Q2 2024 Marinus Pharmaceuticals Inc Earnings Call

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Operator: Drone, Drone, Drone [inaudible] E. E. E. E. E. E. E. E. E. E. E. E. E. E. E. E. E. D.O.A. D.O.T. John Williams, John Williams, John Williams, John Williams, John, E. E. E. E. E. E. A-A-A-A, Music Plays [inaudible] Drone, Drone, Drone, Drone, Drone, Drone, Drone, Drone, Drone, Ruh, Ruh, Ruh, Ruh, Ruh, Ruh, Ruh, Ruh, Ruh, And a few days later, a few days later, a few days later, a few days later, Greetings and welcome to Marinus Pharmaceuticals second quarter financial results and business update call.

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Sonia Weigle: Greetings and welcome to the Mariners Pharmaceuticals second quarter financial results and business update call. If anyone today should require operator assistance during the conference, please press star zero from your telephone keypad. It is now my pleasure to introduce your host, Sonia Weigle, Chief People and Investor Relations Officer. You may now begin, Ms. Weigle.

Operator: If anyone today should require operator assistance during the conference, please press star zero from your telephone keypad. Now, it is my pleasure to introduce your host, Sonya Weigle, Chief People and Investor Relations Officer. You may now begin, Ms. Weigle. Thank you and good morning.

Sonya Weigle: With me from Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer, Lisa Lejuwaan, Senior Vice President and Business Unit Lead, Rare Genetic Epilepsy, 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 under the securities law. 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 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.

Speaker Change: Thank you and good morning.

Speaker Change: With me from Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer.

Speaker Change: Lisa Lejewan, Senior Vice President and Business Unit Lead, Rare Genetic Epilepsy, Dr. Joe Hulihan, Chief Medical Officer, and Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer.

Speaker Change: Before we begin I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws.

Speaker Change: 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.

Speaker Change: 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-K. I will now turn the call over to our CEO, Dr. Scott Braunstein.

Scott Braunstein: I will now turn the call over to our CEO, Dr. Scott Braunstein. Thank you, Sonya, and thanks, everyone, for joining us this morning. On today's call, our team will highlight the significant commercial, clinical, and operational progress that we have made throughout 2024. We will also discuss our plans for the second half of the year and beyond, including how we're preparing for the upcoming phase three readout in Tuberous Sclerosis Complex and expanding access to Zytomy for patients on a global scale.

Scott Braunstein: Thank you, Sonia, and thanks, everyone, for joining us this morning.

Speaker Change: On today's call, our team will highlight the significant commercial, clinical, and operational progress that we have made throughout 2024.

Speaker Change: We'll also discuss our plans for the second half of the year and beyond, including how we're preparing for the upcoming phase 3 readout in Tuberous Sclerosis Complex and expanding access to Zitalme for patients on a global scale.

Scott Braunstein: Starting with tetalme, it has now been two years since our commercial launch for CDKL5 deficiency disorder, and I could not be prouder of the success that we have achieved in growing the brand in the US and the regulatory accomplishments globally.

Speaker Change: Starting with Titalme, it has now been two years since our commercial launch in CDKL5 deficiency disorder and I could not be prouder of the success that we have achieved in growing the brand in the U.S. and the regulatory accomplishments globally.

Scott Braunstein: Launching a new product, particularly in the orphan epilepsy space, is no easy task, but our commercial team has proven its ability to be highly effective, attaining profitability on a commercial investment in the first quarter of 2024, well ahead of our initial expectations. We believe these efforts will only be bolstered by a considerable number of scientific presentations at several medical meetings by year-end. I'm also proud of the progress that we have made to expand access to Zytomy for patients around the world.

Speaker Change: Launching a new product, particularly in the orphan epilepsy space, is no easy task.

Speaker Change: But our commercial team has proven its ability to be highly effective, attaining profitability on a commercial investment in the first quarter of 2024, well ahead of our initial expectations.

Speaker Change: We believe these efforts will only be bolstered by a considerable number of scientific presentations across several medical meetings by year end.

Speaker Change: I'm also proud of the progress that we have made to expand access to Zytomy for patients around the world. In July, we announced that Zytomy was approved in China as the first treatment procedures associated with GDD in patients two years of age and older.

Scott Braunstein: In July, we announced that Cetalme was approved in China as the first treatment procedure associated with GDD in patients two years of age and older. Tanisha Biotechnology is responsible for commercialization of Ganaxolone in China and expects to launch Ptolemy as early as the first quarter of 2025.

Speaker Change: Tanisha Biotechnology is responsible for commercialization of Ganaxolone in China and expects to launch the Ptolemy as early as the first quarter of 2025.

Scott Braunstein: As a reminder, Marinus has established commercial collaboration agreements in Europe and China, distribution agreements in MENA and Russia, and a managed access program to make Gonaxolin available on a named patient basis where permissible under local regulations without regulatory approval. We plan to work with our distribution partners in MENA and Russia to begin to supply Ganaxalone immediately on a named patient basis before regulatory approvals are achieved in those markets. Additionally, we have engaged the Unifar Group, a specialty healthcare company, to supply Ganaxalone on a named patient basis in several additional countries, including Canada and Australia, and expect to have our first patient approved for use within the coming week.

Speaker Change: As a reminder, Marinus has established commercial collaboration agreements in Europe and China, distribution agreements in MENA and Russia, and a managed access program to make Gonaxolin available on a named patient basis where permissible under local regulations without regulatory approval.

Speaker Change: We plan to work with our distribution partners in MENA and Russia to begin to supply Ganaxilone immediately on a named patient basis before regulatory approvals are achieved in those markets.

Speaker Change: Additionally, we have engaged the Unifar Group, a specialty healthcare company, to supply Ganaxalone on a named patient basis in several additional countries, including Canada and Australia, and expect to have our first patient approved for use within the coming weeks.

Scott Braunstein: With Tatami now approved in the U.S., European Union, U.K., and China for patients with TDD, we have made important investments to expand our manufacturing capacity to be able to meet the expected increased demand based on our global forecast, as well as our updated TSD projection. It is critical to have a second manufacturing facility in place to help us achieve our mid and long-range forecast. The investment in the second facility has been ongoing for several months and is proceeding as planned.

Speaker Change: With Tatami now approved in the U.S., European Union, U.K., and China for patients with TDD, we have made important investments to expand our manufacturing capacity to be able to meet the expected increased demand based on our global forecast, as well as our updated TST projections.

Speaker Change: It is critical to have a second manufacturing facility in place to help us achieve our mid- and long-range forecasts. The investment of this second facility has been ongoing for several months and is proceeding as planned.

Scott Braunstein: With the support of our international partners, we expect to have several ex-U.S. launches kicking off in the near term, with the first currently anticipated by the end of this year or early next year. In Europe, Orion Corporation continues to prepare for commercial launches of the Ptolemy in select EU countries, and as noted previously, Tenacia expects to launch into the Chinese market in early 2025.

Speaker Change: With the support of our international partners, we expect to have several ex-U.S. launches kicking off in the near term, with the first currently anticipated by the end of this year or early next year.

Speaker Change: In Europe, Orion Corporation continues to prepare for commercial launches of the Ptolemy in select EU countries. And as noted previously, Tenacia expects to launch into the Chinese market in early 2025.

Scott Braunstein: We also anticipate broader access for patients in MENA and Russia once local regulatory approvals are secured. Finally, we are targeting a Japanese partner to come on board in the first half of 2025, following our TSE phase three data set. Since the incidence of CDV outside the United States is similar to the U.S., we believe that the global opportunity will be meaningful to our ZPTLMI4 campaign. For example, in China, where genetic testing was instituted only a few years ago, over 1,000 TDD patients have already been identified.

Speaker Change: We also anticipate broader access for patients in MENA and Russia once local regulatory approvals are secured. Finally, we are targeting a Japanese partner to come on board in the first half of 2025 following our TSE Phase III dataset.

Speaker Change: Since the incidence of CDD outside the United States is similar to the U.S., we believe that the global opportunity will be meaningful to our ZPTLMI forecast.

Speaker Change: For example, in China, where genetic testing was instituted only a few years ago, over a thousand TDD patients have already been identified.

Scott Braunstein: Broader access to Ptolemy will bring a new therapeutic option to patients and their families, as well as provide support for the company's larger financial objectives, specifically achieving corporate profitability over the coming year. Lisa Lejuwaan, who heads up the U.S. Satomi business, will provide a more in-depth overview of our commercial strategy in her remarks, including our plans to continue to grow the CBD franchise and how the team is preparing for the potential TSC launch in the second half of next year.

Speaker Change: Broader access to the Ptolemy will bring a new therapeutic option to patients and their families, as well as provide support for the company's larger financial objectives, specifically achieving corporate profitability over the coming years.

Lisa LeJuan: Lisa LeJuan, who heads up the U.S. Satomi business, will provide a more in-depth overview of our commercial strategy and her remarks, including our plans to continue to grow the CBD franchise and how the team is preparing for the potential TSC launch in the second half of next year.

Scott Braunstein: Let me move to our clinical pipeline. As Joe will detail in his remarks, our next major milestone is the readout of the global TRUST-TSC trial evaluating SUTALMI for the treatment of seizures associated with TSC. As a reminder, we completed enrollment in May and are on track for the last patient visit by mid-September. We expect to report top-line data in the first half of the fourth quarter and are targeting submission of a supplemental NDA no later than April 2025 with the request for priority review.

Lisa LeJuan: Let me move to our clinical pipeline. As Joe will detail in his remarks, our next major milestone is the readout of the global TRUST-TSC trial evaluating SUTALMI for the treatment of seizures associated with TSC.

Joe: As a reminder, we completed enrollment in May and are on track for the last patient visit by mid-September.

Joe: We expect to report top-line data in the first half of the fourth quarter and are targeting submission of a supplemental NDA no later than April 2025 with a request for priority review.

Scott Braunstein: We are pleased to see both a low overall discontinuation rate and a high percentage of patients rolling over from the double-blind portion of the trial to the open-label extension. Pending a positive outcome and FDA approval, the commercial team plans to leverage the existing Zotomi infrastructure to hit the ground running. We have learned a tremendous amount in the last two years and are well positioned to adapt our formula in TDD to achieve success in the larger TSC market. As I commented earlier, we are now setting our sights on achieving company profitability, which we believe can occur 12 to 18 months following the TSC loss.

Joe: We are pleased to see both a low overall discontinuation rate and a high percentage of patients rolling over from the double-blind portion of the trial to the open label extension.

Speaker Change: Pending a positive outcome and FDA approval, the commercial team plans to leverage the existing ZTALMI infrastructure to hit the ground running.

Speaker Change: We have learned a tremendous amount in the last few years and are well positioned to adapt our formula and TDD to achieve success in the larger TSC market.

Speaker Change: As I commented earlier, we are now setting our sights on achieving company profitability, which we believe can occur 12 to 18 months following the TSC launch.

Scott Braunstein: We also wanted to share that on September 20th, we will host an investor and analyst event focused on our oral franchise. Our leadership team will be joined by key opinion leaders to share a deep dive into the TSC patient journey, the current treatment landscape, and the TSC market opportunity. We will review some of the new findings that continue to make us feel confident that ZTALMI will be successful in its current Phase III study and share our thoughts on why this data readout can create unique growth potential for the organization. Finally, one added note.

Speaker Change: We also wanted to share that on September 20th, we will host an investor and analyst event focused on our oral franchise.

Speaker Change: Our leadership team will be joined by key opinion leaders to share a deep dive into the TSC patient journey, current treatment landscape, and the TSC market opportunity.

Speaker Change: We will review some of the new findings that continue to make us feel confident that Citalmi will be successful in its current phase 3 study and share our thoughts on why this data readout can create a unique growth potential for the organization.

Scott Braunstein: In March of 2023, Marinus initiated a PGR challenging OVID's 817 SE patent for ibogaine axillone on the basis that the claims of the patent were invalid and should not have been issued by the USPTO. I am pleased to share that Marinus was successful in this PGR challenge, with the PTAP concluding that all challenge claims were unpatented. With that, I'll now turn the call over to our Senior Vice President, Lisa Lejuwaan, who will be covering the commercial update for our chief commercial officer, Kristi Shafer. Thank you, Scott. Good morning, everyone.

Speaker Change: Finally, one added note, in March of 2023, Marinus initiated a PGR challenging Ovid's 817 SE patent for ibogaine axillone on the basis that the claims of the patent were invalid and should not have been issued by the USPTO.

Speaker Change: I am pleased to share that Marinus was successful in this PGR challenge, with the PTAB concluding that all challenge claims were unpatentable.

Speaker Change: With that, I'll now turn the call over to our Senior Vice President, Lisa LeJuan, who will be covering the commercial update for our Chief Commercial Officer, Christy Shafer.

Lisa Lejuwaan: I'm Lisa Lejuwaan, Senior Vice President and Business Unit Lead of Rare Genetic Epilepsy at Marinus. Today, I'll be highlighting the significant progress we have made to grow the Zotomi brand since its launch in CDD two years ago, and we'll provide an update on our commercial planning activities for potential expansion into TSC. With approximately 200 patients active on therapy, we continue to see steady growth and adoption of the Tommy and CD-KL-5 deficiency disorders after two years as one. For the second quarter, we generated net product revenue of $8 million, representing growth of over 85% compared to the same period in 2023.

Lisa Lejouon: Thank you, Scott. Good morning, everyone. I'm Lisa Lejuwan, Senior Vice President and Business Unit Lead of Rare Genetic Epilepsy at Marinus.

Speaker Change: Today, I'll be highlighting the significant progress we have made to grow the Zotomi brand since its launch in CDD two years ago, and will provide an update on our commercial planning activities for potential expansion into TSC.

Speaker Change: With approximately 200 patients active on therapy, we continue to see steady growth and adoption of Zytomy and CDKL5 deficiency disorder after two years of launch.

Lisa Lejuwaan: We believe we're on track to achieve our projected full year 2024 revenue guidance of between $33 and $35 million. This growth highlights the vital role of Ditalmy in the comprehensive management of seizures associated with PDD. We continue to hear from HTPs that Tommy is making a difference in patients' lives and changing the way they think about treating this case. We see physicians increasingly prescribing Zitome for younger patients, signifying, we believe, a broader adoption in a patient population where parents are often more cautious about starting new treatments and a growing comfort with Zitome.

Speaker Change: For the second quarter, we generated net product revenue of $8 million, representing growth of over 85% compared to the same period in 2023. We believe we're on track to achieve our projected full year 2024 revenue guidance of between $33 and $35 million.

Speaker Change: This growth highlights the vital role of Zytomy in the comprehensive management of seizures associated with CDD. We continue to hear from HCPs that Zytomy is making a difference in patients' lives and changing the way they think about treating these patients.

Speaker Change: We see physicians increasingly prescribing Zitome for younger patients, signifying, we believe, a broader adoption in a patient population where parents are often more cautious about starting new treatments and a growing comfort with Zitome.

