

Looking ahead, we continue to expect full year 2024 U S. The Tommy net product revenues of between 32 and $34 million.

The midpoint of this range represents growth of nearly 70% versus 2023.

We are executing a number of strategies to maximize CBD market penetration.

Christy Shafer: We're executing a number of strategies to maximize CBD market penetration. For example, we are utilizing new data sources and analytics to better identify patients who are not billed with the CDD ICD-10 code and third-party claims and identify patients who may have CDD but have yet to have a confirmatory genetic test. Leveraging these data, we have also rolled out a genetic testing initiative, which will help accurately diagnose patients. And with the open-label extension data published late last year, we are able to emphasize the TALMI sustained efficacy and safety profile supporting the use of TALMI as a proven treatment for combating seizures associated with CDD. We are excited for the opportunity to bring Zotelme to more CBD patients in need and believe our commercial strategy has us well positioned to realize the potential of this novel treatment. Our experience with Satomi provides Marinus with a solid foundation for two potential commercial launches in 2025.

Youre utilizing new data sources and analytics to better identify patients who are not build with the CDB ICD 10 code and third party claims and identify patients who may have CBD, but have yet to have a confirmatory genetic tests.

Leveraging these data we have also rolled out a genetic testing initiative, which will help accurately diagnosed patients.

And with the open label extension data published late last year, we are able to emphasize the Tommy sustained efficacy and safety profile supporting the use of the Tommy as a proven treatment for combating seizures associated with <unk>.

We are excited for the opportunity to bring the tell me more CBD patients in need and believe our commercial strategy has us well positioned to realize the potential of this novel treatment.

Our experience with the Tom May provides marin with a solid foundation for two potential commercial launches in 2025.

Christy Shafer: These include the TAMI's expansion into TSC and the IV formulation of gonaxalone for RF. Launch planning is well underway for both TSE and RSE in anticipation of two key trial readouts later this year. Let me take a few minutes to summarize our commercial planning in support of each of these programs. Starting with TSC, our Rare Genetic Epilepsy business is led by Senior Vice President Lisa Lejuwan, a 30 year veteran of ultra rare disease.

These include the Tommy is expansion into chassis and the IV formulation of <unk> for RFC.

Launch planning is well underway for both TSV and RSC and anticipation of two key trial Readouts later this year.

Let me take a few minutes to summarize our commercial planning in support of each of these program.

Starting with TSA are rare genetic epilepsy business is led by senior Vice President Lisa, let Joanne a 30 year veteran in ultra rare disease.

Christy Shafer: We're planning to build on the strong foundation we have established with Hitomi and CBD and expand our proven strategy to capture the larger TSC mark. We believe there is a strong business rationale and market opportunity for the expansion of our Zotomi business into TSC, where we know there is a significant unmet need in refractory patients. We plan to take advantage of synergies with CDD and CSC while leveraging market data that will further support an additional commercial line. Research suggests that there is a potential strong overlap with CDD rare disease treaters, and unlike CDD, TSC patients may be easier to identify through a well-established ICD-10 code which has been in use for more than 30 years and the physical TSC attributes, which may be identified at birth.

We are planning to build on the strong foundation, we have established with the telling me and CDB and expand our proven strategy to capture the larger TSA market.

We believe there is a strong business rationale and market opportunity for any expansion of ours. The Tommy business entity assay, where we know there is a significant unmet need in refractory patients.

We plan to take advantage of synergies of CBD and THC, while leveraging market data that will further support and additional commercial launch.

Research suggests that there is a potential strong overlap with CBB rare disease traders and unlike CBD THC patients may be easier to identify through a well established ICD 10 code, which is being used for more than 30 years and the physical TSA attributes, which may be identified at birth.

Yes.

Our early plans to expand into the TSV market include disease State education for Paris engagement with very active and supportive advocacy partners, including the TSA Alliance.

Christy Shafer: Our early plans to expand into the TSC market include disease state education for payers, engagement with very active and supportive advocacy partners, including the TSC Alliance, Trust TSC Data Education with Payers and Formulary Decision Makers in the Advance of an SNBA Submission, and an enhancement of our patient services and specialty pharmacy model. Turning to RSE, with enrollment criteria now satisfied for the interim analysis and the RAGE trial and data anticipated in Q2, let me take a few moments to summarize our commercialization and launch plan. We have assembled a team with extensive commercial experience in the hospital setting under the leadership of industry veteran Kristin Rudisill, our vice president and business unit lead for the acute care franchise.

Trust TSA data agitation with payers and formulary decision makers and the advance and then F N B a submission.

And an enhancement of our patient services and specialty pharmacy model.

Turning to RSA with enrollment criteria now satisfied for the interim analysis and the race trial and data anticipated in Q2, let me take a few moments to summarize our commercialization and launch plans.

We have assembled a team with extensive commercial experience in the hospital setting under the leadership of industry veteran Kristen grid itself, our vice President and business unit lead pretty acute care franchise.

Christy Shafer: In 2024, our acute care business is focusing on aligning development and execution with T-Miles. Driving access post-approval is pivotal to our launch strategy, and this year, we are aiming to complete key access strategies such as channel and distribution plans, end-top filing, and pricing. In addition to strategic planning, we are preparing for execution with the build and deployment of a field access team entering the market as early as this summer.

In 2024 hour acute care business is focusing on aligning development and execution with key milestones.

Driving access post approval is pivotal to our launch strategy and this year, we are aiming to complete key access strategies, such as channel and distribution plans and Pat filing and pricing.

In addition to strategic planning, we are preparing for execution with the build and deployment of our field access team entering the market as early as this summer.

Christy Shafer: Activating this team under the FDAMA 114 guidelines is designed to address key access stakeholder and payer groups with information that addresses their key value drivers. These teams are permitted to disseminate health care economic information that is critically important to financial decision makers who often control or influence formulary decisions for new therapies. With corporate and system-level financial decision makers, we believe engaging with these key stakeholders can accelerate access and awareness, leading to more favorable formulary placement and will ultimately provide patients with earlier access to treatment. The combination of our team's leadership, the commercial plans we have outlined, and the success of Zotomi gives us the confidence that Ganaxalone has the potential to become a blockbuster franchise across CDD, PSE, and RSE.

Activating this team under the <unk> guideline is designed to address key access stakeholder and payer groups with information that addresses their key value drivers.

These teams are permitted to disseminate healthcare economic information that is critically important to these financial decision makers, who often control or influence formulary decisions for new therapies.

With corporate and system level financial decision makers, we believe engaging with these key stakeholders can accelerate access and awareness leading to more favorable formulary placement and well.

Ultimately provide patients with earlier access to treatment.

The combination of our team's leadership the commercial plans, we have outlined and the success of the Tommy gives us the confidence that can exelon has the potential to became a blockbuster franchise across CDB PSC and RSA.

Joseph Hulihan: I look forward to providing further updates on our progress and plans throughout the year. At this time, I would like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan, for an update on our clinical programs and developments. Thank you, Christy. Good afternoon.

I look forward to providing further updates on our progress and plans throughout the year.

At this time I would like to turn the call over to our Chief Medical Officer, Dr. Joe Houlihan for an update on our clinical programs and development. Thank.

Thank you Christy and good afternoon.

Joseph Hulihan: I'm pleased to share an overview of our pipeline progress, which includes two key upcoming phase three data readouts and initiatives to support our continued clinical and scientific understanding of RSE and TSA, starting with the RAISE trial of Ibogaine Axalone and Refractory Stats. After a strong end to 2023, I'm excited to report that in January, we hit our enrollment requirements for the interim analysis. With this critical milestone achieved and the date scheduled for DMC's review of the data, we continue to expect to report top-line results in the second quarter of 2024. Now that we've achieved the required enrollment targets for the interim analysis, the clinical operations team has been hard at work ensuring the integrity and completeness of the study data to be provided to the DMC for their work. Here's what you can expect next in the process.

I'm pleased to share an overview of our pipeline progress, which includes two key upcoming phase III data readouts.

Thats to support our continued clinical and scientific understanding of RSV and Geos.

Starting with the raised trial of IV, you can actually refractory status.

After a strong into 2023 Im excited to report that in January.

Hit our enrollment requirement for the interim analysis with this critical milestone achieved.

Scheduled for DMC review of the data.

Continue to expect to report topline results in the second quarter of 2024.

Now that we've achieved the required enrollment targets for the interim analysis. The clinical operations team has been hard at work, ensuring the integrity and completeness of the study data to be provided to the DMC for their review.

Curious what you can expect next in the process.

Joseph Hulihan: Presently, the clinical operations team is focused on data cleaning in anticipation of generating the interim analysis data set. Once the preparatory steps are complete, the data will be provided to the DMC for a determination of whether the studies met the pre-specified efficacy stopping boundaries on the co-primary endpoints. If this study achieves these pre-specified stopping rules, the Marinus leadership team will then evaluate the... and share top-line results publicly soon thereafter, including both the co-primary and key secondary. Successful results would serve as the basis for submission of a U.S. Regulatory File.

Presently the clinical operations team is focused on data.

In anticipation of generating interim analysis dataset.

Once the preparatory steps are complete the data will be provided to the DMC for a determination of whether the study met the pre specified efficacy stopping boundaries on the co primary endpoints.

If the study achieved these pre specified stopping disease. The Mariners leadership team will then evaluate the data.

Our topline results publicly soon thereafter, including both the co primary and key secondary endpoints.

As for results would serve as the basis for submission of a U S regulatory filings.

Preparation of data for the upcoming Dfc is ongoing as Scott mentioned, we will continue to enroll patients in the double blind phase of the study.