Lisa Lejuwaan: We are very pleased with the patient experience, as highlighted by the low discontinuation rate, with greater than 70% of patients remaining on active therapy sent to our lawn. This matches our experience from the Phase III Marigold trial in CDD and is aligned with our expectations. In terms of coverage, we continue to see widespread acceptance across both commercial and government programs, reflecting the value that Ptolemy brings to CVD patients and families affected by refractory epilepsy. Notably, no CVD patients have been denied coverage to date, underscoring the favorable reimbursement dynamic.

Speaker Change: We are very pleased with the patient experience as highlighted by low discontinuation rates with greater than 70% of patients remaining on active therapy since our launch. This matches our experience from the phase three Marigold trial in CBD and is aligned with our expectations.

Speaker Change: In terms of coverage, we continue to see widespread acceptance across both commercial and government programs, reflecting the value that the PTALMI brings to CDD patients and families affected by refractory epilepsy.

Speaker Change: Notably, no CDD patients have been denied coverage to date, underscoring the favorable reimbursement dynamic.

Lisa Lejuwaan: Over the past two years, we've proven that our rare disease of courage is working. We've built an infrastructure that is lean and efficient, and our sales team continues to reach KOLs and HCPs, both in specialized treatment centers and community settings, resulting in continued strong new patient enrollment and growth of new prescribers driving the domain. To continue to grow and evolve the Batami brand and maximize its impact in the CBD market, we're implementing several key initiatives.

Speaker Change: Over the past two years, we've proven that our rare disease approach is working. We've built an infrastructure that is lean and efficient, and our sales team continues to reach KOLs and HCPs, both in specialized treatment centers and community settings, resulting in continued strong new patient enrollments and growth of new prescribers, driving demand.

Speaker Change: To continue to grow and evolve the Zotomi brand and maximize its impact in the CBD market, we're implementing several key initiatives.

Lisa Lejuwaan: First, we now have robust data analysis with more than 1,000 CDD patients identified. By using new data sources and analytics, we have identified patients not billed with the CDD ICD-10 code in third-party claims and patients who may have CDD but do not yet have a diagnosis. We're educating physicians on the importance of having confirmatory genetic testing, which is supported by the American Epilepsy Society's goal of making sure every patient with unidentified seizures has access to genetic testing to understand the underlying cause of their disease.

Speaker Change: First, we now have robust data analysis with more than 1,000 CDD patients identified.

Speaker Change: By using new data sources and analytics, we have identified patients not billed with the CDD ICD-10 code in third-party claims, and patients who may have CDD but do not yet have a diagnosis.

Speaker Change: We're educating physicians on the importance of having confirmatory genetic testing, which is supported by the American Epilepsy Society's goal of making sure every patient with unidentified seizures has access to genetic testing to understand the underlying cause of their disease.

Lisa Lejuwaan: And second, by showcasing a range of voices and stories to the community, including family members of newly treated patients, we intend to engage more families to elevate Ptolemy and CDD awareness. We are launching our On Demand Shining Moment series, where families can hear from experienced caregivers and patients on how the Ptolemy has affected their lives at a time that fits into their schedule.

Speaker Change: And second, by showcasing a range of voices and stories to the community, including family members of newly treated patients, we intend to engage more families to elevate the Ptolemy and CDD awareness.

Speaker Change: We are launching our On Demand Shining Moment series, where families can hear from experienced caregivers and families on how the Ptolemy has affected their lives at a time that fits into their schedule.

Lisa Lejuwaan: We continue engaging with the International Foundation for CDKL5 Research, most recently at their annual conference, where over a hundred families were in attendance. We're proud of the growing adoption of the Ptolemy and are planning to replicate the success of CDD and TSC with a potential launch in the fourth quarter of 2025. Looking ahead, we plan to build upon the foundation of our proven CDD infrastructure to meet the needs of TSC patients who are also suffering from refractory seizures.

Speaker Change: We continue engaging with the International Foundation for CDKL5 Research, most recently at their annual conference where over 100 families were in attendance.

Speaker Change: We're proud of the growing adoption of the Ptolemy and are planning to replicate the success of CDD and TSC with a potential launch in the fourth quarter of 2025.

Speaker Change: Looking ahead, we plan to build upon the foundation of our proven CDD infrastructure to meet the needs of TSC patients who are also suffering from refractory seizures.

Lisa Lejuwaan: With approximately five to six times the addressable patient population compared to CBD, we have the potential to unlock a significant growth opportunity. Our colleagues from the TSC Alliance and our market research make it clear that there remains a significant unmet need in these patients and that a new therapy would be welcomed. Furthermore, when pulled, physicians are excited about the potential for an effective and safe product that can be used competently with other anti-susur medications. It's easily accessible and has the potential to meaningfully improve quality of life.

Speaker Change: With approximately 5-6 times the addressable patient population compared to CDD, we have the potential to unlock a significant growth opportunity.

Speaker Change: Our colleagues from the TSC Alliance and our market research make it clear that there remains a significant unmet need in these patients and that a new therapy would be welcomed.

Speaker Change: Furthermore, when polled, physicians are excited about the potential for an effective and safe product that can be used concomitantly with other anti-seizure medications, is easily accessible, and has the potential to meaningfully improve quality of life.

Lisa Lejuwaan: When we launched in CDD, we had relatively quick uptake due to the significant unmet medical need in this patient population. However, we anticipate even quicker uptake with TSC for several reasons. First, patient finding in Ulterobare disease is often the largest hurdle.

Speaker Change: When we launched in CDD, we had relatively quick uptake due to the significant unmet medical need in this patient population. However, we anticipate even quicker uptake with TSC for several reasons.

Lisa Lejuwaan: However, this patient population is much easier to identify through a well-known ICD-10 code and through physical and neurological identifiers such as tubers, cardiac rhabdomyomas, and refractory seizures. Trust TSC will be the first phase three global trial executed in TSC that includes prior and concomitant usage of mTOR inhibitors and epidiolex, giving HCPs and families confidence in combining medications and From a payer perspective, we expect rapid and broad access across the majority of payers supported by the protected class of epilepsy and the label extension from CBD to TSC.

Speaker Change: First, patient finding in ultra-rare disease is often the largest hurdle. However, this patient population is much easier to identify through a well-known ICB-10 code and through physical and neurological identifiers such as tubers, cardiac rhabdomyomas, and refractory seizures.

Speaker Change: Trust TSC will be the first phase 3 global trial executed in TSC that includes prior and concomitant usage of mTOR inhibitors and epidiolex, giving HCPs and families confidence in combining medications and further underscoring the current needs in the TSC community.

Speaker Change: From a payer perspective, we expect rapid and broad access across the majority of payers supported by the protected class of epilepsy and the label extension from CBD to TSC.

Lisa Lejuwaan: Patient activation is expected to be straightforward. In refractory TSC patients, seizure control is the main priority, making adding or changing medication an easier choice. The unique GABAergic mechanism of action of the Ptolemy is differentiated from other ASMs and supports the Ptolemy's place in the treatment algorithm.

Speaker Change: Patient activation is expected to be straightforward.

Speaker Change: In refractory TSC patients, seizure control is the main priority, making adding or changing medication an easier choice.

Speaker Change: The unique GABAergic mechanism of action of Cetalme is differentiated from other ASMs and supports Cetalme's place in the treatment algorithm.

Lisa Lejuwaan: Additionally, this will be the second completed global randomized trial of the TALMI, which will have been on the market for over three years by the time of the TSD launch, giving physicians even greater confidence in the brand. The growth and continued uptake of the Tommy in CBD reinforces our confidence that we can replicate and accelerate the success in TSC, which is a significantly larger market opportunity. Our team looks forward to sharing further updates on our progress and plans at our TSC-focused Investor and Analyst Day in September, where we will highlight the work that our commercial team has been doing behind the scenes to prepare for potential expansion into TSC.

Speaker Change: Additionally, this will be the second completed global randomized trial of ZITOMY, which will have been on the market for over three years by the time of a TSD launch, giving physicians even greater confidence in the brand.

Speaker Change: The growth and continued uptake of the Ptolemy in CVD reinforces our confidence that we can replicate and accelerate the success in TSC, which is a significantly larger market opportunity.

Speaker Change: Our team looks forward to sharing further updates on our progress and plans at our TSC-focused Investor and Analyst Day in September , where we will highlight the work that our commercial team has been doing behind the scenes to prepare for potential expansion into TSC.

Speaker Change: This will include key insights from our demand study, value proposition, key product positioning, and patient services portfolio enhancements.

Joe Hulihan: This will include key insights from our Demand Study, Value Proposition, Key Product Positioning, and Patient Services Portfolio Enhancement. I would now like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan, for an update on our clinical program. Thank you, Lisa. Good morning. I'm pleased to share an overview of our pipeline progress, which includes the upcoming phase three data readout in KFC, preparation for our other rare genetic epilepsy programs, and a recap of our phase three raised trial readout and next steps for that. I'll start with the TRUST-TSC trial of oral gonaxalone and tuberous sclerosis complex. TSC is one of the most common genetic epilepsy disorders and is caused by a defect or mutation of the TSC-1 or TSC-2 gene.

Speaker Change: I would now like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan, for an update on our clinical programs.

Joe Hulihan: Thank you, Lisa. Good morning.

Speaker Change: I'm pleased to share an overview of our pipeline progress, which includes the upcoming phase 3 data readout and TFC, preparation for our other rare genetic epilepsy programs, and a recap of our phase 3 RAISE trial readout and next steps for that program.

Speaker Change: I'll start with the TRUST-TSC trial of oral gonaxalone in tuberous sclerosis complex.

Joe Hulihan: Common symptoms include seizures, cognitive impairment, behavioral difficulties, and skin, kidney, or lung abnormalities, among other manifestations. Epilepsy and TSC occur in approximately 80 to 90% of patients, with seizures typically beginning in the first year of life. Cedars and TSC are often difficult to manage and remain resistant to treatment.

Speaker Change: TSC is one of the most common genetic epilepsies.

Speaker Change: and is caused by a defect or mutation of the TSC1 or TSC2 genes.

Speaker Change: Common symptoms include seizures, cognitive impairment, behavioral difficulties, and skin, kidney, or lung abnormalities among other manifestations.

John Williams: John Williams, John Williams, John Williams, Brian Abrahams[inaudible] Greetings and welcome to the Marinus Pharmaceuticals' second quarter financial results and business update call. If anyone today should require operator assistance during the conference, please for a star zero from your telephone keypad.

Speaker Change: Epilepsy and TSC occurs in approximately 80 to 90 percent of patients with seizures typically beginning in the first year of life.

Speaker Change: Seizures in TSC are often difficult to manage and remain resistant to treatment.

Joe Hulihan: Despite the introduction of the disease, specific anti-seizure medication, there's still a significant unmet need for treatments that provide effective seizure control. To address this unmet need, we're evaluating oral Ganaxolone in TSC patients with refractory seizures in the Trust TSC trial. As Scott mentioned, we completed enrollment for the study in May and continue to expect to report the top line results in the first half of the fourth. Trust TSC is a global, phase 3, randomized, double-blind, placebo-controlled trial of adjunctive Ganaxin that enrolled 129 patients with TSC-related

Speaker Change: Despite the introduction of disease-specific anti-seizure medications, there's still a significant unmet need for treatments that provide effective seizure control.

Joe Hulihan: As a reminder, the trial provides 90% power to detect a 25% difference in seizure reductions between gonaxalone and placebo. The trial consists of a four-week baseline period, followed by a 16-week double-blind phase, with the primary endpoint being the percent change in 28-day seizure frequency. Then, for patients continuing to the Open Label Extension, there is a four-week cross-titration from double-blind study medications to Opal Label Ganache. The secondary endpoints of the double-blind portion of the study are the percent change in seizure frequency during the maintenance period.

Speaker Change: To address this unmet need, we're evaluating oral Ganaxolone in TSC patients with refractory seizures in the TRUST-TSC trial.

Speaker Change: As Scott mentioned, we completed enrollment for the study in May and continue to expect report top-line results in the first half of the fourth quarter.

Scott Braunstein: TRUST-TSC is a global, phase 3, randomized, double-blind, placebo-controlled trial of adjunctive ganaxolone.

Scott Braunstein: which enrolled 129 patients with TSC-associated seizures.

Sonya Weigle: It is now my pleasure to introduce your host, Sonya Weigle, Chief People and Investor Relations Officer. You will now begin this Weigle. Thank you and good morning.

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

Scott Braunstein: The trial consists of a four-week baseline period, followed by a 16-week double-blind phase, with the primary endpoint being the percent change in 28-day seizure frequency.

Sonya Weigle: With me from Marinus or Dr. Scott Braunstein, Chairman and Chief Executive Officer, Lisa Lejuwaan, Senior Vice President and Business Unit Lead, Rare Genetic Epilepsy, Dr. Joe Hulahan, 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 under the security 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 uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Form 10K, 10Q and 8K.

Scott Braunstein: Then, for patients continuing to the open label extension, there's a four-week cross titration from double-blind study medications to opal label gonaxalone.

Scott Braunstein: Secondary endpoints of the double blind portion of the study are the percent change in seizure frequency during the maintenance period, the 50% responder rate, and clinical global impression scales reported by the treating clinician and the patient or their caregiver.

Joe Hulihan: 50% Responder Rate, and Clinical Global Impression Scales reported by the treating clinician and the patient or their own, This trial is the first double-blind study in TSC to allow enrollment of patients taking Epidiolex or mTOR inhibitors, including Afinit, relatively newer additions to the range of medication used in TSE men.

Scott Braunstein: This trial is the first double-blind study in TSC to allow enrollment of patients taking Epidiolex or mTOR inhibitors including Afinitor.

Speaker Change: relatively newer additions to the range of medication used in TSC management.

Joe Hulihan: As a reminder, in Marist Phase II TSC trials, patients taking these medications had a 25% and 36% responder rate, respectively. As reported in May, patients entering the trust TSC study had failed a mean of 4.8 anti-seizure medications, with approximately 27% having current or prior experience with Epidile, and approximately 58% having experience with inventory. Patients had a median baseline rate of 50 TSC-associated seizures per 28 days, which we discussed previously based on information from our phase 2 TSC study. We modified the phase three titration.

Speaker Change: As a reminder, in Marist Phase II TSC trial,

Scott Braunstein: I will now turn the call over to our CEO, Dr. Scott Braunstein. Thank you, Sonya, and thanks everyone for joining us this morning. On today's call, our team will highlight the significant commercial, clinical, and operational progress that we have made throughout 2024. We'll also discuss our plans for the second half of the year and beyond, including how we're preparing for the upcoming phase three read-out in two versus complex and expanding access to Zatolmi for patients on a global scale.

Speaker Change: Patients taking these medications have a 25% and 36% responder rate respectively.

Speaker Change: As reported in May, patients entering the TRUST-TSC study had failed a mean of 4.8 anti-seizure medications with approximately 27% having current or prior experience with epidiolex and approximately 58% having experience with in vitro inhibitors.

Speaker Change: Patients had a median baseline rate of 50 TSC associated seizures per 28 days.