Joseph Hulihan: While preparation of data for the upcoming DMT is ongoing, as Scott mentioned, we'll continue to enroll patients in the double-blind phase of the study. Data from these additional patients will be pooled with the interim analysis data set and will serve as the basis for analysis of other secondary and health care utilization. If double-blind enrollment is stopped based on the interim analysis results, we will then enroll new patients in a planned open-label extension. Collect additional safety data that will support upcoming regulatory filings and future discussions with payers and other key stakeholders. As a reminder, the interim analysis will include results from the co-primary and key secondary studies, which measure both onset of action and durability of effect in controlling status epilepsy.

Data from these additional patients will be pooled with the interim analysis data set.

Will serve as the basis for analysis of other secondaries and healthcare utilization in points.

This double blind enrollment has stopped based on the interim analysis results.

Then enroll new patients and our planned open label extension to collect additional safety data to support upcoming regulatory filings and future discussions with payers and other key stakeholders.

As a reminder, the interim analysis will include results of the co primary and key secondary study endpoints, which measure both onset of action and durability of effect and controlling status epilepticus.

Joseph Hulihan: The co-primary endpoints are status cessation within 30 minutes and prevention of escalation to third-line treatment with IV anesthesia. For the key secondary endpoints, we are looking at another measure of onset of action, the time-to-status cessation analysis, and a further measure of treatment durability, lack of progression to IV anesthesia for 72 hours, which encompasses the 24-hour period following the end of the ana

The co primary endpoints are status cessation within 30 minutes and prevention of escalation to third line treatment with IVF centers.

For the key secondary endpoints, we are looking at another measure of onset of action the time to status cessation analysis.

A further measure of treatment durability lack of progression to IV anesthesia for 72 hours, which encompasses the 24 hour period. Following me and we can absolutely huge.

Following release of the topline data analysis will continue and will yield results from other secondary endpoints and important healthcare utilization and outcomes, including time on mechanical ventilation.

Joseph Hulihan: Following release of the top-line data, analysis will continue and will yield results on other secondary evidence and important health care utilization, including time on mechanical ventilation, days in the ICU in the hospital, and discharge destination. Results are anticipated by the fall, and we plan to present them at major medical meetings later this year. Turning to our second refractory status trial, RAISE 2 is a Phase 3, double-blind, placebo-controlled registration study targeting enrollment of 70 patients who have failed first-line benzodiazepine treatment and at least one second-line IV anti-seizure medication.

As in the ICU and hospital discharge destination.

The results are anticipated by the fall and we plan to present the major medical meetings later this year.

Turning to our second refractory status trial raise two is a phase III double blind placebo controlled registration study targeting enrollment of 70 patients who have failed first line benzodiazepine treatments and at least one second line IV FTC her medication.

In this study we're evaluating IV can actually the population earlier in the continuum refractory status until IV anesthesia is less likely to be an imminent next step in treatment.

Joseph Hulihan: In this study, we're evaluating IV gonaxalone in a population that's earlier in the continuum of refractory status, in whom IV anesthesia is less likely to be an imminent next step in treatment. We believe this study, which is expected to complete enrollment by the end of 2025, will support European approval and can be used to expand the U.S. labor market. Theta presented the AES last December, as well as other published data, suggesting that earlier treatment intervention in patients with statinis improves clinical outcomes. At that December meeting, we presented results from a five-year analysis of status epilepticus treatment dynamics in the U.S. This analysis showed that even in the absence of IV anesthesia, refractory status that was treated with three or more IV anesthesia medications had worse outcomes and longer lengths of stay.

We believe this study which is expected to complete enrollment by the end of 2025 will support a European approval and can be used to expand the U S label.

Data presented at Aes last December as well as other published research suggests that earlier treatment intervention in patients with status improves clinical outcomes.

That that December meeting, we presented results from a five year analysis of status epilepticus treatment dynamics in the U S.

This analysis showed that even in the absence of IV anesthesia refractory status that was treated with three or more IV anti seizure medications at worst outcomes and longer lengths of stay.

Joseph Hulihan: A RAVE-2 trial is designed in a way that will allow us to assess the impact of ibogainaxilone on clinical outcomes and healthcare utilization in this subgroup of patients, moving to super refractory status or SRSE. We continue to supply Ibogaine Axanil to physicians upon request under emergency INT for these patients whose life-threatening condition has high rates of morbidity and mortality. To date, over 25 patients have been treated for SRSE with Ganaxolone under EIA, and preliminary data on outcomes have been encouraged, particularly since we implemented a dosing regimen tailored to the treatment of SRS. This regimen incorporates a higher daily dose of approximately 1,000 milligrams of Ganaxolone with 63 grams of capsaicin.

<unk> two trial is designed in a way that will allow us to assess the impact of <unk> on clinical outcomes and health care utilization this subgroup of patients.

Moving to Super refractory status or Src.

We continue to supply Ivy can actually to physicians upon request under emergency <unk> for these patients whose life threatening condition as high rates of morbidity and mortality.

To date over 25 patients have been treated for Src with <unk> under <unk>.

Preliminary data on outcomes has been encouraging.

Particularly since we implemented the dosing regimen tailored to the treatment of Src.

This regimen incorporates a higher daily dose of approximately 1000 milligrams of <unk> loans was 63 grams of Captisol.

Joseph Hulihan: Based on the outcomes we've observed, we intend to conduct a proof-of-concept study of ibogainacillin in approximately 50 patients with SRA. He plans to go to the FDA in the second quarter of this year with this modified dosing and begin the study before you're, Turning to our Zitomy franchise, first with TSA. Seizures in the TSC are often treated with despite the availability of newer disease-specific anti-seizure medications. To address this unmet need, we're evaluating Gonaxalone in TSC patients with refractory seizures in our ongoing TRUST-TSC trial. This is a global phase 3 randomized double-blind placebo-controlled trial of adjunctive Ganaxin, which will enroll approximately 128 patients

Based on the outcomes, we've observed we intend to conduct a proof of concept study did not slow.

Absolutely 50 patients with Src.

We plan to go to the FDA in second quarter of this year with this modified dosing regiments and begin the study before year end.

Turning towards autonomy franchise first with TSV.

Seizures in PSC are often treated consistent despite the availability of newer disease specific anti seizure medications.

To address this unmet need we're evaluating <unk> in <unk> patients with refractory seizures, and our ongoing trust TFC trial.

This is a global phase III randomized double blind placebo controlled trials with adjunct of can absolutely, which will enroll approximately 120 patients with TFC associated seizures.

Joseph Hulihan: As Scott mentioned, we've achieved over 85% of the target enrollment and are confident that we'll complete full enrollment early in the second quarter of this year. As a reminder, the trial provides 90% power to detect a 25% difference in seizure reduction between an axiom and a placebo. As discussed previously, the titration schedule has been modified in consideration of the pharmacokinetics of Ganaxalone and the timing of side effect onset in prior studies.

As Scott mentioned, we've achieved over 85% of the targeted enrollment and are confident that we'll complete full enrollment early in the second quarter of this year.

As a reminder, the trial provides 90% power to detect a 25% difference in seizure reductions between Exelon and placebo.

As discussed previously the titration schedule has been modified and consideration of the pharmacokinetics of can actually.

The timing of side effect onset in prior studies.

Currently the discontinuation rate in this study is below 7%.

Joseph Hulihan: Discontinuation rate in the study is below 7%, giving us confidence in the potential benefit of the revised titration, not just on tolerability but potentially on efficacy as well. In addition, we're seeing over 85% of patients who complete the study transition into the open-label extension, a rate as high or higher than observed in the marigold study. Targeting submission of a supplemental NDA in the first half of 2025 with Additionally, we plan to expand our investment in Zotomi to explore its potential in the treatment of other rare effects. Planning is underway for a clinical trial that would assess oral ganaxinone for the treatment of a broad range of epileptic encephalopathy. Many patients with seizures and neurodevelopmental disorders don't satisfy diagnostic criteria for Lennox-Gastaut syndrome or other well-defined developmental and epileptic encephalopathy.

US confidence in the potential benefit of the revised titration, not just on tolerability, but potentially on efficacy as well.

In addition, we're seeing over 85% of patients who complete the study transitioned into the open label extension already as high or higher than observed in the <unk> study.

Targeting submission of a supplemental NDA in the first half of 2025 with a priority ratio expected.

Additionally, we plan to expand our investments autonomy to explore its potential in the treatment of other rare epilepsy.

Planning is underway for a clinical trial.

Oregon actually one for the treatment of a broad range of epileptic encephalopathy.

Many patients with seizures neurodevelopmental disorders don't satisfy diagnostic criteria for Lennox Gestosis enrollments are other well defined developmental and epileptic encephalopathy or <unk> and.

Joseph Hulihan: And we feel there is a substantial unmet need for seizure treatment in these patients. We plan to initiate a proof-of-concept trial assessing Ganaxolone in approximately 100 patients in the fourth quarter of this year. In closing, helping patients and families suffering from severe refractory seizure disorders remains at the core of what we do. Our clinical team is motivated and focused on ensuring that these lives are transformed with new, safe, and effective treatment options. I'd now like to turn the call over to our CFO and COO, Steven Pfanstiel, for financial advice. Thanks, Joe, and good afternoon, everyone.

And we feel there is a substantial unmet procedure treatment in these patients.

We plan to initiate a proof of concept trial assessing <unk> alone and approximately 100 patients in the fourth quarter of this year.

In closing, helping patients and families suffering from severe refractory seizure disorders remains at the core of what we do.

Our clinical team is motivated and focused on ensuring these slides are transformed with new safe and effective treatment options.

I would now like to turn the call over to our CFO and COO Steven finished steel for a financial update.

Thanks, Joe and good afternoon, everyone I am pleased to be able to provide a financial update as well as share our financial results for the fourth quarter and full year of 2023.

Steven E. Pfanstiel: I am pleased to be able to provide a financial update as well as financial results for the fourth quarter and full year of 2023. First of all, I am proud of how we managed the business in 2023. We ensured that we remained focused on our critical investments in the RSC and TSE trials and on the commercialization of CDD.