Scott Braunstein: Starting with Zatolmi, it has now been two years since our commercial launch and CDTL-5's deficiency disorder. And I cannot be prouder of the success that we have achieved in growing the brand in the US and the regulatory accomplishments globally. Lawn to the New Product, particularly in the orphan epilepsy space, is no easy task, but our commercial team has proven its ability to be highly effective at gaining profitability on a commercial investment in the first quarter of 2024, well ahead of our initial expectations.

Speaker Change: As discussed previously, based on information from our Phase II TSC study, we modified the Phase III titration schedule.

Joe Hulihan: When we reviewed the Phase 2 study results, we believed that canaxalone had been titrated too quickly, leading to increased somnolence and, unexpectedly, that this led to an associated decrease in efficacy, with a discontinuation rate of approximately 20 percent. With the revised titration schedule, the discontinuation rate in the Phase III study is below 7 percent, which is consistent with what we saw in the CDD marigold. Importantly, only two patients have discontinued from the TRUST-TNC study to date due to somnolence-related adverse events.

Speaker Change: When we reviewed the phase 2 study results, we believed the Canaxalone had been titrated too quickly, leading to increased somnolence and unexpectedly that this led to an associated decrease in efficacy with a discontinuation rate of approximately 26 percent.

Speaker Change: With the revised titration schedule, the discontinuation rate in the phase 3 study is below 7%, which is consistent with what we saw in the CDD Marigold study.

Scott Braunstein: We believe these efforts will only be bolstered by a considerable number of scientific presentations across several medical meetings by year end. I'm also proud of the progress that we have made to expand access to Zitalmi for patients around the world. In July, we announced that Zitalmi was approved in China as the first treatment procedure is associated with CDD in patients two years of age and older.

Speaker Change: Importantly, only two patients have discontinued from the TRUST-TSC study to date due to somnolence-related adverse events.

Joe Hulihan: In addition, we are seeing over 90% of patients who complete the Phase 3 study transitioning into the Open Label Extension, suggesting that patients are not only tolerating the drug well, but are likely also benefiting from treatment over time. I look forward to sharing updated information on baseline patient demographics and characteristics at our September investor and analyst event, including details on seizure types, use of competent medications, discontinuation rates, and average patient dose. We're targeting submission of a supplemental NDA in April 2025 with a request for priority review. Assuming all goes according to plan, we anticipate a PDUFA date in the fourth quarter of 2025.

Speaker Change: In addition, we are seeing over 90% of patients who complete the phase 3 study transitioning into the open label extension, suggesting that patients are not only tolerating the drug well, but are likely also benefiting from treatment overall.

Speaker Change: I look forward to sharing updated information on baseline patient demographics and characteristics of our September Investor and Analyst event including details on seizure types, use of concomitant medications, discontinuation rates, and average patient doses.

Scott Braunstein: Tenetia biotechnology is responsible for commercialization of an excellent in China and expects to launch Zitalmi as early as the first quarter of 2025. As a reminder, Marinus has established commercial collaboration agreement in Europe and China, distribution agreements in Mina and Russia, and a managed access program to make an excellent available on a name-patient basis where permissible under local regulations without regulatory approval. We plan to work with our distribution partners in Mina and Russia to begin to supply an excellent immediately on a name-patient basis before regulatory approvals are achieved in those markets.

Speaker Change: We're targeting submission of a supplemental NDA in April 2025 with a request for priority review. Assuming all goes according to plan, we anticipate a PDUFA date in the fourth quarter of 2025.

Joe Hulihan: I plan to present the results of ADS in December, following the announcement of our top line data in early Q4, with the goal of publication in a major journal prior to the commercial loss. In addition to TSC, we plan to expand our investment in Zatomidy to explore its potential in the treatment of other rare epidemics. Planning is underway for a clinical trial that would assess oral ganaxolone for the treatment of a broad range of developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome. LGS is characterized by the presence of developmental delay and fracturing. It affects approximately 48,000 patients in the U.S., which is four times larger than the refractory TSC pump.

Speaker Change: We plan to present the results at AES in December, following the announcement of our top-line data in early Q4, with the goal of publication in a major journal prior to the commercial launch.

Scott Braunstein: Additionally, we have engaged the UNIFAR group, a specialty healthcare company, to supply an excellent on a name-patient basis in several additional countries, including Canada and Australia, and expect to have our first patient approved for use within the coming weeks. With Zitalmi now approved in the US, European Union, UK, and China for patients with CDD, we have made important investments to expand our manufacturing capacity to be able to meet the expected increased demand based on our global forecast, as well as our updated TSC projections.

Speaker Change: In addition to TSC, we plan to expand our investment in tautomaty to explore its potential in the treatment of other rare epilepsies.

Speaker Change: Planning is underway for a clinical trial that would assess oral ganaxolone for the treatment of a broad range of developmental and epileptic encephalopathies, including Lennox-Gastaut syndrome.

Speaker Change: LGS is characterized by the presence of developmental delay and refractory seizures.

Speaker Change: It affects approximately 48,000 patients in the U.S., which is four times larger than the refractory TSC population.

Joe Hulihan: Despite the availability of several anti-seisure medications approved for the treatment of seizures and LGS, there remains a considerable unmet need for effective treatment. We plan to initiate a proof-of-concept trial with SITOMI in the first half of 2025, pending TSC top-line data. We believe Canaxalone could be a valuable addition to the treatment options for LGS and DEEs overall, given its unique mechanism of The Plan Proof of Concept Profile can help guide us in the design and conduct of a future phase 3.

Speaker Change: Despite the availability of several anti-seizure medications approved for the treatment of seizures in LGS

Scott Braunstein: It is critical to have a second manufacturing facility in place to help us achieve our mid and long range forecast. The investment of the second facility has been ongoing for several months and is proceeding its plan. With the support of our international partners, we expect to have several XUS launches kicking off in the near term, with the first currently anticipated by the end of this year or early next year. In Europe, Orion Corporation continues to prepare for commercial launches at Zitalmi in select EU countries, and has noted previously Tanesha expects to launch into the Chinese market in early 2025. We also anticipate broader access for patients in MENA and Russia once local regulatory approvals are secured.

Speaker Change: there remains a considerable unmet need for effective treatment.

Speaker Change: We plan to initiate a proof-of-concept trial with SITOMI in the first half of 2025, pending the TSC top-line data.

Speaker Change: We believe the ConAxone could be a valuable addition to the treatment options for LGS and DEEs overall, given its unique mechanism of action.

Speaker Change: The planned proof-of-concept trial can help guide us in the design and conduct of a future Phase III study.

Joe Hulihan: Additionally, we're continuing our efforts to develop a second-generation Ganax loan product. Our goals are to optimize PK parameters for efficacy, tolerability, and dosing for. We've initiated IND-enabling studies for a Ganaxalone Pro drug, which are expected to be completed by the end of 2024. Lastly, I'll briefly recap the results of our Phase 3 Raised Trial of Ivy Ganaxelone and Refractory Static Eplep, and we'll also share the next steps in our clinical and regulatory.

Speaker Change: Additionally, we're continuing our efforts to develop a second-generation Ganax Lone product.

Speaker Change: Our goals are to optimize PK parameters for efficacy, tolerability, and dosing frequency.

Speaker Change: We've initiated IND-enabling studies for a ganaxaline prodrug, which are expected to be completed by the end of 2025.

Scott Braunstein: Finally, we are targeting a Japanese partner to come on board in the first outside of the United States. Similar to the U.S., we believe that the global opportunity will be meaningful to our Zitalmi Force. For example, in China, where genetic testing was instituted only a few years ago, over 1,000 CDD patients have already been identified. Brother access to the autonomy will bring a new therapeutic option to patients and their families, as well as provide support for the company's larger financial objectives, specifically achieving corporate profitability over the coming years.

Speaker Change: Lastly, I'll briefly recap the results of our Phase 3 RAYS trial of Iveganaxelone and refractory status epilepticus.

Speaker Change: and we'll also share the next steps in our clinical and regulatory approach.

Joe Hulihan: We believe that the totality of the reported trial data showed that Gneckslohn produced rapid cessation of symptoms and evidence of durable cessation in a highly refractory patient bup. Specifically, the onset of effect was rapid, with 80% of patients receiving a vegan axelome having status epileptic cessation within 30 minutes, compared to 13% for placebo, a result that was statistically significant with a p-value of less than 0.0001.

Speaker Change: We believe that the totality of the RAISE trial data showed that Ganaxolone produced rapid cessation of status and evidence of durable cessation in a highly refractory patient population.

Speaker Change: Specifically, onset of effect was rapid with 80% of patients receiving iVeganAxlone having status epilepticus cessation within 30 minutes compared to 13% for placebo.

Speaker Change: a result that was statistically significant with a p-value of less than 0.0001.

Scott Braunstein: Lisa Lejuwaan, who heads up the U.S, to Tommy business, will provide a more in-depth overview of our commercial strategy in her remarks, including our plans to continue the growth of CDD franchise and how the team is preparing for the potential TSE launch in the second half of next year. Let me move to our clinical pipeline. As Joe will detail in his remarks, our next major milestone is the readout of the Global Trust TSE trial evaluating to Tommy for the treatment of seizures associated with TSE.

Joe Hulihan: Unfortunately, the second co-primary endpoint, lack of progression to IV anesthesia within 36 hours, failed to achieve statistical significance. However, our analysis of the RAISE data showed that the use of IV anesthesia was likely driven by clinical and treatment factors unrelated to the status quo. In contrast, continuous CEG monitoring demonstrated objective and durable control of status. Specifically, analysis of 36 hours of continuous EEG data demonstrated a median 93% reduction in EEG seizure burden in the absence of IV anesthesia for Ganaxolone-treated patients, compared to 36% for placebo.

Speaker Change: Unfortunately, the second co-primary endpoint, lack of progression to IV anesthesia within 36 hours, failed to achieve statistical significance.

Speaker Change: Our analysis of the RAISE data showed that the use of IV anesthesia was likely driven by clinical and treatment factors unrelated to status severity.

Speaker Change: In contrast, continuous CEG monitoring demonstrated objective and durable control of status.

Speaker Change: Specifically, analysis of 36 hours of continuous EEG data demonstrated a median 93% reduction in EEG seizure burden in the absence of IV anesthesia for ganaxolone treated patients compared to 36% for placebo.

Scott Braunstein: As a reminder, we completed enrollment in May and are on track for the last patient visit by mid-September. We expect to report top-line data in the first half of the fourth quarter and our targeting submission of a supplemental NDA no later than April 2025 with the request for priority review. We are pleased to see both a low overall discontinuation rate and a high percentage of patients rolling over from the double-blind portion of the trial to the open label extension.

Joe Hulihan: Based on our assessment of the RAISE data set, we plan to submit a request to the FDA this month for a meeting to discuss the trial results and determine next steps for the program. This was the first placebo-controlled trial conducted in refractory status. We are proud of our team's success in enrolling and completing a complex hospital-based study in this area of tremendous unmet need. We're hopeful that the data set can support moving forward with our program for Ivy Megan Axelone and the Treatment of Status Up. I'd also mention that we've provided IV ginaxalone for the treatment of superrefractory status epilepticus for over 30 patients under emergency INDF.

Speaker Change: Based on our assessment of the RAISE data set, we plan to submit a request to the FDA this month for a meeting to discuss the trial results and determine next steps for the program.

Speaker Change: This was the first placebo-controlled trial conducted in refractory status.

Speaker Change: We're proud of our team's success in enrolling and completing a complex hospital-based study in this area of tremendous unmet need.

Scott Braunstein: Pending a positive outcome and FDA approval, the commercial team plans to leverage the existing to Tommy infrastructure to hit the ground running. We have learned a tremendous amount in the last two years and are well positioned to adapt our formula in CDD to achieve success in the larger TSE market. As I commented earlier, we are now setting our sights on achieving company profitability, which we believe can occur 12 to 18 months following the TSE launch.

Speaker Change: We're hopeful that the RAISE dataset can support moving forward with our program for Ivegan-Axelone and the treatment of status epilepticus.

Speaker Change: I'd also mention that we've provided iV Gynaxolone for treatment of super refractory status epilepticus for over 30 patients under emergency IND applications.

Steve Pfanstiel: Looking ahead, results from the RAISE trial have been accepted for a platform presentation at the Neurocritical Care Society meeting in October, and we plan to submit additional data for presentation at this year's American Epilepsy Society annual meeting. In closing, our clinical research team is passionately committed to bringing safe, effective, and innovative treatments to patients suffering the consequences of refractory seizures and status. I'd now like to turn the call over to our CFO and COO, Steve Pfanstiel, for a financial update. Thanks, Joe, and good morning.

Speaker Change: Looking ahead, results from the RAISE trial have been accepted for a platform presentation at the Neurocritical Care Society meeting in October and we plan to submit additional data for presentation at this year's American Epilepsy Society annual meeting.

Scott Braunstein: We also wanted to share that on September 20th, we will host an investor and analyst event focused on our oral franchise. Our leadership team will be joined by key opinion leaders to share deep dive into the TSE patient journey, current treatment landscape, and the TSE market opportunity. We will review some of the new findings that continue to make us feel confident that the Tommy will be successful in its current phase three study, and share our thoughts on why this data readout can create a unique growth potential for the organization.

Speaker Change: In closing, our clinical research team is passionately committed to bringing safe, effective, and innovative treatments to patients suffering the consequences of refractory seizures and status epilepticus.

Speaker Change: I'd now like to turn the call over to our CFO and COO, Steve Pfanstiel, for a financial update.

Steve Pfanstiel: I'm pleased to be able to provide a financial update as well as share our financial results for the second quarter of 2024. In the second quarter of 2024, we took several significant actions as a result of the Phase 3 RAISE trial to further extend our cash runway, which is now projected into the second quarter of 2025. Cost reduction plans were initiated in April this year and remain ongoing, with the full impact of cost savings expected to be achieved in the third quarter.

Steve Pfanstiel: Thanks, Joe, and good morning, everyone. I am pleased to be able to provide a financial update as well as share our financial results for the second quarter of 2024.

Scott Braunstein: Finally, one added note. In March of 2023, Marinus initiated a PGR challenging Ovid's 817SE patent for Ivygan Axelone on the basis that the claims of the patent were invalid and should not have been issued by the USPTO. I am pleased to share that Marinus was successful in this PGR challenge with the P tabs including that all challenge claims were unpatentable.

Steve Pfanstiel: In the second quarter of 2024, we took several significant actions as a result of the Phase III race trial to further extend our cash runway, which is now projected into the second quarter of 2025.

Steve Pfanstiel: Cost reduction plans were initiated in April this year and remain ongoing, with the full impact of cost savings expected to be achieved in the third quarter.

Steve Pfanstiel: We now project our combined selling, general, and administrative, and R&D expenses to decrease by approximately 30% from 80.3 million in the first half of 2024 to between 55 and 60 million in the second half of 2024. This new reduced cost structure also aligns with our near-term focus on the oral epilepsy franchise, which can be efficiently leveraged upon an indication expansion into TSA. In June of this year, we restructured our credit agreements with both Oak Tree Capital and Cicard Health.