First of all I am proud of how we manage the business in 2023, we ensure that we remain focused on our critical investments in the RSC and TLC trials and on the commercialization of CBD.

Steven E. Pfanstiel: On the latter, we now project a breakeven on our CED commercial investment in the first half of 2024, which is ahead of our projections and less than two years from the launch. We were also not afraid to make tough decisions, such as discontinuing the established status epilepticus trial and making other cost reductions to ensure adequate cash runway headed into two significant data readouts. As a result, we ended 2023 with cash, cash equivalents, and short-term investments of $150.3 million.

On the latter we now project a breakeven on our CD commercial investment in the first half of 2024, which is ahead of our projections and less than two years from the launch. We're also not afraid to make tough decisions such as discontinuing the established status epilepticus trial, and making other cost reductions to ensure adequate cash runway headed into two significant data read.

<unk>.

As a result, we ended 2023 with cash cash equivalents and short term investments of $150 3 million. This.

Steven E. Pfanstiel: This is expected to provide cash runway late into the fourth quarter of 2024, and importantly, we project a cash balance of greater than $100 million at the expected RSE readout. We announced early in the quarter that we project 2024 U.S. Satomi net product revenues of between $32 and $34 million. As Christy mentioned, this increase from 2023 represents continued strong and steady execution on the launch. However, unlike 2023, we are not providing full year 2024 operating expense guidance at this time, as the level of investment will depend on the outcome of the RSC and TSE phase 3 trials. However, we expect operating expenses and cash burn in the near term to be consistent with the 2023 trend. I'll now take a few minutes to summarize our financial results for 2023. We recognize Ptolemy product revenues of $6.6 million and $19.6 million for the three and 12 months ended December 31, 2023, as compared to $2.3 million and $2.9 million for the same periods in the prior year. The full year total of $19.6 million exceeded our revised autonomy revenue guidance range of between $18.5 and $19 million.

This is expected to provide cash runway late into the fourth quarter of 2024, and importantly, we project a cash balance of greater than $100 million at the expected RSC readout.

We announced earlier in the quarter that we project 2024 U S. Tommy net product revenues of between 32% and $34 million.

As Christie mentioned this increase from 2023 represents continued strong and steady execution on the launch.

Unlike 2023, we are not providing full year 2020 for operating expense guidance at this time as the level of investment will depend on the outcome of the RSC and PSC phase III trials.

However, we expect the operating expenses and cash burn in the near term to be consistent with the 2023 trends.

I'll now take a few minutes to summarize our financial results for 2023.

We recognize that Tommy product revenues of $6 6 million and $19 6 million for the three and 12 months ended December 31, 2023, as compared to $2 3 million and $2 9 million for the same periods in the prior year.

The full year total of $19 6 million exceeded our revised the Tommy revenue guidance range of between $18 5 million to $19 million.

Separately, we recognize barter revenues of <unk> 6 million and 11 4 million for the three and 12 months ended December 31, 2023, as compared to $1 8 million and $6 9 million for the same periods in the prior year.

Steven E. Pfanstiel: Separately, we recognize BARDA revenues of $0.6 million and $11.4 million for the 3 and 12 months ended December 31, 2023, as compared to $1.8 million and $6.9 million for the same periods in the prior year. Our actual 2023 BARDA revenue of $11.4 million was within our guidance range of between $11 and $12 million. Research and development expenses were $26.4 million and $99.4 million for the three and 12 months ended December 31, 2023, as compared to $21.4 million and $79.9 million for the same periods in the prior year. The year-to-date change was due to increased costs associated with our API on-shoring effort, increased TSC and RSC clinical trial activity, and increased headcount. As a reminder, the API on-shoring effort is approximately 70% funded by BARDA, so the increase in R&D expenses is partially offset by the increased BARDA revenue. Selling general and administrative expenses were $15.4 million and $61.2 million for the three and 12 months ended December 31, 2023, as compared to $14.7 million and $56.8 million for the same periods in the prior year.

Our actual 2023 BARDA revenue of $11 4 million was within our guidance range of between 11 and $12 million.

Research and development expenses were $26 4 million and $99 4 million for the three and 12 months ended December 31 2023.

As compared to $21 4 million and $79 9 million for the same periods in the prior year.

The year to date change was due to increased costs associated with our API onshoring effort increased TFC in RSV clinical trial activity and increased head count.

As a reminder, the API onshoring effort is approximately 70% funded by BARDA. So the increase in R&D expenses is partially offset by the increased BARDA revenue.

Selling general and administrative expenses were $15 4 million and $61 2 million for the three and 12 months ended December 31, 2023, as compared to $14 7 million and $56 8 million for the same periods in the prior year.

The primary drivers of the change on a year to date basis were in utilization of the U S. So Tommy launch costs and increased head count.

Steven E. Pfanstiel: The primary drivers of the change on a year-to-date basis were annualization of the U.S. Satomi launch costs and increased headcount. Full year 2023 GAAP operating expenses, consisting of both SG&A and R&D expenses, were $160.5 million, which was within our revised guidance range of between $158 and $162 million. Interest income was $1.7 million and $8.1 million for the 3 and 12 months ended December 31, 2023, as compared to $1.7 million and $2.4 million for the same periods in the prior year. The increase in interest income was driven by an overall increase in cash, cash equivalents, and short-term investments and increased yield on those balances. Interest expense was $4.3 million and $16.9 million for the three and 12 months ended December 31, 2023, as compared to $3.7 million and $10.7 million for the same periods in the prior year.

Full year 2023, GAAP operating expenses, consisting of both SG&A and R&D expense was $165 million, which was within our revised guidance range of between 158 and $162 million.

Interest income was $1 7 million and $8 1 million for the three and 12 months ended December 31, 2023, as compared to $1 7 million and $2 4 million for the same periods in the prior year.

The increase in interest income was driven by the overall increase in cash cash equivalents and short term investments and increase the yield on those balances.

Interest expense was $4 3 million and $16 9 million for the three and 12 months ended December 31, 2023, as compared to $3 7 million and $10 7 million for the same periods in the prior year.

The increase was driven by a drawdown of an additional $30 million of credit under the <unk> agreement in March 2022, and noncash interest expense related to a revenue interest financing with regard.

Steven E. Pfanstiel: The increase is driven by the drawdown of an additional $30 million of credit under the Oak Tree Agreement in March 2022 and non-cash interest expense related to our revenue interest financing list of guards. The company reported a net loss before income taxes of $41.8 million and $142.9 million for the 3 and 12 months ended December 31, 2023, as compared to a net loss before income taxes of $32.7 million and $16.4 million for the same periods in the prior year. As a reminder, the prior year's results included the one-time sale of our Priority Review Voucher in the third quarter. These totals include non-cash stock-based compensation expense of $3.9 million and $15.6 million for the 3 and 12 months ended December 31, 2023, as compared to $3.8 million and $14.9 million for the same periods in the prior year. Cash used in operating activities was $118 million for the 12 months ended December 31, 2023, as compared to cash used in operating activities of $112.9 million in the prior year.

The company reported a net loss before income taxes of $41 8 million and $142 9 million for the three and 12 months ended December 31, 2023, as compared to a net loss before income taxes of $32 7 million and $16 4 million for the same periods in the prior year.

As a reminder, the prior year's results included the one time sale of our priority review voucher in the third quarter.

These totals include noncash stock based compensation expense of $3 9 million and $15 6 million for the three and 12 months ended December 31, 2023, as compared to $3 8 million and $14 9 million for the same periods in the prior year.

Cash used in operating activities was $118 million for the 12 months ended December 31, 2023, as compared to cash used in operating activities of $112 9 million in the prior year.

Before we move to the Q&A I will make a few concluding remarks.

We are very pleased with our progress to date all of which has led to a number of potentially transformational milestones in 2024, we.

We have two key data readouts and RSC and TLC that if positive could drive significant growth for our <unk> franchise, and we look forward to sharing these and other important updates in the months ahead. Thanks.

Thanks again for your continued interest in Meredith Operator, you may now open the call to questions.

Yeah.

Thank you.

And as a reminder, if you would like to ask a question press Star and then the number one on your telephone keypad.

Steven E. Pfanstiel: Before we move to the Q&A, I will make a few concluding remarks. We are very pleased with our progress to date, all of which has led to a number of potentially transformational milestones in 2024. We have two key data readouts in RSC and TSC that are positive to drive significant growth for our Ganaxone franchise, and we look forward to sharing these and other important updates in the months ahead. Thanks again for your continued interest in Marinus.

To be able to take as many questions as possible. We do ask that you. Please limit yourself to one question.

We will pause for just a moment to compile the Q&A roster.

And we will take our first question from Brian Abrahams with RBC capital markets. Your line is open.

Hi, there.

Good afternoon, congrats on the enrollment completion.

Interim cohort and thanks for taking my question.

On TLC as we think about the potential future commercial opportunity there.

Unknown Executive: Operator, you may now open the call to questions. Thank you. And as a reminder, if you would like to ask a question, press star and then the number one on your telephone keypad. However, to be able to take as many questions as possible, we do ask that you please limit yourself to one question. We will pause for just a moment to compile the Q&A roster, www.larryweaver.com, and we will take our first question from Brian Abrahams with RBC Capital Markets. Your line is open. Hi there. Good afternoon.

I am curious how the reimbursement dynamics that youre seeing would say Tommy both on and on and off label use are shaping your view of what the ultimate.

The future dynamics might look like commercially.

In the TSA indication.

Thanks, Brian.

Kick it off this is Scott thanks for the congratulations and then I'll kick it over to Christie.

We're incredibly proud of the job that Christies team has done within six or so months of launch we had every state Medicaid program reimbursing. The tall me. We currently have over 80% of commercial plans with with relatively straight guidelines and we've yet to have a patient who had been denied.