Steve Pfanstiel: We now project our combined selling, general, and administrative and R&D expenses to decrease by approximately 30% from $80.3 million in the first half of 2024 to between $55 and $60 million in the second half of 2024.

Unknown Executive: With that, I'll now turn the call over to our senior vice president, Thank you Scott.

Steve Pfanstiel: This new reduced cost structure also aligns with our near-term focus on the oral epilepsy franchise Which can be efficiently leveraged upon an indication expansion into TSC

Lisa Lejuwaan: Good morning everyone. I'm Lisa Lejuwaan, Senior Vice President and Business Unit Lead of Rare Genetic Epilepsy at Marinus. Today I'll be highlighting the significant progress we have made to grow the Zatomi brand since it's launched in CDD two years ago and will provide an update on our commercial planning activities for potential expansion into TSC. With approximately 200 patients active on therapy, we continue to see steady growth and adoption of Zatomi in CDKL for our five deficiency disorder after two years of launch.

Steve Pfanstiel: As a result, the $15 million minimum liquidity requirement has been removed from both agreements, and amortization payments due to Oaktree in 2024 have been reduced by 50%. In return, Marinus made a one-time principal payment of $15 million to Oaktree, reducing our outstanding principal with Oaktree to $60 million.

Steve Pfanstiel: In June of this year, we restructured our credit agreements with both Oaktree Capital and Sicard Healthcare.

Steve Pfanstiel: As a result, the $15 million minimum liquidity requirement has been removed from both agreements and amortization payments due to Oaktree in 2024 have been reduced by 50%.

Steve Pfanstiel: In return, Marin has made a one-time principal payment of $15 million to Oaktree, reducing our outstanding principal with Oaktree to $60 million.

Steve Pfanstiel: As a result of these actions, we ended June 2024 with cash and cash equivalence of $64.7 million, extending our projected cash runway into the second quarter of 2025. As mentioned by Scott and Lisa, we remain committed to growing this autonomy franchise and have made important investments to expand our manufacturing capacity to support expansion outside of the U.S. and in preparation of a potential launch in TSA. We are proud of the progress we have made to expand patient access on a global scale while also creating meaningful revenue opportunities from markets outside the U.S. We expect to see positive returns from our managed access program before the end of the year and remain eligible to receive several milestone payments from our commercial partners upon the achievement of certain CDD and TSC-related regulatory and commercialization activities.

Lisa Lejuwaan: For the second quarter, we generated net product revenue of 8 million representing growth of over 85% compared to the same period in 2023. We believe we're on track to achieve our projected full year 2024 revenue guidance of between 33 and 35 million. This growth highlights the vital role of Zatomi in the comprehensive management of features associated with CDD. We continue to hear from HCP that Zatomi is making a difference in patients lives and changing the way they think about treating patients.

Steve Pfanstiel: As a result of these actions, we ended June 2024 with cash and cash equivalents of $64.7 million, extending our projected cash runway into the second quarter of 2025.

Speaker Change: As mentioned by Scott and Lisa, we remain committed to growing the Satomi franchise and have made important investments to expand our manufacturing capacity to support expansion outside of the U.S. and in preparation of a potential launch in TSC.

Speaker Change: We are proud of the progress we have made to expand patient access on a global scale while also creating meaningful revenue opportunities for markets outside the U.S.

Lisa Lejuwaan: We see physicians increasingly prescribing Zatomi for younger patients, signifying we believe a broader adoption in a patient population where parents are often more cautious about starting new treatment and a growing comfort with Zatomi. We are very pleased with the patient experience as highlighted by low discontinuation rate with greater than 70% of patients remaining on active therapy since our launch. This matches our experience from the phase three miracle trial in CDD and is aligned with our expectations.

Speaker Change: We expect to see positive returns from our Managed Access Program before the end of the year and remain eligible to receive several milestone payments from our commercial partners upon the achievement of certain CDD and TSC-related regulatory and commercialization activities.

Steve Pfanstiel: Full-year 2024 guidance remains unchanged with projected Zatami net product revenues between 33 and 35 million and combined SG&A and R&D expense in the range of approximately 135 to 140 million, including non-cash stock-based compensation expense of approximately 20 million. I'll now take a few minutes to summarize our financial results for the second quarter. We recognize Tommie product revenues of $8 million and $15.5 million for the three and six months ended June 30, 2024, as compared to $4.2 million and $7.6 million for the same periods in the prior year.

Speaker Change: Full year 2024 guidance remains unchanged with projected Zotomi net product revenues between $33 and $35 million, and combined SG&A and R&D expense in the range of approximately $135 to $140 million, including non-cash stock-based compensation expense of approximately $20 million.

Lisa Lejuwaan: In terms of coverage, we continue to see widespread acceptance across both commercial and government programs, reflecting the value that Zatomi brings to CDD patients and families affected by refractory epilepsy. Notably, no CDD patients have been denied coverage to date, underscoring the favorable reimbursement dynamic. Over the past two years, we've proven that our rare disease of growth is working. We've built an infrastructure that is lean and efficient and our sales team continues to reach KOLs and HCPs both in specialized treatment centers and community setting, resulting in continued strong new patient enrollment and growth of new prescribers driving demand.

Speaker Change: I'll now take a few minutes to summarize our financial results for the second quarter.

Speaker Change: We recognize the Tommie product revenues of $8 million and $15.5 million for the three and six months ended June 30, 2024, as compared to $4.2 million and $7.6 million for the same periods in the prior year. This represents robust quarterly growth of 87% over the second quarter of 2023.

Steve Pfanstiel: This represents robust quarterly growth of 87% over the second quarter of 2020. Additionally, separately, we recognize BARDA revenues of $0.1 million and $0.2 million for the three and six months ended June 30, 2024, as compared to $1.8 million and $8.9 million for the same periods in the prior year.

Speaker Change: Separately, we recognize BARDA revenues of $0.1 million and $0.2 million for the three and six months ended June 30, 2024, as compared to $1.8 million and $8.9 million for the same periods in the prior year.

Lisa Lejuwaan: To continue to grow and evolve the Zatomi brand and maximize its impact in the CDD market, we're implementing several key initiatives. First, we now have robust data analysis with more than 1000 CDD patients identified. By using new data sources and analytics, we have identified patients not build with the CDD ICD-10 code in third party claims and patients who may have CDD but do not yet have a diagnosis. We're educating physicians on the importance of having confirmatory genetic testing, which is supported by the American Epilepsy Society's goal of making sure every patient with unidentified seizures has access to genetic testing to understand the underlying cause of their disease.

Steve Pfanstiel: As a reminder, the first quarter of 2023 included activity associated with the startup of the API on ensuring, and the base period funding was completed in the fourth quarter of 2020. Research and development expenses were $20.9 million and $45 million for the three and six months ended June 30, 2024, as compared to $21.4 million and $49.3 million for the same periods in the prior year. The year-to-date change was due to decreased costs associated with their API onshore. Selling general and administrative expenses were $16.7 million and $35.3 million for the three and six months ended June 30, 2024, as compared to $15.7 million and $30.9 million for the same periods in the prior year.

Speaker Change: As a reminder, the first quarter of 2023 included activity associated with startup of the API Onshoring Initiative, and the base period funding was completed in the fourth quarter of 2023.

Speaker Change: Research and development expenses were $20.9 million and $45 million for the 3 and 6 months ended June 30, 2024, as compared to $21.4 million and $49.3 million for the same periods in the prior year. The year-to-date change was due to decreased costs associated with our API on-shoring effort.

Speaker Change: Selling general and administrative expenses were $16.7 million and $35.3 million for the three and six months ended June 30, 2024, as compared to $15.7 million and $30.9 million for the same periods in the prior year.

Lisa Lejuwaan: Second, by showcasing a range of voices and stories to the community, including family members of newly treated patients, we intend to engage more families to elevate Zatomi and CDD awareness. We are launching our on-demand shining moment series where families can hear from experienced caregivers and families on how Zatomi has affected their lives at a time that fits into their schedule. We continue engaging with the International Foundation for CDKL5 Research, most recently at their annual conference, where over 100 families were in attendance.

Steve Pfanstiel: The primary drivers of the change on a year-to-date basis were increased commercial and personnel expansion. Restructuring costs were $2 million for the three months ended June 30, 2024. These one-time expenses reflect severance costs and the termination of trial-related lease assets. Interest income was $1.1 million and $2.6 million for the three and six months ended June 30, 2024, as compared to $2.1 million and $4.5 million for the same periods in the prior year. The decrease in interest income was given by the overall decrease in cash, cash equivalence, and short term investments.

Speaker Change: The primary drivers of the change on a year-to-date basis were increased commercial and personnel expense.

Speaker Change: Restructuring costs were $2 million for the three months ended June 30, 2024. These one-time expenses reflect severance costs and the termination of trial-related lease assets.

Speaker Change: Interest income was $1.1 million and $2.6 million for the three and six months ended June 30, 2024 as compared to $2.1 million and $4.5 million for the same periods in the prior year. The decrease in interest income was driven by the overall decrease in cash, cash equivalents, and short-term investments.

Lisa Lejuwaan: We're proud of the growing adoption of the Tomy Interplaning to replicate the success of CDD in TSC with a potential launch in the fourth quarter of 2025. Looking ahead, we plan to build upon the foundation of our proven CDD infrastructure to meet the needs of TSC patients who are also suffering from refractory seizures. With approximately five to six times the addressable patient population compared to CDD, we have the potential to unlock a significant growth opportunity.

Steve Pfanstiel: Interest expense was $4.6 million and $9 million for the three and six months ended June 30, 2024, as compared to $4.2 million and $8.4 million for the same periods in the prior year. The increase is primarily driven by interest expense associated with the $15 million prepayment to OCR. The company reported and let lost before-income taxes of $35.8 million and $74.5 million for the three and six months ended June 30th, 2024, as compared to a net loss before-income taxes of $33.5 million and $68.2 million in the same periods in the prior year.

Speaker Change: Interest expense was $4.6 million and $9 million for the three and six months ended June 30, 2024, as compared to $4.2 million and $8.4 million for the same periods in the prior year. The increase is primarily driven by interest expense associated with the $15 million prepayment to Oaktree.

Speaker Change: The company reported a net loss before income taxes of $35.8 million and $74.5 million for the three and six months ended June 30, 2024, as compared to a net loss before income taxes of $33.5 million and $68.2 million in the same periods in the prior year.

Lisa Lejuwaan: Our colleagues from the TSC Alliance and our market research make it clear that there remains a significant unmet need in these patients and that a new therapy would be welcomed. Furthermore, when pulled, physicians are excited about the potential for an effective and safe product that can be used concurrently with other anti-fusure medications. It's easily accessible and has the potential to meaningfully improve quality of life. When we launched in CDD, we had relatively quick uptake due to the significant unmet medical need in this patient population.

Steve Pfanstiel: These totals include non-cash stock-based compensation expense of $4.9 million and $10.1 million for the three and six months ended June 30, 2024, as compared to $3.9 million and $7.6 million for the same period in the prior year. Cash used in operating activities increased to $68.3 million for the six months ended June 30, 2024, as compared to cash used in operating activities of $65.8 million in the prior year. Before we move to the Q&A, I will make a few concluding remarks.

Speaker Change: These totals include non-cash stock-based compensation expense of $4.9 million and $10.1 million for the three and six months ended June 30, 2024, as compared to $3.9 million and $7.6 million for the same periods in the prior year.

Speaker Change: Cash used in operating activities increased to $68.3 million for the six months ended June 30, 2024, as compared to cash used in operating activities of $65.8 million in the prior year.

Lisa Lejuwaan: However, we anticipate even quicker uptake with TSC for several reasons. First, patient finding an ultra-various disease is often the largest hurdle. However, this patient population is much easier to identify through a well-known ICB-10 code and through physical and neurological identifiers such as tubers, cardiac rhodomyomas, and refractory seizures. Trust TSC will be the first phase 3 global trial executed in TSC that includes prior and concomitant usage of mTOR inhibitors and epidylex, giving HCTs and families confidence in combining medications and further underscoring the current needs in the TSC community.

Steve Pfanstiel: We are proud of what we have been able to achieve these past two years in both delivering the first product to market specifically for patients with CDD and driving continued development of Gnascone through our trusted TSE and phase three trials. We remain committed to the further development of Gnascone with a strong belief in the positive impact we can make on patients suffering from refractory epilepsy.

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

Speaker Change: We are proud of what we've been able to achieve these past two years in both delivering the first product to market specifically for patients with CDD and driving continued development of gonafzone through our Trust TSC and RAISE phase 3 trials.

Speaker Change: We remain committed to the further development of Ganaxolone with a strong belief in the positive impact we can make on patients suffering from refractory epilepsy.

Steve Pfanstiel: We are proud of what we have been able to achieve in these past three trials. Finally, as Scott mentioned, we will be hosting an Investor and Analyst Day event that will focus on TSC and our broader oral epilepsy franchise. The event will be in-person and webcast on the morning of Friday, September 12th.

Speaker Change: Finally, as Scott mentioned, we will be hosting an Investor and Analyst Day event that will focus on TSC and our broader oral epilepsy franchise. The event will be in person and webcasted on the morning of Friday, September 20th.

Steve Pfanstiel: More details will follow in the coming weeks. We look forward to seeing many of you in attendance. Thanks again for your continued interest in Marinus.

Lisa Lejuwaan: From a payer perspective, we expect rapid and broad access across the majority of payers supported by the protected class of epilepsy and the label extension from CDD to TSC. Patient activation is expected to be straightforward. In refractory TSC patients, seizure control is the main priority, making adding or changing medication an easier choice. The unique GABA-ERGIC mechanism of action of the TOMI is differentiated from other ASMs and supports the TOMI's place in the treatment algorithm.

Speaker Change: More details will follow in the coming weeks. We look forward to seeing many of you in attendance.

Operator: Operator, you may now open the call to questions. Thank you. We'll now be conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue.

Speaker Change: Thanks again for your continued interest in Marinus. Operator, you may now open the call to questions.

Speaker Change: Thank you. We will now be conducting a question and answer session.

Speaker Change: If you'd like to ask a question, please press star 1 on your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.

Operator: For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the start key. So we may address questions from as many participants as possible, we ask you please zoom in on one question. One moment, please, while we assemble the queue.

Lisa Lejuwaan: Additionally, this will be the second completed global randomized trial of the TOMI, which will live in on the market for over 3 years by the time of a TSC launch, giving physicians even greater confidence in the brand. The growth and continued uptake of the TOMI and CDD reinforces our confidence that we can replicate and accelerate the success in TSC, which is a significantly larger market opportunity.

Speaker Change: So we may address questions from as many participants as possible. We ask you to please limit yourself to one question.

Charles Duncan: Thank you. And our first question today comes from the line of Charles Duncan with Cantor Fitzgerald. Yeah, hi, good morning, Scott and team.

Speaker Change: One moment please while we assemble the queue.

Speaker Change: Thank you and our first question today comes from the line of Charles Duncan with Cantor Fitzgerald. Please proceed with your question.

Scott Braunstein: Thanks for the update and congratulations on the commercial progress in the quarter. I wanted to ask you about Zotomi specifically, and I had a pipeline question, but I'll stick with one. In terms of the new patients and additions in the quarter, could you provide a little bit more color on that? And then if Lisa could perhaps clarify a little bit about her statement around 70% of patients remaining active on drugs since launch, could you give us a sense of a little bit better sense of persistence on patients or that patients have on drugs? Thanks. Thanks, Charles. I'll kick it off, and then I'll turn it over to Lisa.

Charles Duncan: Yeah, hi, good morning Scott and team

Charles Duncan: Thanks for the update and congrats on the commercial progress in the quarter.

Lisa Lejuwaan: Our team looks forward to sharing further updates on our progress and plans at our TSC-focused investor and analyst day in September, where we will highlight the work that our commercial team has been doing behind the scenes to prepare for potential expansion into TSC. This will include key insights from our demand study, value proposition, key product positioning, and patient services portfolio enhancements.

Charles Duncan: I wanted to ask you about Zitomi specifically.

Speaker Change: And I did have a pipeline question, but I'll stick with one. In terms of the new patients' ad additions in the quarter, could you provide a little bit more color on that?

Speaker Change: And then if Lisa could perhaps clarify a little bit.

Joe Hulihan: I would now like to turn the call over to our chief medical officer, Dr. Joe Hula-Han, for an update on our clinical programs. Thank you, Lisa. Good morning. I'm pleased to share an overview of our pipeline progress, which includes the upcoming phase 3 data readout in TSC, preparation for our other rare genetic epilepsy programs, and a recap of our phase 3 raised trial readout and next steps for that.

Speaker Change: about her statement around 70% of patients remaining active on drugs since launch. Could you give us a sense of, a little bit better sense of persistence on patients or that patients have on drugs? Thanks.

Scott Braunstein: I think one of the things we've seen with this launch, almost from the get-go, is a relatively steady growth in new patient ads every quarter. There's always some variation quarter to quarter, but I think we really understand that this is a patient population that has a lot on their plate. Very often it's months to get started on new therapy, one that we think is going to be very different than the TSE population where seizure control is really a paramount issue in those patients' lives. And so I think we've generally been very consistent with the growth of the franchise since the time of launch.

Speaker Change: Thanks, Charles. I'll kick it off and then I'll turn it over to Lisa.

Lisa: I think one of the things we've seen with this launch, almost from the get-go, is a relatively steady

Joe Hulihan: I'll start with a trust TSC trial of oral and axelone and tuberous sclerosis complex. TSC is one of the most common genetic epilepsies and is caused by a defect or mutation of the TSC1 or TSC2 genes. Common symptoms include seizures, cognitive impairment, behavioral difficulties, and skin kidney or lung abnormalities among other manifestations. Epilepsy and TSC occurs in approximately 80 to 90 percent of patients with seizures typically beginning in the first year of life.

Lisa: growth in new patient ads every quarter.

Lisa: There's always some variation quarter to quarter.

Speaker Change: But I think we really understand that this is a patient population that has a lot on their plate.

Speaker Change: very often it's months to get started on new therapy, one that we think is gonna be very different than the TSC population where seizure control is really a paramount issue in those patients' lives. And so I think we've generally been

Speaker Change: very consistent with the growth of the franchise since the time of launch. And certainly there was a small bolus of patients and clinical trials from the beginning of our launch.

Scott Braunstein: And certainly, there was a small bolus of patients in clinical trials from the beginning of our launch. In terms of discontinuation rates, you know, if you go back to Marigold, we saw about 70% of patients on long-term therapy, a good number that we lost two to three years in follow-up. But the persistence of effect has really been one of the nicer experiences we've seen with the drug. And to date, our commercial experience really mirrors or is incrementally better than what we saw in Marigold.

Joe Hulihan: Seizures and TSC are often difficult to manage and remain resistant to treatment. Despite the introduction of disease-specific anti-seizure medications, there's still a significant unmet need for treatments to provide effective seizure control. To address this unmet need, we're evaluating oral and axelone in TSC patients with refractory seizures in the trust TSC trial. As Scott mentioned, we completed enrollment for the study in May and continued to expect report pop line results in the first half of the fourth quarter.

Speaker Change: In terms of the discontinuation rates, if you go back to Marigold,

Speaker Change: We saw about...

Speaker Change: About 70% of patients on long-term therapy, a good number that we lost two to three years in follow-up, but the persistence of effects has really been one of the

Lisa: Nicer experiences we've seen with the drug and to date our commercial experience really mirrors or Incrementally better than what we saw in marigold. So we're still north, you know, Lisa's comments north of 70% I'm persistent seeing very durable effect

Joe Hulihan: Trust TSC is a global Phase III randomized double-blind placebo-controlled trial of adjunctive ganaxelone, which enrolled 129 patients with TSC associated seizures. As a reminder, the trial provides 90 percent power to detect a 25 percent difference in seizure reductions between ganaxelone and placebo. The trial consists of a four-week baseline period, followed by a 16-week double-blind phase, with the primary endpoint being the percent change in 28-day seizure frequency. Then, for patients continuing to the open-label extension, there's a four-week cross-tie creation from double-blind study medications to opal-label ganaxelone.

Scott Braunstein: So we're still north of, you know, Lisa's comments, north of 70% on persistence, seeing very durable effects. We're going to also show some durability data in the TSC population at the analyst day and then at AES. But Lisa, I'm happy to flip it over to you for some additional comments on what you're seeing in the marketplace, both in terms of new patient starts and persistence. Thanks so much, Scott.

Lisa: We're going to also show some durability data in the TST population at the Analyst Day and then at AES. But Lisa, I'm happy to flip it over to you for some additional comments on what you're seeing in the marketplace, both in terms of new patient starts and persistence.

Lisa Lejuwaan: I think you covered most of it there, but I'll just add that we're extremely proud of the work the team has done to reach a significant portion of the market's CDD patients, with many more patients yet to be found. Our team is also very proud of the durability of this drug. When you talk about a 30%, less than 30% discontinuation rate, this speaks to the unique mechanism of action of this drug. And these patients have a very complicated mix of multiple therapies, and we're proud of the fact that these patients have remained on Zitome, signifying that they are getting the seizure reduction that they need with relatively few, if any, side effects.

Lisa: Thanks so much, Scott. I think you covered most of it there, but I'll just add that we're extremely proud of the work the team has done to reach a significant portion of the market CDD patients with

Lisa: Many more patients yet to find. Our team is also very proud of the durability of this drug when you talk about a 30%

Joe Hulihan: The two secondary endpoints of the double-blind portion of the study are the percent change in seizure frequency during the maintenance period, the 50 percent responder rate, and clinical global impression scales reported by the treating clinician and the patient or their caregiver. This trial is the first double-blind study in TSC to allow enrollment of patients taking epidial X or M-tor inhibitors, including a finitor, relatively newer additions to the range of medication used in TSC management.

Speaker Change: This speaks to the unique mechanism of action of this drug, and these patients, it's a very complicated mix of multiple therapies, and we're proud of the fact that these patients have remained on Zotomy, signifying that they are getting the seizure reduction that they need with relatively few, if any, side effects, and it has such a wonderful drug-drug interaction profile that the community is quite happy with.

Lisa Lejuwaan: And it has such a wonderful drug-drug interaction profile that the community is quite happy with. Thanks, Lisa. Charles, I want to make one other comment. The second half of the year tends to be stronger for us.

Joe Hulihan: As a reminder, in Maris Phase II TSC trial, patients taking these medications have a 25 percent and 36 percent responder rate respectively. As reported in May, patients entering the trust TSC study had failed a mean of 4.8 anti-seger medications, with approximately 27 percent having current or prior experience with epidial X, and approximately 58 percent having experience with end-label toward inhibitors. Patients had a median baseline rate of 50 TSC associated seizures per 28 days.

Scott Braunstein: A lot of the medical meetings are really back and weighted, certainly AES and some other additional pediatric meetings which are really critical to the best of the day. There's really a positive side to medical meetings in the first half of the year. So we're really looking forward to the second half of the year and the medical meetings and the interest that we see almost immediately following medical meetings for [inaudible]. So that drives prescribing, or does it take prescribers out of the office? What are the countervailing... Oh, I see.

Speaker Change: Dysresponse

Charles Duncan: Thanks Lisa. Charles, I'll make one other comment. The second half of the year tends to be stronger for us. A lot of the medical meetings are really back and waited.

Speaker Change: certainly AES and some other additional pediatric meetings which are really critical to the messaging.

Speaker Change: There's really a paucity of medical meetings in the first half of the year, so we're really looking forward to the second half of the year and the medical meetings and the interest that we see almost immediately following medical meetings for Zitomy.

Joe Hulihan: As discussed previously, based on information from our Phase II TSC study, we modified that Phase III titration schedule. When we reviewed the Phase II study results, we believed that Kinexlone had been titrated too quickly, leading to increased somnolence and unexpectedly, that this led to an associated decrease in F... Pricacy, with a discontinuation rate of approximately 26 percent. With the revised titration schedule, the discontinuation rate in the phase three study is below 7 percent, which is consistent with what we saw in the CDD-Marigold study.

Speaker Change: So that drives prescribing, or does it take prescribers out of the office? What are the countervailing... Generally, we've seen very strong prescription trends following our medical meetings.

Scott Braunstein: Yeah. Generally, we've seen very strong prescription trends following our medical... Okay, got it. Thank you. Our next question is from the line of Brian Abrahams with RBC Capital Markets. Please answer your question.

Speaker Change: Okay, got it. Thank you.

Speaker Change: Our next question is from the line of Brian Abrams with RBC Capital Markets. Please receive your question.

Brian Abrahams: Hi, this is Joon on behalf of Brian. Thank you for taking our question. On TNC, can you talk about some of the subgroup analysis you've done for the Phase 2 Open Label Study that gives you the most confidence that the Phase 3 Study will read out positively? How consistent was the seizure reduction for those who stayed on the therapy until the end of the maintenance phase? And, I guess, for the ongoing Phase 3 Study, can you tell us how many patients had their last visit? And we have entered into the Open Label Extension so far. Thank you. Yeah, well, let me start with the last question.

Speaker Change: Hi, this is Johan for Bryan. Thank you for taking our question.

Speaker Change: On TNC, can you talk about some of the subgroup analyses you've done for the Phase 2 open label study that gives you most confidence that Phase 3 study will read out positively? How consistent was the seizure reduction for those who stayed on the therapy until the end of the maintenance phase?

Joe Hulihan: Importantly, only two patients have to discontinue it from the TRUST-TSC study to date due to somblins-related adverse events. In addition, we are seeing over 90 percent of patients who complete the phase three study transitioning into the open label extension, suggesting that patients are not only tolerating the drug well, but are likely also benefiting from treatment overall.

Speaker Change: And I guess for the ongoing phase 3 study, can you tell us how many patients had their last visit and entered into the Open Label Extension so far? Thank you.

Scott Braunstein: And I'll turn it over to Joe to talk a little bit about what we saw in phase two. But we are well north of 100 patients now, close to 110 patients that are into the open label. The last patient visit is in September, the first or second week in September.

Joe Hulihan: We look forward to sharing updated information on baseline patient demographics and characteristics of our September investor analyst event, including details on seizure types, use of concomitant medications, discontinuation rates, and average patient doses. We are targeting submission of a supplemental NDA in April 2025 with a request for priority review. Assuming all goes according to plan, we anticipate a pedophadate in the fourth quarter of 2025. We plan to present the results of AES in December following the announcement of our top-line data in early Q4, with the goal of publication and a major journal prior to the commercial launch.

Speaker Change: Let me start with the last question and then I'll turn it over to Joe to talk a little bit about what we saw in the phase two.

Speaker Change: But we are well north of 100 patients now, close to 110 patients that are into the open label. The last patient visit is in September. The first or second week in September, we should have the last patient visit in the study. So, the vast majority of patients have now rolled into open label.

Scott Braunstein: We should have the last patient visit in the study. Thus, the vast majority of patients have now rolled into open label. And to your question, I think we continue to see consistency of those high percentages of patients rolling into open label. We're north of 90% of patients completing the study who are rolling into open label and staying on open label. So we'll give the final numbers at analyst day, but certainly from, you know, we haven't seen a bump in those discontinuations early on in the trial.

Speaker Change: to the question, I think we continue to see consistency of those high percentages of patients rolling into open-label. We're north. We're south. We're north. We're north. We're north. We're north. We're north.

Speaker Change: of 90% of patients completing the study who are rolling into open label and staying on open label.

Speaker Change: So, we'll give the final numbers at the analyst day, but...

Joe Hulihan: In addition to TSC, we plan to expand our investments at all many to explore its potential in the treatment of other rare epilepsy. Planning is underway for a clinical trial that will assess organ axelome for the treatment of a broad range of developmental and epileptic encephalopathies, including Linux Guestos Syndrome. LGS is characterized by the presence of development of delay and fractory seizures. It affects approximately 48,000 patients in the US, which is four times larger than the refractory TSC population.

Speaker Change: Certainly from, you know, we haven't seen a bump in those discontinuations early on in the trial. We feel very confident that now north of a hundred patients are really tolerating the drug extremely well. Very different than what we saw in phase two. As a reminder, we had a 26% discontinuation rate in the phase two. And I think we're in a different place today much because of the work that Joe has done and the team has done to reconfigure the dosing paradigm.

Joe Hulihan: We feel very confident that now, north of 100 patients are really tolerating the drug extremely well, very different than what we saw in phase two. As a reminder, we had a 26% discontinuation rate in phase two. And I think we're in a different place today, much because of the work that Joe has done and the team has done to reconfigure the dosing paradigm. Joe, would you like to talk about some of the highlights that we saw in phase two and our confidence going into phase three? Yeah, yeah, Scott.

Speaker Change: Joe, you want to talk about some of the highlights that we saw in Phase 2 and our confidence going into Phase 3?

Joe Hulihan: Yeah, as you mentioned, as Scott mentioned, there were 26% discontinuations for side effects. So that was six patients for side effects, right? So really, you know, despite the rapid titration in phase two, we had four patients discontinued due to adverse events. Now, the one thing about the current open-label study that's ongoing, patients from the phase two study could roll into the open-label study. And so we have a combined open-label extension for phase three and phase two.

Joe Hulihan: Despite the availability of several anti-seizure medications approved for the treatment of seizures in LGS, there remains a considerable unmet need for effective treatment. We plan to initiate a proof of concept trial with Sitalmi in the first half of 2025, pending the TSC top-line data. We believe that an axelome could be a valuable addition to the treatment options for LGS and DEEs overall, given its unique mechanism of action. The plan proof of concept trial can help guide us in the design and conduct of a future Phase III study.

Joe Hulihan: Yeah, yeah, Scott. Yeah, as you mentioned, as Scott mentioned, you know, there were 26% discontinuations.