Scott Braunstein: Congratulations on the enrollment completion of the interim cohort, and thanks for taking my question. I guess on TSC, as we think about the potential future commercial opportunity there, I'm curious how the reimbursement dynamics that you're seeing with Zytelme both for on and off-label use are shaping your view of what the future dynamics might look like commercially in the TSC indication. Thanks, Brian. I'll kick it off. This is Scott.

Therapy.

Equally interesting since launch we've had a meaningful number about 10% of our current sales are coming from spontaneous use refractory epilepsy or the patients.

Patients and we're seeing overall about two thirds of those scripts those prior authorization forms being reimbursed by the payers. So I think we really understand that the payors.

Scott Braunstein: Thanks for the congratulations. And then I'll kick it over to Christy. You know, we're incredibly proud of the job that Christy's team has done. Within six or so months of launch, we had every state Medicaid program reimburse Zitalme. We currently have over 80% of commercial plans with relatively straight guidelines, and we've yet to have a patient who's been denied therapy. Equally interesting, since launch, we've had a meaningful number, about 10% of our current sales, are coming from spontaneous use, refractory epilepsy, or DE patients. And we're seeing overall about two-thirds of those, and President-elect Joe Biden recognize that there is not a lot of therapy for these refractory patients.

Recognize that there are not a lot of therapy for these refractory patients we have a limited data set and we're very pleased with the reimbursement dynamics as of today and I think going into TLC.

We'll have a second randomized controlled study showing the value proposition, we will have a patient population in PSC, which in many ways mimics the CBD population a highly refractory patient population that has failed multiple prior therapies Ah patient population current.

Getting standard of care, either epidiorite, <unk> or <unk> or <unk> inhibitors, and this will be the first add on study ever with affinity award Thats randomized double blind placebo control. So I think we're going to go into all of our discussions with a high level of.

I would say a high level and high expectations that well, we will share with payers will be equally compelling to that.

Scott Braunstein: We have a limited data set, and we're very pleased with the reimbursement dynamics as of today. And I think going into TSC, we will have a second randomized control study showing the value proposition. We'll have a patient population in TSC that, in many ways, mirrors the CDD population, a highly refractory patient population that has failed multiple prior therapies, a patient population currently getting the standard of care, either Epidiolex or Afinitor or mTOR inhibitors.

The data in CDK <unk> me.

Christie you want to add and I know I rambled on I apologize, but anything you want to add.

Nothing additional that I want to add but I think the most important thing is is that we regularly are confirming assumptions that in the refractory patient population that payers have.

Very very distinct appreciation for what these patients have gone through that it's a different disease states and CBD, yet, but I do think that data is suggesting that although these patients have gone through many many different medications. They still are significantly a need in a refractory patient population.

Scott Braunstein: And this will be the first add-on study ever with Afinitor that's randomized double-blind placebo control. So I think we're going to go into all of our discussions with a high level of, I would say, high expectations that what we will share with payers will be equally compelling as that of the data in CDKL5 for ZTAL. Christy, you want to add something? I know I rambled on, and I apologize. But is there anything you want to add?

<unk> is an indicator of that success that we've had an affinity population will be we'll be thrilled to see that again in TSA.

Got it thanks, Thanks, Brian.

Scott Braunstein: Nothing additional that I want to add, but I think the most important thing is that we regularly are confirming assumptions that in the refractory patient population, payers have a very, very distinct appreciation for what these patients have gone through. It's a different disease state than CDD, yes, but I do think that data are suggesting that although these patients have gone through many, many different medications, they are still significantly in need in the refractory patient population. If CDD is an indicator of the success that we've had in the CDD population, we'll be thrilled to see that again in TSC. I got it.

And we will take our next question from Peyton contact with TD Cowen Your line is open.

Hi, guys. Good afternoon, and thanks for taking our questions I guess.

Looking forward to potentially if the data is positive what remains to be done for the NDA package. How quickly do you think.

The guidance that <unk>, given and is there anything to outstanding on either the safety database that needs to be completed or TMT and that's it for me.

Yes, let me kick it off and then I'll pass it over to Joe So for everyone out there as a reminder, this.

This is the same API material that we have approved in the Tommy So a substantial proportion of the NDA package has already been effectively blessed by the FDA certainly the process from API too.

Christy Shafer: Thanks, Brian. And we will take our next question from Peyton Bonsack with TD Cowan. Your line is open.

Scott Braunstein: Hi guys, good afternoon, and thanks for taking our questions. I guess I'm looking forward to potentially seeing positive data. What remains to be done for the NDA package? How quickly do you think, besides the guidance that you've given? And is there anything outstanding on either the safety database that needs to be completed or TMC? And that's it for me.

And IV product is will be new.

We have as many of you know we made a formulation change over a year ago, we did that with guidance from the FDA about half of the study will be actually in patients who have received that new formulation and over the coming weeks. After positive data, we will set up a meeting with the FDA.

Pre NDA CMC meeting very similarly, what we did with Vitol me and that was an incredibly successful strategy for the filing we will want to gather all the data from a roughly a 100 patients to provide that to the FDA, although our expectation that the label will be driven.

Scott Braunstein: Yeah, let me kick it off and then I'll pass it over to Joe. So, for everyone out there, as a reminder, this is the same API material that we have approved in Zitalme. So a substantial proportion of the NDA package has already been effectively blessed by the FDA. Certainly, the process of going from API to an IV product will be new.

From those from the interim and just to share with folks we actually will have 83 patients in the interim we had two patients enrolled in the same day to finish the study because we're Meredith nothing is ever simple.

Scott Braunstein: We have, as many of you know, we made a formulation change over a year ago. We did that with guidance from the FDA. About half of the study will be in patients who have already received that new formulation. And in the coming weeks, after positive data, we will set up a meeting with the FDA, a pre-NDA CMC meeting, very similarly to what we did with Zitalme. And that was an incredibly successful strategy.

But so that anyone will be based on <unk>.

<unk> 83 patients, but we will we are expecting a label around around those 83 patients, but certainly we'll provide all of the safety data and all of the double blind data from all 100 patients as part of the filing we will keep our sites open and we will enroll patients should should the interim I'll be stopped for efficacy.

Scott Braunstein: For the filing, we will want to gather all of the data from roughly 100 patients to provide that to the FDA, although our expectation is the label will be driven from the interim. And just to share with folks, we actually will have 83 patients in the interim. We had two patients enrolled on the same day to finish the study because we're Marinus; nothing is ever simple.

We will continue to enroll patients.

In an open label fashion too.

To allow physicians to experience using the drug and we will also file that that additional open label data with the FDA.

Scott Braunstein: But so that interim will be based on efficacy in 83 patients, but we will, and we were expecting a label around those 83 patients, but certainly, we'll provide all of the safety data and all of the double-blind data from all 100 patients as part of the filing. We will keep our sites open, and we will enroll patients should the interim be stopped for efficacy. We will continue to enroll patients in an open-label fashion to continue to allow physicians to experience using the drug, and we'll also file that additional open-label data with the FDA. Certainly, the regulatory team is expecting to have a pre-NDA meeting with the FDA soon after the top line data, with our current plan for filing the NDA in the first quarter of 25, early in the first quarter.

Certainly the regulatory team is expecting to have a pre NDA meeting with the FDA soon after the top line data with.

With our current plan for filing the NDA in the first quarter of 'twenty five early in the first quarter and Thats really aligned both with the data that we have to compile but equally important.

Our commercial teams best thinking about the time of launch and when we're thinking about major reimbursement, including and tap in 2026. So the wheels are in place tomorrow standpoint to be 100% prepared.

Scott Braunstein: And that's really aligned both with the data that we have to compile, but equally important with our commercial team's best thinking about the time of launch and when we're thinking about major reimbursement, including NTAP in 2026. So the wheels are in place from our standpoint to be 100% prepared, and we'll walk you through as we go through these processes through 2024. Joe, anything that you want to add to the data sets?

I will walk you through.

As we go through these processes through 2020 for Joe anything that you want to add on on the datasets.

No I mean.

Scott mentioned I mean, the pivotal data set for efficacy is going to be the 83 patients from the interim analysis and then we will be supplementing that especially the secondary endpoints will be looking at we expect somewhere around I don't.

We will continue to enroll until the DMC meets but that full data set.

Scott Braunstein: No, I mean, as Scott mentioned, the pivotal data set for efficacy is going to be the 83 patients from the interim analysis. And then we'll be supplementing that, especially the secondary endpoints, we'll be looking at somewhere around, I don't know, we'll continue to enroll until the DMC meets, but that full data set of, who knows how many patients. Enrollment has picked up quite a bit.

How many patients enrolled.

Enrollment has picked up quite a bit.

We will analyze health.

Health care utilization endpoints and secondary endpoints.

On that larger dataset.

And so that will give us more patients with those secondary endpoints.

We will have a good sized safety data set as well as Scott said, especially with continuing to enrol open label, if the DMC stopped the study for efficacy.

Yeah.

Great. Thank you guys. So much. Thank you for your question.

Scott Braunstein: We'll analyze healthcare utilization endpoints and secondary endpoints on that larger data set. And so that'll give us more patience with those secondary endpoints. And, and we'll have a good-sized safety data set as well. As Scott said, especially with continuing to enroll open label at the DMC stopping the study for, Great, thank you guys so much for taking our questions. Thank you. And we will take our next question from Andrew Tsai with Jeffreys. Your line is open. Hey, thanks. Good afternoon,

Thank you.

And we will take our next question from Andrew Tsai with Jefferies. Your line is open.

Hey, Thanks, good afternoon, congrats on the enrollment completion as well as other update so.

Maybe an open ended question for you guys as an investor.

Ask you what are maybe one or two things that keep you up at night.

The phase III <unk> study.