Joe Hulihan: For side effects, so that was six patients, for side effects it was four.

Speaker Change: So really, you know, despite the rapid titration in phase two, we had four patients discontinued due to adverse events.

Speaker Change: Now, the one thing about the current open label study that's ongoing, patients from the Phase II study could roll into the open label, and so we have a combined open label extension for the Phase III and the Phase II.

Joe Hulihan: And we still have patients, the latest number is not at the tip of my tongue, but we have patients from phase two who have continued to this point in the open label extension. And so I think, you know, the titration really makes a big difference.

Joe Hulihan: Additionally, we're continuing our efforts to develop a second-generation genaxelome product. Our goals are to optimize PK parameters for efficacy, tolerability, and dosing frequency. We've initiated IND enabling studies for a genaxelome prodrug, which are expected to be completed by the end of 2025.

Speaker Change: And we still have patients, the latest number is not at the tip of my tongue, but we have patients from phase 2 who have continued to this point in the open label extension.

Joe Hulihan: I mean, I think you asked about subpopulations, and we looked at patients with focal seizure types, and they had a better response, a 25% reduction compared to the overall population. And then we looked at patients on cannabidiol and everolimus, and they also had a good response, particularly everolimus, a 20% greater response in the population as a whole. So again, encouraging signals. Can I answer your question

Speaker Change: And so I think the titration really makes a big difference. I think you asked about...

Joe Hulihan: Lastly, I'll briefly recap the results of our Phase III raised trial of IV genaxelome in refractory status epilepticus, and we'll also share the next steps in our clinical and regulatory approach. We believe that the totality of the raised trial data showed that genaxelome produced rapid cessation of status and evidence of durable cessation in a highly refractory patient pups.

Speaker Change: Subpopulations, you know, I mean we looked at patients with focal seizure types. They had a better response 25% reduction compared to the overall

Speaker Change: population, and then we looked at patients on cannabidiol and everolimus, and they also had a good response, particularly everolimus, 20% greater response than the population as a whole. So again, encouraging signals. Did I answer your question?

Joe Hulihan: Congratulations. Specifically, on set of effect was rapid, with 80% of patients receiving a vegan axelome having status epileptic cessation within 30 minutes compared to 13% for placebo, a result that was statistically significant with a p-value of less than 0.001. Unfortunately, the second co-primary endpoint, lack of progression to IV anesthesia within 36 hours, failed to achieve statistical significance. Our analysis of the raised data showed that the use of IV anesthesia was likely driven by clinical and treatment factors unrelated to status severity.

Joe Hulihan: Yes, thank you. Thank you, Scott. Thank you, Joe. Yeah, let me add one or two comments to Joe's comments. Joe hit the mark in terms of what we saw in phase two. And as a reminder, what we said publicly is that about 70% of the seizure types, close to 75%, that we're seeing in the blinded phase three are focal in nature. So that's exactly what we had hoped to see.

Speaker Change: Yes. Thank you. Thank you, Scott. Thank you, Joe.

Speaker Change: Yeah, let me add one or two comments to Joe's comments. Joe hit the mark in terms of what we saw in the phase two and as a reminder what we said publicly is about about 70% of the

Speaker Change: of the seizure types, close to 75 percent that we're seeing in the blinded Phase 3 are focal in nature. So that's exactly what we had hoped to see. So to Joe's point, you know, strong signal in Phase 2, even with the tolerability issues, which is why we expect that number to be more robust in the Phase 3.

Scott Braunstein: So to Joe's point, you know, strong signal in phase two, even with the tolerability issues, which is why we expect that number to be more robust in phase three. And in phase three, more than half the patients are coming into the study on mTOR inhibitors. And again, that was our strongest 50% responder number from phase two. And certainly, we saw a robust responder number with the cannabidiol group, which will make up about 25% of the population.

Speaker Change: And in the phase 3, more than half the patients are coming into the study on mTOR inhibitors. And again, that was our strongest 50% responder number from the phase 2. And certainly, we saw a robust responder number with the cannabidiol group, which will make up about 25% of the population.

Joe Hulihan: In contrast, continuous EEG monitoring demonstrated objective and durable control of status, specifically analysis of 36 hours of continuous EEG data demonstrated a median 93% reduction in EEG seizure burden in the absence of IV anesthesia for an axelome treated patients compared to 36% for placebo. Based on our assessment of the raised data set, we plan to submit a request to the FDA this month for a meeting to discuss the trial results and determine next steps for the program.

Scott Braunstein: So we have all the right subtypes in phase three; we have the right seizure types, and certainly that's where the efficacy signals were strongest, even in the setting of some real tolerability issues in phase two. So we have a lot of confidence going into phase three. Thanks for the question. Our next question is from the line of Joseph Tomei with TD Cowan. Please proceed with your question. Hi there, good morning, and thank you for taking my question.

Speaker Change: So, we have all the right subtypes in the Phase III, we have the right seizure types, and certainly that's where the efficacy signals were strongest.

Speaker Change: Even in the setting of some real tolerability issues in the phase two. So so we have a lot of confidence going into the phase three Thanks for the question

Joe Hulihan: This was the first placebo controlled trial conducted in refractory status. We're proud of our team success in enrolling and completing a complex hospital-based study in this area of tremendous unmet need. We're hopeful that the raised data set can support moving forward with our program for IV genaxelome in the treatment of status epilepticus. I'd also mention that we've provided IV genaxelome for treatment of super refractory status epilepticus for over 30 patients under emergency IND applications.

Speaker Change: Our next question is from the line of Joseph Tomei with TD Cowan. Please proceed with your question.

Joseph Tomei: Maybe a little bit of a follow-on to your explanation from the last question, but phase 3 looks like the baseline seizure frequency is a little bit higher than what you saw in phase 2, and the number of prior therapies failed is also a little bit higher in the phase 3 blinded data than in phase 2. I guess, does that indicate that you think it's potentially going to be a little bit easier to show a benefit of Ganaxolone in phase 3, or are these more challenging patients to treat? Kind of based on your experience in CVD and phase 2, what's your sort of expertise? Thank you. Yes, Thanks, Joe. Let me take it off, and then I'll turn it over to Joe.

Joe Hulihan: Looking ahead, results from the raised trial have been accepted for a platform presentation at the Neurocritical Care Society meeting in October, and we plan to submit additional data for presentation at this year's American Epilepsy Society annual meeting.

Joseph Tomei: Hi there, good morning, and thank you for taking my question. Maybe a little bit of a follow-on to your explanation from the last question, but the phase 3 looks like the baseline seizure frequency is a little bit higher than what you saw in the phase 2, and the number of prior therapies failed is also a little bit higher in the phase 3 blinded data than versus the phase 2, I guess.

Speaker Change: Does that indicate that you think it's potentially going to be a little bit easier to show a benefit of Ganaxalone in the phase 3? Or are these more challenging patients to treat? Based on your experience in CVD and in the phase 2, what's sort of your expectations?

Scott Braunstein: I will tell you my experience, at least from talking to some of our key investigators. What's really critical in a study like this is that we have patients who, for lack of a better word, are seizing up through their medications at a steady state so that there isn't an acute acceleration or worsening of their symptoms, which would tend to set yourself up for failure just because the disease is progressing whether or not. Any therapy can kind of acutely address that.

Speaker Change: there. Thank you. Thanks, Joe. Let me kick it off, and then I'll turn it over to Joe. I will tell you my experience, at least from talking to some of our key investigators.

Joe Hulihan: In closing, our clinical research team is passionately committed to bringing safe, effective, and innovative treatments to patient suffering the consequences of refractory seizures and status epilepticus.

Joe Hulihan: What's really critical in a study like this is that we have patients who, for lack of a better, are seizing through their medications at a steady state, that there isn't an acute acceleration or worsening of their symptoms.

Steven Pfanstiel: I'd now like to turn the call over to our CFO and COO Steve Fanstil for a financial update. Thanks, Joe, and good morning, everyone. I am pleased to be able to provide a financial update as well as share our financial results for the second quarter of 2024. In the second quarter of 2024, we took several significant actions as a result of the Phase III raised trial to further extend our cash runway, which is now projected into the second quarter of 2025.

Joe Hulihan: which would tend to set yourself up for failure just as the disease is progressing whether or not any therapy can kind of acutely address that. So I think, you know, I give Joe all the credit in the world that he really stuck to our guns.

Scott Braunstein: So I think you know, I give Joe all the credit in the world that he really stuck to our guns and kept our enrollment criteria at more than eight seizures per month. And I think that's a critical factor for minimizing the placebo rate. You can imagine that if a patient was allowed to enroll with only four seizures per month and there was natural variability, the placebo response could be 25% if they went from four to three. So Joe was really instrumental in driving the team and keeping us at eight seizures per month, which is higher than what you see in multiple seizure studies.

Joe Hulihan: kept our enrollment criteria at more than eight seizures per month.

Speaker Change: And I think that's a critical factor for minimizing placebo rate. You can imagine that if a patient was allowed to enroll with only four seizures per month and there was natural variability, the placebo response could be 25% if they went from four to three.

Steven Pfanstiel: Cross-reduction plans were initiated in April of this year and remain ongoing with the full impact of cost savings expected to be achieved in the third quarter. We now project our combined selling, general, and administrative, and R&D expenses to decrease by approximately 30 percent from 80.3 million in the first half of 2024 to between 55 and 60 million in the second half of 2024. This new reduced cost structure also aligns with our near-term focus on the oral epilepsy franchise, which can be efficiently leveraged upon an indication expansion into T.S.

Joe Hulihan: So, Joe was really instrumental in driving the team and keeping us at eight seizures per month, which is higher than what you see in multiple seizure studies, but again,

Joe Hulihan: Our view is how do we minimize placebo rate to maximize success? So I think, you know, controlling for placebo is going to be critical for us.

Scott Braunstein: But again, our view is how do we minimize the placebo rate to maximize success. So I think, you know, controlling for placebo is going to be critical for us. You know, my experience from talking to our investigators is that we're getting a group of patients, a little bit older, many who have gone through surgery, many have gone through multiple medications. I think it's a very classic phenotype in this population.

Joe Hulihan: You know, look, my experience from talking to our investigators is that we're getting a group of patients.

Steven Pfanstiel: C. In June of this year, we restructured our credit agreements with both Oak Tree Capital and Cicard Health Care. As a result, the 15 million minimum liquidity requirement has been removed from both agreements and amortization payments due to Oak Tree in 2024 have been reduced by 50%. In return, Marinus made a one-time principal payment of 15 million to Oak Tree, reducing our outstanding principal with Oak Tree to 60 million. As a result of these actions, we ended June 2024 with cash and cash equivalents of 64.7 million, extending our projected cash run rate into the second quarter of 2025.

Joe Hulihan: A little bit older, many who have gone through surgery, many have gone through multiple medications. I think it's a very classic phenotype.

Scott Braunstein: Certainly, that's what Lisa's market research is showing. And I, and again, to this discussion, I think just the high seizure burden really will minimize the placebo effect. So yeah, when you ask this question, I think we feel good about the efficacy. We feel very good about placebo rates, not only because of baseline seizure type, but where we went or countries. We, we, we, we really convinced in our minds folks that if you go back to the GW study, the placebo rate was about 25%. Poland was the second largest enroller in that study. We had a very unfortunate experience in Poland with TDKL 5.

Lisa: In this population, certainly that's what Lisa's market research is showing, and I again to this discussion I think just the high seizure burden really will minimize placebo effects. So yeah, when you have this.

Speaker Change: I think we feel good about the efficacy. We feel very good about placebo rates, not only because of baseline seizure type, but where we went or countries we

Steven Pfanstiel: As mentioned by Scott and Lisa, we remain committed to growing this autonomy franchise and have made important investments to expand our manufacturing capacity to support expansion outside of the US and in preparation of a potential launch in TSC. We are proud of the progress we have made to expand patient access on a global scale, while also creating meaningful revenue opportunities from markets outside the US. We expect to see positive returns from our managed access program before the end of the year and remain eligible to receive several milestone payments from our commercial partners upon the achievement of certain CDD and TSC-related regulatory and commercialization activities.

Speaker Change: We really enrolled in. I'll remind folks that if you go back to the GW study, the placebo rate was about 25%

Scott Braunstein: That was a very high placebo rate. Certainly, the GW study suggested a high placebo rate. So we chose to stay out of Eastern European countries to minimize the risk of high placebo rates.

Speaker Change: Poland was the second largest enroller in that study. We had a very unfortunate experience in Poland with CDKL5 that was a very high placebo rate.

Speaker Change: Certainly, the GW study suggested a high placebo rate.

Speaker Change: So we chose to stay out of Eastern European countries to minimize the risk of high placebo.

Scott Braunstein: So between that and the eight years per month, we feel very good about the placebo rate coming in somewhere in the high single digits, no more than the low double digits, which gives us the best chance to win. So you want to comment on additional seizure types or anything else that we've seen in that? Blirebade in the face of green in terms of seizures that give you comfort. Yeah, well, a lot of things.

Speaker Change: So, between that and the 80 years per month.

Speaker Change: We feel very good about the placebo rate coming in somewhere in the high single digits, no more than low double digits.

Steven Pfanstiel: Full year 2024 guidance remains unchanged with projected autonomy net product revenues between 33 and 35 million and combined SG&A and R&D expense in the range of approximately 135 to 140 million, including non-cash stock-based compensation expense of approximately 20 million.

Speaker Change: which gives us the best chance to win. Joe, you want to comment additionally on seizure types or anything else that we've seen in the data in terms of seizures that give you comfort?

Joe Hulihan: One, I mean, you mentioned seizure types. The vast majority of the patients coming into phase three have vocal onset seizures, where we expect to see good efficacy and less variability in the response in patients with vocal onset seizures than we saw, say, with atonic or tonic seizures. Still a good effect size, and I'm talking about CVD, still a good effect size, but there was less variability in patients with focal seizures.

Joe Hulihan: Yeah, well a lot of things. One, I mean you mentioned seizure types. The vast majority of the patients coming into the phase three have focal onset seizures where we expect to see good efficacy and less variability in the response in the patients with focal onset seizures.

Steven Pfanstiel: I'll now take a few minutes to summarize our financial results for the second quarter. We recognize the Tommy product revenues of 8 million and 15.5 million for the three and six months ended June 30 at 2024 as compared to 4.2 million and 7.6 million for the same periods of the prior year. This represents robust quarterly growth of 87% over the second quarter of 2023. Separately, we recognize bar to revenues of 0.1 million and 0.2 million for the three and six months ended June 30 at 2024 as compared to 1.8 million and 8.9 million for the same periods in the prior year.

Speaker Change: that we saw, say, with atonic seizures.

Speaker Change: Still a good effect size, and I'm talking about CVD. Still a good effect size, but the variability is less in the patients with focal seizures.

Joe Hulihan: And to just tag on to what Scott said about patients coming in, it's really eliminating those patients with very few seizures. It's not really linear in terms of seizure frequency, you know, the bigger the number at baseline, the more response you get. But it's really just those patients with very low seizure numbers that there's that kind of mathematical problem with, you know, not being able to get much better.