That what what things could have been done better or on an execution or a trial design standpoint, what would they be and then really quickly. If the stopping criteria is not met would you still provide some type of update right away to the street. Thank you yeah. Thanks, Andrew I'll take the second one we will unequivocally update you all on.

Scott Braunstein: Congratulations on the enrollment completion as well as other updates. So maybe an open ended question for you guys. If an investor were to ask you what maybe one or two things that keep you up at night with the phase three RSE study, you know, what things could have been done better or from an execution or a trial design standpoint, what would they be? And then really quickly, if the stopping criteria was not met, would you still provide some type of update? Right away to the street.

Should this should the DSM be suggest that we continue the study. So you should expect some some update from us in the in the first part of the second quarter.

Scott Braunstein: Thank you. Yeah, thanks, Andrew. I'll take the second one.

I think one of the things is probably in the last few weeks that was keeping me awake. These are very complex patients.

Scott Braunstein: We will unequivocally update you all on should the DSMB suggest that we continue the study. So you should expect some updates from us in the first part of the second quarter. I think one of the things probably in the last few weeks that was keeping me awake was these are very complex patients. In our phase two, we had one patient who was on 100 different drugs, and just collecting all of that data, to me, it could create issues. I'm going to really give a shout out to our clinical team who several months ago started to create computer generated checkpoints for the data to make sure that the individual data sets were aligning with our primary end points accordingly and with what physicians were filling out and what was being filled out at the site.

Our phase two we had one patient who was on a 100 different drugs and just collecting all of that data.

Can be.

It could create issues I'm going to really give a shout out to our clinical team with several months ago started to create really computer generated checkpoints for the data to make sure that the individual datasets, we're aligning with our primary endpoints accordingly.

And with the.

Physician Brookdale hung out and what was being filled out at the site and we could do that in a way to really ensure a high quality of the data I would say as Joe as Joe mentioned in his prepared remarks.

Scott Braunstein: And we could do that in a way to really ensure the high quality of the data. I would say, as Joe mentioned in his prepared remarks, we finished enrolling the study at the end of January. We've now had several weeks to start cleaning the data, and so I feel what was keeping me awake at night was the integrity and the complexity, but I think the team has really worked hard to get us there, and we're confident in delivering the data set as we talked about and probably even more excited about sharing some of the secondaries in the fall as well. Great, Andrew. So, in the last few weeks, the team's made great progress, and we are looking forward to seeing you. This has been a three-year project, a labor of love.

Finished enrolling the study at the end of January we've now had several weeks to start clean in the data and so I feel.

What was keeping me awake at night was the integrity and the complexity, but I think the team has really worked hard to get us there.

We're confident in delivering the data set as we talked about and.

And probably even more excited about sharing some of the secondaries in the fall as well Andrew So.

Last few weeks.

Team has made great progress and we are looking forward. This has been a three year project a labor of love.

Scott Braunstein: I think our clinical team has done an amazing job of enrolling the right type of patients for this study, and I think we're going to unequivocally know that not only does this drug work, but it can have a material impact in the treatment of refractory status patients. And I was just at a meeting in Orlando this weekend.

I think our clinical team has done an amazing job and they're rolling the right type of patients for this study and I think we're gonna unequivocally no that not only does this drug work, but can it have a material impact in the treatment of refractory status patients and I was just at a meeting in Orlando This weekend and that with five investigators.

Scott Braunstein: I met with five investigators, and there was a lot of excitement about the data set from the investigator team. And I think they're equally excited to see the results as well. Thanks for the question. Great. Yep. Fingers crossed. Thank you. Bye. We will take our next question from Charles Duncan with Cantor Fitzgerald. Your line is open.

It was there was a lot of excitement about the data set from from the investigator team in and I think they're equally excited to see the results as well.

Thanks for the question.

Fingers crossed thank you Scott.

Thanks.

We will take our next question from Charles Duncan with Cantor Fitzgerald. Your line is open.

Yeah, Hey, good afternoon, Scott and team congrats on completing that enrollment and commercial progress in the year I had a question regarding raise one I can't recall, if you've ever shared with us stopping rules and if you don't want to be all that granular. If you could just give us some guideposts and then also I guess.

Scott Braunstein: Yeah, hey, good afternoon, Scott and team. Congratulations on completing that enrollment and commercial progress this year. I had a question regarding RAISE-1. I can't recall if you've ever shared with us stopping rules. And if you don't want to be all that granular, if you could just give us some guideposts.

Hear anything about second generation <unk> do you have any color on the progress there.

Scott Braunstein: And also, I didn't hear anything about second-generation Orokin Axelon. Do you have any color on the progress there? Thanks. Thanks, Charles. I'm going to pass over the stopping criteria to Joe, but I'll just quickly say we didn't talk on this call. We were trying to keep the call brief, number one, so we kept it to 30 minutes.

Thanks, Charles I'm going to pass over the stopping criteria to Joe, but I'll just quickly say we didn't talk on the on this call. We were trying to keep the <unk> brief number one so we kept it to 30 minutes on the second Gen program.

I would tell you all of that we're really thinking about our pro drug program now being our lead candidate <unk>.

We're doing our IND, enabling work we have a very high reason to believe that the prodrug both.

Scott Braunstein: On the second-gen program, I would tell you all that we're really thinking about our prodrug program now being our lead candidate. We are doing IND-enabling work. We have a very strong reason to believe that the prodrug, both Gadasolone and the cleavage of the prodrug, structurally looks incredibly safe. We will have that data over the summer, which, in my view, is a de-risking event. For those of you who are not too familiar with what we talked about in the prodrug program, the data looks to have a once-a-day dosing regimen, a blunted C-max, we'll have new intellectual property, we'll have improved cost of goods, and there are some other important business issues that we will talk about over the coming months in the prodrug program.

AST alone and the cleavage of the prodrug structurally looks incredibly safe, we will have that data over the summer, which in my view as a derisking event for those of you who are not too familiar with what we've talked about in the pro drug program.

The data looks to have a once a day dosing regimen, a blunted C. Max will have new intellectual property will have improved cost of goods and there are some other important business issues.

Issues that we will talk about over the coming months on the project program and so our hope would be that we will finish that IND, enabling work by year end and be able to take that program into the clinic next year.

And quite honestly, that's going to align great with TLC data and the additional study that we're going to.

To start in the fourth quarter in other refractory Epilepsies, Joe you want to talk about the stopping criteria.

Yes sure.

Wanted to share with the details of that are so the stopping criteria based on the co primary endpoints.

Scott Braunstein: Our hope is that we will finish that IND-enabling work by year-end and be able to take that program into the clinic next year. I think, quite honestly, that's going to align great with TSC data and the additional study that we're going to start in the fourth quarter in other refractory epilepsy. Joe, do you want to talk about the stocking criteria?

Cessation within 30 minutes and lack of progression to IV anesthesia within 36 hours.

Each of their co primary endpoints of both of those need to hit on the statistical significance independently and the way.

The powering is based on an alpha spending function.

P value required P value at the interim 0.0 to 93.

Joseph Hulihan: Yeah, sure. We're glad to share what the details of that are. So the stopping criteria are based on the co-primary endpoints, cessation within 30 minutes and lack of progression to IV anesthesia within 36 hours. So both of those co-primary endpoints, so both of those need to hit statistical significance independently. And the way, you know, the power is based on an alpha spending function.

And that with that P value, we have over 90% power to detect a 40% treatment difference.

With that said if we get.

Delta is 20.

25%, 30% it will still be statistically significant the analysis is very robust.

And so.

We have a lot of power at the interim analysis based on based on the 83 patients.

And then we'll also be looking at the key secondary endpoints at the interim but.

Joseph Hulihan: The P value required P value at the interim is 0.0293. And with that P value, we have over 90% power to detect 40% treatment. You know, with that said, if we get deltas of 25-30%, it will still be statistically significant. The analysis is very robust.

The stopping rules depend on the co primaries.

Very helpful. Thanks for the added color.

Thanks Charles.

And we will take our next question from Joon Lee with true Securities. Your line is open.

Hey, congrats on the enrollment as well and picking and thanks for taking our questions.

Good to hear that you're already planning for the launch of support me in aggregate are slow next year.

Joseph Hulihan: And so, we have a lot of power at the interim analysis based on the 83 patients. And then we'll also be looking at the key secondary endpoints at the interim, but the stopping rules depend on the co-primary. Very helpful. Thanks for that. Shruthi.

As you do the market research and preparation for launch is there a specific efficacy profile that patients are looking for the docs are looking for and is that consistent with your pre specified prespecified stopping criteria. Thank you.

Joseph Hulihan: Thanks, Charles. And we will take our next question from Joon Lee with Truist Securities. Your line is open.

Christy Shafer: Hey, congrats on the enrollment as well and thanks for taking our questions. You know, it's good to hear that you're already planning for the launch of the POMI and IBK National next year. You know, as you do the market research in preparation for launch, is there a specific efficacy profile that patients are looking for, the doctors are looking for, and is that consistent with your pre-specified stopping criteria? So I just want to be clear about the market research on the IV form of Zithromax and Ganaxalone. Yeah, or or Zutomi for TSC.

So I just wanted to be clear the market research on the IV form of the top.

<unk>.

Yeah.

Or is it told me for TLC I wanted to be clear.

I think in that growth actually both actually but I think it might be.

Yes.

Christy I'm happy to pass it to you.

Yeah as Scott mentioned.

Do you think that keeps him up at night is that these patients are quite sick and I think what we've learned in our market right. There. Yes patients are quite secondly that the value that we believe that <unk> can bring its quite expensive because everything is confirmatory everything that had been done and raised one to identify these patients.

Christy Shafer: I wanted to be clear. Yeah, both actually. Both actually, but I think an actual would be nice.

Christy Shafer: Yeah. Chrissy, I'm happy to pass it to you. Yeah, as Scott mentioned, one of the things that keeps him up at night is that these patients are quite sick. And I think what we've learned in our market research is, yes, these patients are quite sick. And the value that we believe that iVEGAN-XLO can bring is quite extensive because everything is confirmatory; everything that has been done in Phase 1 to identify these patients is really what we've seen in real world evidence as well. So they really mirror each other.

Really what we've seen in real world evidence as well so they really near each other in quite frankly that super supportive that the commercialization efforts that we're trying to down similarly on the Tommy side of the business.

I think that it is really important that we realize that that's in the refractory patient population and entrust JSC. It didnt exactly what they've been doing there as well little bit different from <unk>, but again, it's super refractory patient and kind of again exactly who would be commercial I think bore.

Christy Shafer: And quite frankly, that's super supportive of the commercialization efforts that we're trying to build. Similarly, on the Zotomi side of the business, I think that it is really important that we realize that this is the refractory patient population. And in Trust TSC, that is exactly what they have been doing there as well.

Yeah, and the only thing I'll add to Christy's comments is that I mean.

The literature is quite clear that IV anesthesia leads increased morbidity and mortality and I think we design that phase III trials, specifically to replace <unk>.

Christy Shafer: Little bit different from CBD, but again, it's super refractory patients. And so again, exactly who we'd be commercializing for. Yeah, and the only thing I'd add to Christy's comments is that, you know, the literature is quite clear that IV anesthesia leads to increased morbidity and mortality, and I think we designed that phase 3 trial specifically to replace a treatment paradigm that is antiquated and really deleterious to the patient's outcome. So, in my mind, the study design, in and of itself, is exactly what physicians told us they wanted, and certainly I Thanks for the question. I'm looking forward to it. Thank you, www.thevenusproject.com, and we will take our next question from Marc Goodman with Lyrinc Partners. Your line is open. Hi, good afternoon. This is Basma on behalf of Marc.

A treatment paradigm, which is antiquated and and really deleterious to the patient to outcome.

That in my mind.

The study design in of itself, it's exactly what physicians told us they wanted.

And certainly I think it is going to be critical for the for the IV launch. Thanks. Thanks for the question June looking.

I'm looking for thank you.

Yeah.

And we will take our next question from Marc Goodman with Leerink Partners. Your line is open.

Hi, Good afternoon. This is Matt on for Mark Thanks for taking our question.

I have a question regarding grace.

First of all and connect your line is a proven ISC how much off label use would you expect in the U S. E. S. S E settings.

Scott Braunstein: Thanks for taking our question. I have a question regarding race. So if race is successful and gonaxaline is approved in RSE, how much off-label use would you expect in the ESE and SRSE settings? And along the same lines, you mentioned that 10% of Ptolemy sales are coming from off-label use. Would you expect this percentage to stabilize or increase? Thank you. Well, let me start with the second question, and then we'll work our way to the first.

And along the same lines. What you mentioned that there are 10% of <unk> sales are coming from off label use.

Would you expect this percentage to stabilizer to increase.

Thank you.

Well, let me.

Let me start with the second question and then we'll work our way than the first.

Look I think we as a company will never predict nor give specific estimates about off label use.

Scott Braunstein: Look, I think we, as a company, will never predict nor give specific estimates about off-label use. Our sales organization is hyper-focused on the CDD population, hyper-focused on educating physicians about the use of genetic testing, and we would be the same with TSC. That said, traditionally, I mean, you know the market better than we do.

Our sales organization is hyper focused on the CBD population hyper focused on educating physicians about the use of genetic testing and we would be the same with PSC that said traditionally as you know the market better than us when GW is was an independent company.

Scott Braunstein: When GW was an independent company, we saw epidiolic sales as high as 20 or 25 percent in the spontaneous use category. I think we will focus on doing additional studies, either with Zytomy or second generation, and drive for label expansion over the coming years, but I think it's pretty clear that there are a significant number of patients with needs in the refractory epilepsy population. So, you know, I think it's great to see that physicians are asking payers to try Zytomy. It's great that payers are reimbursed, and we're seeing about the same discontinuation rates in CDKL5 patients, a low 20 percent range.

But I'll, let sales as high as 20 or 25% in the spontaneous use category I think we will focus on doing additional studies, either with Vitol me or second generation and dry for label expansion over the coming years, but I think it's pretty clear that there is a significant number of patients with <unk>.

With needs in the refractory epilepsy population. So I think it's great to see that physicians are asking payers. Two tries. It told me it's great that payers are reimbursing and we're seeing about the same discontinuation rates and CDK <unk> five patients.

Low 20% range. So that's also encouraging on the efficacy side on the IV side. The commercial team will be hyper focused on the refractory status population.

Scott Braunstein: So, that's also encouraging on the efficacy side. On the IV side, the commercial team will be hyper-focused on the refractory status population. I think that is our best strategy for reimbursement, for formulary acceptance. I think we really believe that there are three major parts of the refractory population, and we will start with the most difficult to treat and continue to focus on the importance of earlier intervention, where there is significant data in the literature that the later you treat status patients, the worse their outcomes. The longer status patients are in status, the worse their outcomes, and we have good justification for moving up the treatment paradigm, starting with RAISE-2, but other studies that we are considering today. I think we find equally compelling the super refractory opportunity.

That is our best strategy for reimbursement for formulary acceptance I think we really believed that there are three major parts of the refractory population and we will start with the most difficult to treat and continue to focus on the importance of earlier intervention where.

There is significant data in the literature that the later you treat status patients the worst outcomes the longer status patients are in status the worst outcomes and we have good justification for moving up to treatment paradigm, starting with the raise too but other studies that we are we are.

And today I think we find equally compelling is the super refractory opportunity. We think there are about 5000 patients in the U S. Today suffering from Super refractory status. The typical <unk> patients that we are seeing today.

Scott Braunstein: We think there are about 5,000 patients in the U.S. today suffering from super refractory status. The typical EIND patients that we are seeing today are spending about 30 days in the ICU, as physicians are asked to use our drug on a compassionate use basis. We continue to get one to three requests a month.

Spending about 30 days in the ICU as physicians asked to use our drug on a compassionate use basis, we continue to get one to three requests a month. We've had two more request. This month as <unk> and I think are a critical goal for us is to go back.

Scott Braunstein: We've had two more requests this month for EINDs, and I think our critical goal for us is to go back to the FDA and agree on a dosing strategy, which would change from the RAISE dosing of 830 milligrams and 50 grams of Captazol to a daily dose of about a little over 1,000 milligrams of Gonaxalone and 63 grams of Captazol. We think there's adequate safety there, but we do want to go to the FDA, get their approval, and Joe is working on that final clinical trial design. Christy, on the commercial side, do you want to add anything? You know, honestly, Scott, I think you hit on all points beautifully. Thanks. Good Thanks so much.

To the FDA and align on a dosing strategy, which would change from the raise dosing of 830 milligrams and 50 grams of Captisol to a daily dose of about a little over 1000 milligrams of <unk> 63 grams of Captisol, we think there's adequate safety.

There, but we do want to go to the FDA get their alignment and Joe is working on that final clinical trial design of Christie on the commercial side do you want to add anything.

Got it. Thank you hit on a point I wonder if I could.

Thanks, so much thanks for the question.

Scott Braunstein: Thanks for the question. Thank you. And we will take our next question from Douglas Tsao with H.C. Wainwright. Your line is open.

Kim.

And we'll take our next question from Douglas Tsao with H C. Wainwright Your line is open.

Christy Shafer: Hi, good afternoon; thanks for taking the questions and congratulations on all the progress. Maybe starting with Satomi, just given that now we're entering our, I guess, third year of commercialization, I'm just curious if we've seen a shift in where new patients are coming from and how that's evolved, and how you expect to see that sort of change over the next 12 to 24 months. And then I have a follow-up on the IV franchise. Chris, do you want to jump in?

Hi, good afternoon, Thanks for taking my questions and congrats on all the progress.

Maybe starting with tatami, just given now where we're entering our I guess, our third year of commercialization.

Curious.

Yes, we've seen a shift in where new patients are coming from and how that's evolved and how you expect to see that sort of change over the next 12 12 months to 24 months and then I have a.

A follow up on on the IV franchise.

Okay.

Chris you want to jump in.

Absolutely alright, thanks for the call.

Christy Shafer: Absolutely. Thanks for the call, Doug. You know, over time, we launched this drug in September of 2022, and there were a couple of interesting things to start.

You know over time, where we launch this drug in September of 2022, and there were a couple of interesting things to start after we really leveled off patients are coming from a myriad of places we get an enormous amount of patience from our centers of excellence I'll remind you there's 10 of them.

Christy Shafer: But after we really leveled off, patients are coming from a myriad of places; we get an enormous number of patients from our Centers of Excellence, I'll remind you, there are 10 of them across the United States. But these patients are also being seen by their local or community physicians on a regular basis. And so we tend to see great involvement from pediatric neurologists or pediatricians in some sort of function around these patients throughout. So what we do know is that the targeting that we've done has been very, very good from 22 to now. We've now given that a little bit more of a kick, if you will, and it's a little bit more robust for 2024. And we've broadened our scope a little bit on who we're targeting. But I don't see us targeting differently, just a little bit more broad going into 2024.

Across the United States, but these patients also are being seen by their and their local our community physicians on a regular basis and so we tend to see great involvement from pediatric neurologists or PD attrition is in Santa Clara function around these patients throughout so.

We do know is that.

The targeting that we've done has been very very good from 'twenty two to now we've now given that a little bit more of a check if you will and it's a little bit more robust for 2024, and waves, which broadened our scope a little bit on who we're targeting but I don't see us targeting differently, just a little bit more broad going.

Into 2024, and Theres not wild shifts on who is writing for the drug.

Christy Shafer: And there are not wild shifts in who's writing for the drug. Okay, great. That's really helpful.