Speaker Change: And to just tag on to what Scott said about patients coming in, it's really eliminating those patients with very few seizures.

Steven Pfanstiel: As a reminder, the first quarter of 2023 included activity associated with startup of the API-on-choring initiative and the base period funding was completed in the fourth quarter of 2023. Research and development expenses were 20.9 million and 45 million for the three and six months ended June 30 at 2024 as compared to 21.4 million and 49.3 million for the same periods in the prior year. The year-to-date change was due to decreased costs associated with our API-on-choring effort.

Scott Braunstein: It's not really linear in terms of seizure frequency, you know, the bigger the number at baseline the more response you get, but it's really just those patients with very low seizure numbers.

Scott Braunstein: that there's that kind of mathematical problem with, you know, not being able to get much better.

Joe Hulihan: But once you get beyond eight or ten seizures a month, you know, the response doesn't differ that much depending on baseline seizure rate. Higher is better, but just really eliminating the very low patients. The other thing I'll mention, too, that gives it, well, a couple of things.

Scott Braunstein: But once you get beyond eight or ten seizures a month, the response doesn't differ that much depending on baseline seizure rate. Higher is better, but just really eliminating the very low patients.

Steven Pfanstiel: Selling general and administrative expenses were 16.7 million and 35.3 million for the three and six months ended June 30 at 2024 as compared to 15.7 million and 30.9 million for the same periods in the prior year. The primary drivers of the change on a year-to-date basis were increased commercial and personnel expense. Restructuring costs were two million for the three months ended June 30 at 2024. These one-time expenses were severance costs and the termination of prior related lease assets.

Joe Hulihan: One is we want to make sure the patients had disease stability coming in so that they didn't have, you know, quote, regression to the mean when they came into the study. So we want them to have seizures in each of the two months at a certain frequency and no more than one week seizure-free during those months to make sure the disease is stable when they go into baseline. And the other thing, too, is somnolence.

Scott Braunstein: The other thing I'll mention too...

Speaker Change: Well, a couple of things. One is we want to make sure the patients had disease stability coming in.

Speaker Change: So that they didn't have regression to the mean when they came into the study. So we want them to have seizures in each of the two months at a certain frequency and no more than one week seizure free during those months.

Speaker Change: to make sure the disease is stable when they come into the baseline. And the other thing, too, is the somnolence.

Joe Hulihan: The lower, you know, the titration rate and the lower discontinuations due to somnolence, we saw this odd relationship between somnolence, higher somnolence, and lower efficacy. And so by reducing the somnolence, that also gives me optimism about the efficacy we're going to see in phase three. Our next question is from the line of Joon Lee with Truist. I'm pleased to see you with your question. Good morning, this is Asim Rana, for June. Thanks for taking the questions.

Steven Pfanstiel: Interest income was 1.1 million and 2.6 million for the three and six months ended June 30 at 2024 as compared to 2.1 million and 4.5 million for the same periods in the prior year. The decrease in interest income was driven by the overall decrease in cash, cash equivalence, and short-term investments. Interest expense was $4.6 million and $9 million for the $3.6-month send-in June 30, 2024, as compared to $4.2 million and $8.4 million for the same periods in the prior year.

Speaker Change: The lower, you know, the titration rate and the lower discontinuation due to somnolence...

Speaker Change: We saw this odd relationship between higher somnolence and lower efficacy. And so by reducing the somnolence, that also gives me optimism about the efficacy we're going to see in Phase III.

Speaker Change: Let's go to the next question. Thank you. Our next question is from the line of June Lee with Truist. Pleased to see you with your question.

Steven Pfanstiel: The increase is primarily driven by interest expense associated with the $15 million prepayment to Oak Tree. The company reported on let loss before income taxes of $35.8 million and $74.5 million for the $3.6-month send-in June 30, 2024, as compared to a net loss before income taxes of $33.5 million and $68.2 million in the same periods in the prior year. These totals include non-cash stock based compensation expense of $4.9 million and $10.1 million for the $3.6-month send-in June 30, 2024, as compared to $3.9 million and $7.6 million for the same periods in the prior year. Cash used in operating activities increased to $68.3 million for the $6-month send-in June 30, 2024, as compared to cash used in operating activities of $65.8 million in the prior year.

Asim Rana: Just curious what the timing of the tight-team meeting with the SDA is and what scenarios you think could come out of the meeting. And then, I know this is mentioned on the call, but you don't want to be sure what the discontinuation rate due to semblance was in the stage 3 trust TSC trial and what that number was in the phase 2 trial. Thank you. Thank you. Thanks Drew.

Speaker Change: Good morning, this is Austin Wong for June. Thanks for taking the questions.

Austin Wong: I'm just curious what the timing on the Type C meeting with the FDA is and what scenarios you think could come out of the meeting. And then I know this is mentioned on the call, but I just want to be sure what the discontinuation rate due to somnolence was in the Phase 3 TRUST-TSC trial and what that number was in the Phase 2 trial. Thank you.

Scott Braunstein: Just to start backwards, we've only reported a total discontinuation rate of 26% from phase two, and the vast majority of those were related to tolerability issues. You know, we believe all of them were related to tolerability.

Speaker Change: Thanks, Drew. Just to start backwards, we've only reported the total discontinuation rate of 26% from the Phase 2. The vast majority of those were related to tolerability issues. You know, we believe all of them were related to tolerability issues.

Scott Braunstein: And certainly, you know, the other piece of that puzzle; more than 70% of the patients in phase 2 required dosing adjustments. So they were, the patients were really struggling with the dosing, and it was really something we didn't become aware of until very effectively until the trial was completed. One of the physicians who will be at our analyst day is quite excited because he was in our phase 2 and really struggled with the patients on the phase 2 dosing regimen.

Speaker Change: and certainly you know the other piece of that puzzle is more than 70% of the patients in the phase two required dosing adjustments.

Steven Pfanstiel: Before we move to the Q&A, I will make a few concluding remarks. We are proud of what we have been able to achieve these past two years in both delivering the first product to market specifically for patients with CDD and driving continued development of Gnaxone through our trust TSE and RAIS Phase III trials. We remain committed to the further development of Gnaxone with a strong belief in the positive impact we can make on patients suffering from refractory epilepsy.

Speaker Change: So they were

Speaker Change: Patients were really struggling with the dosing and it was really something we didn't become aware of.

Speaker Change: until a very

Speaker Change: effectively until the trial was completed.

Speaker Change: One of the physicians who will be at our Analyst Day, I'm quite excited about because he was in our Phase 2 and really struggled with the patients on the Phase 2 dosing regimen. It took a lot of personal convincing from our medical team and myself to get this physician to participate in the Phase 3, and I think he'll share with you at the Analyst Day what a good response that he's had, at least in a blinded fashion.

Scott Braunstein: It took a lot of personal convincing from our medical team and myself to get this physician to participate in phase 3, and I think he'll share with you at analyst day what a good response he's had, you know, at least in a blinded fashion, from phase 3 thus far. June, I really apologize.

Steven Pfanstiel: Finally, as Scott mentioned, we will be hosting an investor NAO's day event that will focus on TSE and our broader oral epilepsy franchise.

Steven Pfanstiel: The event will be in-person and webcasted on the morning of Friday, September 20. More details will follow in the coming weeks.

Steven Pfanstiel: We look forward to seeing none of you in attendance. Thanks again for your continued interest in Marinus.

Operator: Operator, you may now open the call to questions. Thank you.

Scott Braunstein: I forgot your first question. Oh, I was just curious about the timing of the type C meeting with the FDA and what scenarios you think could come out of that. Thanks. Absolutely. Yeah.

Speaker Change: from the phase three thus far. June, I really apologize, I forgot your first question.

Operator: Well now we're conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad and the confirmation tone indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. So we may address questions as many participants as possible. We ask you please send them yourself to one question. One moment please, will we assemble the queue?

June Lee: Oh, I was just curious about the timing on the type C meeting with the FDA and what scenarios you think could come out of that.

Scott Braunstein: So, Joe, and Alex, the regulatory team has been working incredibly hard putting together, you know, going through the IV data set and really understanding that data. And there's no question, you know, to Joe's comments, we are quite convinced that the drug was highly efficacious and had a durable effect. I think, unfortunately, the endpoint that we chose had a great deal of variability and did not really reflect the durability of the drug. It really reflected what we believe is more physician practice, and that's unfortunate.

Speaker Change: Absolutely, yeah. So Joe, Alex, the regulatory team has been working incredibly hard putting together, you know, going through the IV data set.

Speaker Change: and really understanding that data. There's no question, you know, to Joe's comments.

Speaker Change: We are quite convinced that the drug was highly efficacious and had a durable effect. I think, unfortunately, the endpoint that we chose had a great deal of variability.

Scott Braunstein: Thank you and our first question today comes from the line of Charles Duncan with Cantor Fitzgerald. Please use your question. Yeah, hi. Good morning, Skype and team. Thanks for the update and congrats on the commercial progress in the quarter. I wanted to ask you about the Tommy specifically, and I did have pipeline question, but I'll stick with one in terms of the new patients add additions in the quarter. Could you provide a little bit more color on that?

Speaker Change: did not really reflect the durability of the drug. It really reflected what we believe is more physician practice, and that's unfortunate. That's really counterintuitive.

Scott Braunstein: That's really counterintuitive to what we were told going into the study time and time again by the medical community and the experts that we talked to. So, our real goal for the meeting with the FDA is really to align on endpoints that we think are much more objective, so we can define the durability of the product. That will be the critical piece in really thinking about a study design, and certainly, we're going to share our data set with the FDA and have what we hope is a very robust discussion. Our hope and goal is to get the filing in by the end of the month, and a typical type C meeting is a 90-day review.

Speaker Change: Thanks to what we were told going into the study time and time again by the medical community and the experts that we talked to.

Scott Braunstein: And then if Lisa could perhaps clarify a little bit about her statement around 70% of patients remaining active on drugs since launch. Could you give us a sense of a little bit better sense of persistence on patients or that patients have on drugs? Thanks. Thanks Charles. I'll kick it off and then I'll turn it over to Lisa. I think one of the things we've seen with this launch almost from the get go is a relatively steady growth in new patient ads every quarter.

Speaker Change: So, our real goal for this meeting with the FDA is really to realign on endpoints that we think are much more objective, that we can define the durability of the product.

Speaker Change: That will be the critical piece in really thinking about a study design, and certainly we're going to share our data set with the FDA and have what we hope is a very robust discussion. Our hope and goal is to get the filing in by the end of the month, and a typical type C meeting is a 90-day review.

Scott Braunstein: So, our hope is to have that meeting in the early part of the fourth quarter. I think we really understand the data set. Joe's done an amazing job looking at the EEG data set, looking at practice patterns.

Joe Hulihan: Our hope is to have that meeting in the early part of the fourth quarter. And I think, you know, we really understand the data set. Joe's done an amazing job looking at the EEG data set, looking at practice patterns.

Scott Braunstein: There's always some variation quarter to quarter, but I think we really understand that this is a patient population that has a lot on their plate very often. And it's it's months to get started on new therapy, one that we think is going to be very different than the TSE population where seizure control is really a paramount issue in those patients lives. And so I think we've generally been, very consistent with the growth of the franchise since the time of launch.

Scott Braunstein: Unfortunately, I think we're learning about an ICU study where physicians leave after 12 hours, and new physicians come in. We've just seen a lot of practice patterns, which are disheartening to me as a physician, but certainly it's helping us rethink how to best show the efficacy of this drug. I mean, there's nothing in this study that gave us pause about the efficacy of this drug.

Joe Hulihan: And unfortunately, you know, I think we're learning an ICU study where physicians leave after 12 hours, new physicians come in, it's just, we've just seen a lot of practice patterns.

Speaker Change: which are disheartening to me as a physician, but certainly it's helping us rethink how to best show the efficacy of this drug. I mean, there's nothing in this study that gave us pause for the efficacy.

Scott Braunstein: And certainly there was a small bowl of the patients and clinical trials from the beginning of our launch. In terms of the discontinuation rates, you know, if you go back to Marigold, we saw about about 70% of patients on long-term therapy, a good number that we lost two to three years in follow-up, but the persistence of effects has really been one of the nicer experiences we've seen with the drug and to date our commercial experience really mirrors or incrementally better than what we saw in Marigold. So we're still north, you know, at least in comments north of 70% on persistence being very durable.

Scott Braunstein: I think the other thing that will really align with the FDA is how we should think about enrolling this population. We saw some variability in terms of differences in patient outcomes, and we want to agree on a stratification strategy with the FDA to make sure that there are no significant imbalances and we can really show the value of the drug. Last note is we'll be presenting the vast majority of this data at a medical meeting in October, the NCS meeting, and it will be a platform presentation, so folks will really get to see all of what we've seen in terms of the efficacy and the tolerability of the drug, and certainly, we're going to share all of that with the FDA as well. Thank you.

Speaker Change: The other thing that will really align with the FDA is how we should think about

Speaker Change: Enrolling this population, we saw some variability in terms of differences in patient outcomes and we want to align on a stratification strategy with the FDA to make sure that there are no significant imbalances and we can really show the value crop of the drug.

Speaker Change: I'll finally, I'll just, you know, last note is we'll be presenting the vast majority of this data at a medical meeting in October, the NCS meeting.

Speaker Change: and it will be a platform presentation. So folks will really get to see all of what we've seen in terms of the efficacy and the tolerability of the drug. And certainly we're gonna share all of that with the FDA as well. Thanks for the question.

Lisa Lejuwaan: In fact, we're going to also show some durability data in the TST population at the analyst day and then at AES, but Lisa, I'm happy to flip it over to you for some additional comments on what you're seeing in the marketplace, both in terms of that I'll just add that we're extremely proud of the work the team has done to reach a significant portion of the market to the patients with many more patients yet to find. Our team is also very proud of the durability of this drug when you talk about a 30% less than 30% discontinuation rate.

Andrew Tsai: Thanks for the question. Our next question is from the line of Andrew Tsai with Jeffreys. I'm pleased to see you with your question. Hey, thanks, good morning.

Speaker Change: Our next question is from the line of Andrew Tsai with Jeffries. Pleased to see you with your question.

Scott Braunstein: Thanks for taking my question. And so, on top of the RFC, thanks for sharing all those tidbits. If you had to run another study after the FDA meeting, how would you design it to not only succeed but also have it done, say, within one to two years? Or is there anything you can think of to ensure that it does?

Andrew Tsai: Hey, thanks. Good morning. Thanks for taking my question. And so on top of the RFC, thanks for sharing all those tidbits. If you had to run another study after the FDA meeting, how would you design it to not only succeed, but also have it done, say, within one to two years, or is there anything you can think of to ensure? Thanks.

Scott Braunstein: Thanks. Yeah, well, Andrew, first and foremost, thanks for the question. I think we're going to be very, very thoughtful about the trial design. I think, you know, once we got through our protocol amendment and our product issues, you know, recall we had some manufacturing issues that we were able to resolve, and we now have great stability and shelf life of the product.