Okay, Great. That's really helpful. And then just to understand a little bit what you are trying to do and Src.

Scott Braunstein: And then just to understand a little bit what you're trying to do in SRSC, Joe, you spoke about, and Scott as well, about getting alignment with the FDA in terms of the higher doses. My guess is you're not planning on sort of doing another sort of placebo-controlled study in SRSC. I'm just curious in terms of the language or sort of on the dosing, would it be sort of just because SRSC in theory should be on label as your label will be in terms of RSC. Would it just be labeling to give specific guidance for that 1,000 milligram dose for an SRSC patient or would it just be sort of providing looser language that you can dose up to 1,000 milligrams a day? Thank you. Let me kick it off, and then, Joe, I'll pass it to you.

Joe you spoke about and Scott as well about getting alignment with the FDA in terms of the higher dosing.

Mhm.

My guess is youre not planning on sort of doing another sort of placebo controlled study in Src I'm just curious in terms of the language or sort of on the dosing would it be but it is just because src in theory should be on label to what your label will be in terms of RSA would it just be labeling to give specific guidance.

For that thousand milligrams dose.

And Src patient or would it just be sort of providing lucia language that you can dose up to 1000.

Milligrams a day thank you.

Let me kick it off and then Joe I'll pass it to yet.

Scott Braunstein: Yeah, Doug, I mean, you know, we're expecting our label to be the raised regimen, which is that 830 milligrams over 24 hours, which contains 50 grams of capsizole. So we want to unequivocally align with the agency that that higher dose can be studied safely. We don't think it'll be an issue. Almost all of these EID patients have gotten 63 grams of capsizole. We have not seen a renal signal. We've never asked the agency because we've never had to go that high for a raise.

We're expecting our label is going to be the the.

The rays regimen, which is that 830 milligrams over 24 hours, which contained 50 grand for Captisol. So we want to unequivocally align with the agency that that higher dose can be studied safely.

Don't think there'll be an issue almost all of these patients have gotten <unk> in caps is all we have not seen a renal signal we've never ask the agency because we never had to go that high for array. So we want to get their buy in and and along with that buying we will be doing what will be a single arm study and I'm going to pass.

Scott Braunstein: So we want to get their buy-in, and along with that buy-in, we will be doing what will be a single-arm study, and I'm going to pass it over to Joe. And, yeah, I don't think there's any reason that we need to do a double-blind placebo-controlled trial in this population. I think we need to show safety in this population, but all of those patients would have failed multiple therapies, and I think that's the way we're approaching it. I think we also want to really create a more robust data set for the drug outside of simply our raise and raise-to populations. Joe, do you want to talk about what you're thinking about for a trial design?

It over to Joe and Yeah, I don't think there's any reason that we need to do a double blind placebo controlled trial in this population I think we need to show safety in this population, but all of those patients would have failed multiple therapies.

And I think that's the way we're approaching it and I think we also wanted to really create.

A more robust data set for the drug outside of simply are raised and raised two populations. Joe you want to talk about what Youre thinking about trial design.

Joseph Hulihan: Yeah, we've been working on this with Henrikas Vaitkevicius, you know, our former Brigham ICU doc who's been really leading the design on this, and we're looking at Scott mentioned a single arm open label trial. The dosing regimen is different. It raises 48 hours, has been several days this dosing regimen we've implemented more recently for the emergency INDs and without as much of a bolus up front. It's really a different approach.

Yes, we've been working on this with Henry <unk>.

Barbara <unk> former Brigham.

<unk>, who has been really leading the design on this.

We're looking.

Looking at Scott mentioned single arm open label trial.

The dosing regimen is different.

Whereas races 48 hours.

<unk> been several days.

Dosing regimen, we implemented more recently for the emergency IND.

And without as much of a bolus upfront, it's really a different approach we start the drug while the patients on IV anesthesia continue it for a period of time and then bring it down and then dosing totaled a highest daily doses.

Joseph Hulihan: We start the drug while the patients are on IV anesthesia and continue it for a period of time, and then bring it down to a dose of total highest daily dose is 1050 milligrams per day, and as Scott mentioned with 63 grams of captives, And as I said, you know, we've treated over 25 patients with this regimen, including children. And we haven't seen any safety signals from this higher dose. And it looks like this higher dose regimen, it's hard to say based on the EINDs with 100% certainty, but it looks like it's having an effect beyond the regimen that we had used previously, which was basically the RAISE regimen. So we really want to make sure that, you know, if doctors are going to use it, that they use it appropriately. It's not anything we promote, but I do think, potentially, they'd use it.

50 milligrams per day, and as Scott mentioned with 63 grams of Captisol and as I said, we've treated over 25 patients with this regimen, including children and we haven't seen any safety signals from this higher regimen.

And it looks like this higher dose regimen.

It's hard to say based on the <unk> with 100% certainty, but it looks like it's having an effect beyond the regimen that we used previously which was basically the raise regimen. So we really want to make sure that.

If docs are going to use it that they.

They use it.

Appropriately.

Not anything we promote but I do think potentially they abuse it and so the dosing regimen is different and we want to we want to get some data on that from a clinical trial.

Joseph Hulihan: And so the dosing regimen is different. And we want to, we want to get some data on that from a clinical trial. And so, Joe, just as a final clarification, would you anticipate having that new dosing regimen on the label itself, or would it just be to get the higher dosing limits sort of on the label? I mean, this is a first step.

And so just as the final clarified so would you anticipate having that new dosing regimen on the label itself or would it just be to get the higher dosing limits.

On the label.

This is a first step it's a proof of concept study.

Joseph Hulihan: It's a proof of concept study, so I think it depends on what we see there. But, I mean, we're just taking it a step at a time. We really need to see, you know, some kind of safety and preliminary efficacy from a proof of concept study. And, Scott, I don't know if you have any more comments about the dosing and... No, I think you're right on target, Joe. I think, Doug, after we have this data, we'll go to the FDA, the team's ready to go, and we'll hear what they have to say, and we certainly see it as next steps. I mean, I think I'd love to see us get safety into the label, but we haven't had those discussions with the agency yet. But, certainly, that would be our goal, our hope, and our plan. Okay, great. Thank you so much. Thanks for the question....

So I think it depends on what we see there.

But I mean, we're just taking it a step at a time when we really need to see.

Kind of safety and preliminary efficacy from a proof of concept study and Scott I don't know if you have any more comments about the dosing at me.

No I think youre right on target with Joe I think I think Doug. After we have this data will go to the FDA and the team is ready to go and we will hear well, we'll hear what they have to say and we certainly see it as next steps I think I'd love to see us get safety into the label, but we haven't had those discussions with the agency, yet, but but certainly that would be our goal.

Our open our plan.

Okay, great. Thank you so much.

Thanks for the question.

Okay.

Scott Braunstein: And we'll take our next question from Jason Butler with Citizens JMP. Your line is open. Hi, thanks for taking the question, and let me add my congratulations on all the progress. Just one about the proof-of-concept study for oral gonaxalone and Lennox-Gastaut and the other rare epilepsies. Can you maybe just speak to the amount of data you would need to generate from that study before moving into a registration study in any specific patient population? And would there be any opportunity in that study to introduce the next-gen formulation, the prodrug formulation, or when would be the first time that you could bring that formulation into this patient population? Thank you.

And we will take our next question from Jason Butler with citizens JMP. Your line is open.

Hi, Thanks for taking my question and let me add my congrats on all the progress just one about the the proof of concept study for Oregon ex loan in Lennox Gusto and.

The other rare epilepsy.

Could you speak to the amount of data you would need to generate from that study before moving into a registration study and any any specific patient population and would there be any opportunity in that study to introduce the next gen formulations of the prodrug formulation or when would be the first time that you could bring that.

Enter into this patient population. Thank you.

Joseph Hulihan: John, let me kick it off, and then I'll pass it over to you for the trial design. Jason, what we're really thinking is that this will be a Zitolamie study, and I think, quite honestly, five years ago, I would have felt crazy to run this study. But given what we now understand about Zitolamie, the PK, the PD, the blood levels, and what we've seen over the years, a consistent improvement in serum concentrations of the drug. And when we finish the TSC study, we'll be happy to share some of the blood levels in TSC, but we've seen them in other healthy volunteer studies, our SAD, and MAD studies, and certainly, we're feeling good about the discontinuation rates in the real world.

Germany kick it off and then I'll pass it over to you for the trial design, Jason what we're really thinking that this will be as the Tommy study and I think quite honestly five years ago I would have felt crazy to run this study, but given now what we understand about the telling me the PK the PD the blood levels.

And what we've seen over the years of consistent improvement in serum concentrations of the drug and buy the and when we finished the PSC study, we'll be happy to share some of the so we haven't seen the blood levels and TLC, but we've seen them in other healthy volunteer studies.

<unk> studies and certainly we're feeling good about the discontinuation rates in the real world. So I have a heck of a lot more confidence today that in any study with Vitol me, we can get the vast majority of patients to a therapeutic blood level and.

Joseph Hulihan: So I have a heck of a lot more confidence today that in any study with Zitolamie, we can get the vast majority of patients to a therapeutic blood level. And I think our goal in this study is to really show that proof of concept, and I'll let Joe talk about that. I think what we also want to walk away with is where we think Gnaxolone as a molecule is most effective, if not only in LGS but in other refractory DEEs.

And I think our goal in this study is to really show that proof of concept then I'll, let Joe talk about it I think what we also want to walk away is where do we think good axon as a molecule is most effective if not only in lgs, but it is in other refractory <unk>, but I would not expect this stuff.

Scott Braunstein: But I would not expect this study that we will kick off to really include that second gen. We'll use this study to help guide us on efficacy and where we want to go with the Pivotal, and we'll take the next gen through the SAD and MAD studies, and hopefully those will align in terms of what we want to do with the pro-drug program. And I think we have the luxury of a little time to get this right, to be thoughtful. We've got two launches that we'll be planning for in the next 25, so that will keep us pretty busy.

With that we will kick off to to really include that second Gen. We will use this study to help guide us on efficacy, where we want to go with a pivotal and we'll take the next gen do the Ma.

<unk> studies and hopefully those will align in terms of what we wanted to do with the with the pro drug program.

And I think we have the luxury of a little time to get this right to be thoughtful.

We've got two launches that will be planning for and 25, so that will keep us pretty busy and but that being said I think there are not a lot of folks who are really thinking about these patients and it is a priority for us to get there do you want to talk a little bit more about the trial design.

Joseph Hulihan: But that being said, I think there are not a lot of folks who are really thinking about these patients, and it is a priority for us to get there. Joe, do you want to talk a little bit more about the trial design? Yeah, so again, these would be the initial trials, proof of concept, single-arm open label. We have not yet done the detailed discussions about what statistical signal we want to see to say the drug is particularly effective in condition X. I mean, I think there are a lot of things we can get out of such a study besides signal finding. I mean, we can look at signals based on the genetic etiology, the seizure phenotype, and the type of seizure.

Yes.

The trial design.

So.

Again this would be the initial trials proof of concept single arm open label.

We have not yet done.

Detailed discussions about.

Whats statistical signal, we'd want to see.

To say the drug is particularly effective and condition X I think there are a lot of things we can get out of such a study.

Besides signal finding I mean, when you look at signals based on the genetic etiology.

Seizure phenotype type of seizure.

Joseph Hulihan: We could also get information on non-seizure outcomes, um, some preliminary PK PD data, and also information to inform other pieces of the study selection of the clinical endpoint. Even, you know, how we collect the data, how we do the measurement, and a basis for statistical, more than statistics within the study itself, a basis for statistical powering on any subsequent study we would do. The general comment would be, if everything, if we overall get a good effect and every, you know, every subset seems to be trending in the same direction, um, that'll tell us one thing, but if something happens to pop up, we may get patients in the study with specific disorders of GABAergic, and Transmission that may show a differential effect. All of those things will be reported.

We can also get information on non seizure outcomes.

Some preliminary PK PD data.

And also information to inform other pieces of our study design.

Selection of the clinical end points.

How we collect the data how we do the measurement.

And a basis for statistical more than statistics within the study itself a basis for statistical powering on any subsequent study we would do.

The general comment would be.

If everything.

If overall, we get a good effect in every every subset seems to be trending in the same direction.

That'll tell us one thing, but if something happens to park, we may get patients in the study with specific disorders of Gaba urgent.

Transmission.

So a differential effect all of those things will be informative.

Joseph Hulihan: In terms of how much of a signal we don't think we have a, We haven't done the statistical powering on that yet. A lot of the, a lot of the descript, a lot of the statistical descriptions in the study will be purely descriptive statistics without any priority. Statistical Power.

In terms of how much of a signal.

I don't think we have.

We haven't done the statistical powering on that yet.

A lot of a lot of the Descript a lot of the statistic.

Statistical descriptions.

In the study will be purely descriptive statistics without a priori.

Statistical powering.

Okay, great. Thanks for the question operator, we're going to take one more question from the call in and then we're going to have to cut the call.

Joseph Hulihan: Thanks Joe, thanks for the question. Operator, we're going to take one more question from the caller and then we're going to have to cut the call. Thank you. We will take our final question from Brian Skorney with Baird. Your line is open.

We will take our final question from Brian <unk> with Baird. Your line is open.

Scott Braunstein: Hey, good afternoon, guys. I just wanted to ask a question about RAID and sort of the powering assumptions there. And it was originally powered for 40 percent delta, and I think you've been talking about as low as 30 percent delta to reach STAT-SIG. I'm just wondering how to kind of think about that 30 percent delta. Is that based on blinded response rates overall in this study, just kind of going through the powering analysis and how different results wind up hitting STAT-SIG at 83 patients? So, I don't know, is that informed at all by blinded analysis, or is that consistent with the original analysis? And can you review any of the statistical assumptions underpinning the time to cessation analysis as a secondary endpoint since it's not a binary outcome? Just what sort of separation do you need to see there to be STAT-SIG? Thanks. Joe, let me kick it off, and then I'll turn it over to you.

Hey, good afternoon guys.

Just wanted to ask a question on also on raising sort of powering assumptions.

It was originally powered for 40% felt and I think you've been talking about as low as 30% Delta to reach that so I'm just wondering how I'm trying to think about that 30%.

Delta is that based on blinded response rates overall in the study just kind of going through the powering analysis, how different results wind up hitting stops.

At 83 patients.

So does that inform that all backed by a blinded analysis of surgeries, but consistent with the original analysis can you review or any of the statistical assumptions underpinning the time for cessation analysis.

The secondary endpoints and so it's not binary outcome, just what sort of separation you need to see there to be satisfied.

Joe Let me kick off and then I'll turn it over to you. So Brian we have not looked at the blinded data. It's had no impact on our decision making here I think when we started the study we really could not get a.

Joseph Hulihan: So, Brian, we have not looked at the blinded data. It's had no impact on our decision making here. I think when we started the study, we really could not get a very comfortable handle on where placebo rates would be in the study. But it was very clear to us that once we started the study and we added a protocol amendment and we had our physicians really screening every patient, our confidence continued to grow that we were seeing a highly refractory population that was very likely going to have a low placebo rate. You know, we've shared that blinded data with you.

Comfortable handle on where placebo rates would be in the study I think it was.

Very clear enough to once we started the study and we added a protocol amendment and we had our physicians really screening every patient our confidence continued to grow that we were seeing a highly refractory population that was very likely going to have a low placebo rate.

We've shared with you that blinded data the average patient in this study is not failing three and a half drugs three three and a half drugs. They are being observed for 24 hours compared to about eight hours for our phase two.

Scott Braunstein: The average patient in the study is failing three and a half drugs, three to three and a half drugs. They're being observed for 24 hours compared to about eight hours for our phase two, and, you know, giving us a lot of confidence that physicians have run out of options. And our clinical team has pressed every enrollment, every physician on enrollment, making it crystal clear that if a patient was to be enrolled, the physician had to feel comfortable that an IV anesthetic was the next drug of choice. Now, that being said, there are still going to be some placebo patients that probably, or drug patients that still are having epileptiform activity and are not getting IV anesthesia. Physicians are not perfect beasts, but we feel quite confident that the placebo rate will come in lower than our original assumption of 30 to 40%. I don't think we had any magical way to really think about that when the study started, given that the only publication suggested about a 9% response rate in third-line patients. So I think we have just seen this patient, this study progress. We feel very good about it.

Giving us a lot of confidence that that physicians have run out of options and our clinical team has pressed every enrollment every physician on enrollment may.

Making it crystal clear that if a patient wants to be enrolled the physician how to feel comfortable that IV anesthetic was an extra added choice now that being said there are still going to be some placebo patients that probably or or drug patients that still are having epileptiform activity and are not getting IV anesthesia positions are not perfect piece.

But we feel quite confident that the placebo rate.

Come in lower than our original assumption of 30% to 40% and I don't think we had any magical.

A way to really think about that when the study started giving up the only publications suggest at about a 9% response rate in third line patients. So I think we have just seen this patient.

This study progress we feel very good about it we feel that we're <unk>.

Scott Braunstein: We feel that we're likely overpowered for a 40% delta from where we were, and we think for the interim analysis, these 83 patients will be more than sufficient. Joe, do you want to talk about the secondaries and then we're going to wrap? Yeah, yeah, yeah. Yeah, just real quick about, I mean, the power calculation. The hardest data we had was from a survey of the investigators of the sites.

Likely overpowered for a 40% Delta, where we were and.

And we think for the interim analysis. These 83 patients will be more than sufficient Joe you want to talk about the secondaries and then we're gonna Rep. Yeah, Yeah, Yeah, just real quick about the power calculations. The hardest data we had was from a survey of the investigators.

Of the sites when they when we presented them with the profile based on the inclusion criteria. They said that they were advanced to IV anesthesia.

Joseph Hulihan: When we presented them with the profile based on the inclusion criteria, they said that they would advance to IV anesthesia 70% of the time within two hours. And so 70%, you know, advanced that gives the 30% not advanced there, would be basically what we would translate to the placebo rate of 30-35 percent. In terms of the secondaries, you know, the time to status cessation, we expect that actually to be. It's a continuous variable, so even more robust than the responder analysis on the primary, and the way status would stop. In phase two, it was a median of five minutes in the Ganaxalong group, but patients in the placebo group aren't going to stop spontaneously. When they will stop, it's when they're treated, and so that's going to be a period of hours, probably in most cases. And so that continuous variable is extremely robust in terms of Statistical Power.

70% of the time within two hours.

So 70%.

Advance that gives the 30% not advance theres there would be basically what we would translate to the placebo rate 30% 35%.

In terms of the secondaries, the time to scatter cessation.

We expect that actually to be.

It's a continuous variable so even more robust than the responder analysis on the primary and the waste status would stop.

In the phase II. It was a median of five minutes in the in the <unk> group.

Patients in the placebo group aren't going to stop spontaneously when they'll stop it when they're they're treated and so that's going to be a period.

Ours, probably in most cases.

So that continuous variables extremely robust in terms of.

Statistical power.

Great. Thanks, a lot.

<unk>.

And ladies and gentlemen that is all the time, we have for questions. Today. This will also conclude today's call. We thank you for your participation and you may now disconnect.

Joseph Hulihan: Great, thanks a lot. Mm-hmm. And ladies and gentlemen, that is all the time we have for questions today. This will also conclude today's call. We thank you for your participation, and you may now disconnect.

Okay.

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Sure.

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