Andrew Tsai: Well, I think, Andrew, first and foremost, thanks for the question. I think we're going to be very, very thoughtful about the trial design. I think

Lisa Lejuwaan: This speaks to the unique mechanism of action of this drug and these patients, it's a very complicated mix of multiple therapies and we're proud of the fact that these patients have remained on to tell me, signifying that they are getting a seizure reduction that they need with relatively few, if any, side effects and it has such a wonderful drug-drug interaction profile that the community is quite happy with this response. Thanks Lisa, Charles. Thank you.

Andrew Tsai: You know...

Andrew Tsai: Once we got through our protocol amendment and

Andrew Tsai: and our

Andrew Tsai: Product issues, you know recall we had some manufacturing issues that we were able to resolve and

Scott Braunstein: So once we got through those issues, we were screening about 15 patients per month. And quite honestly, you know, all of those patients, the vast majority would be eligible for what we think is the right patient population to study in a future study. So I don't worry a tremendous amount about enrollment.

Andrew Tsai: We now have great stability and shelf life of the product.

Andrew Tsai: So once we got through those issues, we were screening about...

Scott Braunstein: The second half of the year tends to be stronger for us. A lot of the medical meetings are really back and weighted. Certainly AES and some other additional pediatric meetings which are really critical to the best of the day. There's really a positive of medical meetings in the first half of the year, so we're really looking forward to the second half of the year and the medical meetings and the interest that we see almost immediately following medical meetings for the toll meet. So that drives prescribing or does it take prescribers out of the office? What are the counter-vailage? Generally, we've seen very strong prescription trends following our medical meetings. Thank you.

Andrew Tsai: 15 patients per month.

Andrew Tsai: And quite honestly, you know, all of those patients, the vast majority, would be eligible for what we think is the right patient population to study.

Scott Braunstein: I think we know which sites are very powerful, and I think they're eager to be involved in another study. But I think, to be honest, we really have to think about the financial impact of that on the company and where we want to place our resources. But fortunately, we have multiple strategic partners that we started engaging for the data. The vast majority of those strategics are still in our data room, talking to us regularly, and really curious, I think, about the FDA outcome.

Andrew Tsai: in a future study.

Speaker Change: So, I don't worry a tremendous amount about the enrollment. I think we know which sites are very powerful. I think they're eager to be involved in another study. But I think, to be honest, we really have to think about the financial impact of that to the company and where we want to place our resources.

Scott Braunstein: We're still in conversations with BARDA. BARDA unequivocally wants this product available commercially so that in an unfortunate case, and let's hope there never is, a nerve gas attack within the United States, they would have access to it. They would have access to Ganaxalone for that.

Speaker Change: But fortunately, we have multiple strategics that we started engaging for the data. The vast majority of those strategics are still

Speaker Change: in our data room talking to us regularly.

Speaker Change: really curious, I think, about the FDA outcome. We're still in conversations with BARDA. BARDA unequivocally wants this product available commercially so that in the unfortunate case, and let's hope there never is,

Joe Hulihan: Our next question is from the line of Brian Abrams with RBC Capital Markets. Please just use your question. Hi, this is Joe on for Brian. Thank you for taking our question. On TNC, can you talk about some of the subgroup analysis you've done for the Phase 2 Open Label Study that gives you most confidence that Phase 3 study will read out positively. How consistent was the seizure reduction for those who stayed on the therapy until the end of the main and phase?

Scott Braunstein: And so we are really thinking hard about ways to finance another trial with the help of another party. And certainly, I think getting alignment with the agency, thinking about the size of the trial, which, you know, I think we're thinking right now roughly in the 150 plus or minus patient range, is really quite doable within a two-year window. But again, I think from a resource allocation standpoint, we put almost all our resources behind the oral program.

Speaker Change: a nerve gas attack within the United States, they would have access to Ganaxalone for that.

Speaker Change: And so we are really thinking hard about ways to finance another trial with the help of another party.

Speaker Change: and certainly I think getting alignment with the agency, thinking about the size of the trial, which I, you know, I think we're thinking right now roughly in the 150.

Joe Hulihan: And I guess for the ongoing Phase 3 study, can you tell us how many patients had their last visit and entered into the Open Label Extension so far? Thank you. Yeah, well, let me, let me start with the last question and I'll turn over to Joe to talk a little bit about what we saw in the face, too. But we are well north of 100 patients now close to 110 patients that are into the open label.

Speaker Change: plus or minus patient range.

Speaker Change: is really quite doable within a two-year window.

Speaker Change: But again, I think from a resource allocation standpoint, we put almost all our resources behind the ORO program.

Speaker Change: We really want to see a future for the IB program.

Scott Braunstein: We really want to see a future for the IV program, but we also have to recognize that it has to be a smart financial investment. So we'll see how the meeting goes with the FDA. I think we're very optimistic we can get to an alignment on some of these key elements. Then, we can really run a study in a reasonable amount of time, and we'll figure out the best way to finance that study with, you know, shareholder interest certainly in mind.

Speaker Change: But we also have to recognize that it has to be a smart financial investment.

Joe Hulihan: The last patient visit is in September. The first or second week in September, we should have the last patient visit in the study. So the vast majority of patients have now rolled into open label. And to your, you know, to the question, I think we continue to see consistency of those high percentages of patients rolling into open label were north of 90% of patients completing the study or who are rolling into open label and staying on open label.

Speaker Change: We'll see how the meeting goes with the FDA. I think we're very optimistic we can get to an alignment on some of these key elements. We then feel we can really run the study in a reasonable amount of time, and we'll figure out the best way to finance that study with shareholder interest certainly in mind.

Douglas Tsao: So that's kind of where we stand, and I think we'll be able to walk away from our interaction with the FDA with a relatively clear path forward. I think we think the solution is relatively simple. I think the agency has been a great thought partner, so we're looking forward to meeting with them and getting this drug to market. I think it's, you know, a critically important resource for physicians to have, but we recognize the hospital environment is one that we have to be able to show the value, and that's our plan.

Speaker Change: So that's kind of where we stand, and I think we'll be able to walk away from our interaction with the FDA with a relatively clear path forward. We think the solution is relatively simple. I think the agency has been a great thought partner, so we're looking forward to meeting with them.

Joe Hulihan: So we'll be the final numbers at the analyst day, but certainly from, you know, we haven't seen a bump in those discontinuations early on in the trial. We feel very confident that now north of 100 patients are really tolerating the drug extremely well. Very different than what we saw in phase two as a reminder, we had a 26% discontinuation rate in the phase two. And I think we're in a different place today much because of the work that Joe has done and the team has done to reconfigure the dosing paradigm.

Douglas Tsao: So that's how we're going to move forward, and we will be really excited to share those plans with you in the coming months. Thanks for the question. Appreciate it. Our next question is from the line of Douglas Tsao with H.C. Wainwright. Pleased to see you.

Speaker Change: and getting this drug to market, I think it's, you know, a critically important resource for physicians to have, but we recognize the hospital environment is one that we have to be able to show the value.

Speaker Change: And that's our plan, so that's how we're going to move forward and we will be really excited to share those plans with you in the coming months. Thanks for the question. Appreciate it.

Joe Hulihan: Joe, you want to talk about some of the highlights that we saw on phase two when our confidence goes into the phase two. Yeah. Yes, Scott. Yeah. As you mentioned, Scott mentioned, you know, there were 26% discontinuations for side effects. So that was six patients for side effects. It was four. So really, you know, despite the rapid titration in phase two, we had four patients discontinued due to adverse events. Now, the one thing about the current open label study that's ongoing patients from the phase two study could roll into the open label.

Speaker Change: Our next question is from the line of Douglas Sow with H.C. Wainwright. Pleased to see you. It's your question.

Scott Braunstein: Hi, good morning, thanks for taking the questions. Just... in terms of the... Analysis of the IV program, Scott. Obviously, we've seen, you know, there were challenges in terms of position behavior. I'm just curious, have you had a chance to look at the results? I cite my individual site with their particular sites that really sort of deviated from your expectations and what your sort of expectation and understanding of treatment patterns would be, especially in terms of advancing patients to IV anesthesia, or was it really just a broader phenomenon that you saw in the study?

Douglas Sow: Hi, good morning, thanks for taking the questions. Just in terms of the...

Douglas Sow: analysis of the IV program, Scott. Obviously, we've seen, you know, there were challenges in terms of physician behavior. I'm just curious, have you had a chance to look at results?

Speaker Change: Bye Sites!

Speaker Change: By individual site, were there particular sites that really sort of deviated from your expectations and what your sort of expectation and understanding of treatment patterns would be, especially in terms of advancing patients to IV anesthesia? Or was it really just a broader phenomena?

Joe Hulihan: And so we have a combined open label extension for the phase three in the phase two. And we still have patients. The latest number is not my tongue. We have patients from phase two who have continued to this point in the open label extension. And so I think the, you know, the titration really makes a big difference. I mean, I think you asked about some populations, you know, and we looked at patients with focal seizure types.

Scott Braunstein: Yeah, thanks, Doug. We did an analysis of how our larger sites did. And certainly, there was a stronger signal for the drug in our bigger sites, in our high enrolling sites. And I think, quite honestly, that was driven as much by the factor that those physicians advanced care more commonly. We're not afraid or concerned about moving to IV anesthesia.

Speaker Change: Thank you for joining us.

Speaker Change: Thanks, Doug. We did look at an analysis of how our larger sites did, and certainly there was a stronger signal.

Speaker Change: for the drug in our bigger sites, in our high-enrolling sites. And I think, quite honestly, that was driven as much by the factor that...

Joe Hulihan: They had a better response to 25% reduction compared to the overall population. And then we looked at patients on can have a dial and ever all of us. And they also had a good response, particularly ever all of us. 20% greater response than the population as a whole. So again, encouraging signals. Did I answer your question? Yes. Thank you. Thank you, Scott. Thank you, Jim. Yeah. Let me add one, one or two comments to Joe's come Joe, Joe hit the mark in terms of what we saw in the phase two.

Speaker Change: Those physicians advance care more commonly. We're not afraid or concerned about moving to IV anesthesia. So as a result...

Scott Braunstein: So as a result, there were lower placebo rates, and certainly, the Delta was larger than the overall study. I think to be quite fair, that matters a bit, but not necessarily. I think we would not feel comfortable enrolling another study where advancement to IV anesthesia is the end point. I think what we learned is that, regardless of what physicians told us, which was that they would move to IV anesthesia 80% of the time after failing two drugs, patients who received an excellent in the study typically received three drugs, typically were in and out of status for about a day and a half, and even in that scenario, or in this case, the control group, physicians were only advancing care 50% of the time.

Speaker Change: There were lower placebo rates And and certainly the Delta was was larger than the overall study. I think to be quite fair

Speaker Change: That matters a bit, but not necessarily, I think. I think we would not feel comfortable

Speaker Change: enrolling in another study where advancement to IV anesthesia is the end point. I think what we learned is that regardless of what physicians told us, which was they would move to IV anesthesia 80% of the time after failing two drugs.

Joe Hulihan: And as a reminder, what we said publicly is about about 70% of the seizure types close to 75% that we're seeing in the blinded phase three are focal in nature. So that's exactly what we had hoped to see. So to Joe's point, you know, strong signal in phase two, even with the tolerability issues, which is why we expect that number to be more robust in the phase three. And then the phase three more than half the patients are coming into the study on inventory inhibitors.

Speaker Change: Patients who received Gnaxolone in the study typically received three drugs.

Speaker Change: Typically, we're in and out of status for about a day and a half.

Speaker Change: And, you know, and even in that scenario, or in this case, the control group, you know, physicians were only advancing care 50% of the time. So, and that may have been.

Joe Hulihan: And again, that was our strongest 50% responder number from the phase two. And certainly so robust responder number with the kind of dial group which will make up about 25% of the population. So we have all the right sub types in the phase three. We have the right seizure types. And certainly that's where this, that's where the F2 signals were strongest, even in the setting of some real power ability issues in the phase two. So we have a lot of confidence going into the phase three. Thanks for the question.

Scott Braunstein: So, and that may have been changing EEG patterns, it may have been changing physicians, it may have been not necessarily following the behaviors of the EEG, but I think we've just learned that this is too subjective an end point, regardless of what physicians do.

Speaker Change: Changing EEG patterns, it may have been changing physicians, it may have been not necessarily following behaviors of the EEG, but I think we've just learned that this is too subjective an end point, regardless of what physician behavior.

Joe Hulihan: Physicians have told us time and time again and remember we did a very big survey We specifically went to all our sites. We asked for their practice patterns And and I think yes, we saw a much more consistent treatment pattern in our bigger enrolling sites And I would say a variation in those in those patterns and sites that enrolled one or two patients I think by nature when you have a study and you have sites that are enrolling one or two patients You do run the risk of site bias that is their site behavior influencing the outcome of the study That certainly played a factor here But I don't think the biggest factor Joe is anything you want to add and then you know, I don't much time data, Yeah, yeah, no, I don't think there were particular sites, as you mentioned, Scott, it was, you know... Kind of some patient at each site or not at every site, but no, and I think we're doing a lot to minimize the variability if we do another study. I think we don't understand a lot.

Speaker Change: Physicians have told us time and time again, and remember we did a very big survey, we specifically went to all our sites, we asked for their practice patterns, and I think yes, we saw a much more consistent treatment pattern in our bigger enrolling sites.

Joe Hulihan: Thank you for taking my question. Maybe a little bit of a follow-on to your explanation from the last question, but the phase three looks like the baseline seizure frequency is a little bit higher than what you saw in the phase two and the number prior therapies failed is also a little bit higher in the phase three blinded data than versus the phase two. I guess the phase two is a little bit higher.

Speaker Change: And I would say a variation in those in those patterns and sites that enrolled one or two patients I think by nature when you have a study and you have sites that are enrolling one or two patients You do run the risk of site bias that is

Joe Hulihan: their site behavior influencing the outcome of the study That certainly played a factor here, but I don't think the biggest factor Joe is anything you want to add I mean you know I don't much time data

Joe Hulihan: Does that indicate that you think it's potentially going to be a little bit easier to show a benefit of an excellent in the phase three or are these more challenging patients to treat, kind of based on your experience in CDD and the phase two, what sort of your expectation there. Thank you. Yes, thanks, Joe. Let me take it off and then I'll turn over to Joe. I will tell you my experience, at least from talking to some of our key investigators.

Joe Hulihan: Yeah, yeah, no, I don't think there were particular sites as you mentioned Scott it was You know

Scott Braunstein: We've learned a lot from the race study, obviously, in terms of what endpoints to look at and patient selection, and Scott mentioned stratification. We want to make sure that we get a representative population, a population that's likely to respond in another study. So, I think that we've learned a lot now from raising money, and that'll pay off when it comes time to do another study. And I think, Doug, the big thing that we want to really discuss with the FDA is, you know, what is the right endpoint?

Speaker Change: and many more. Thank you. Thank you.

Speaker Change: Some patients at each site or not at every site, but

Speaker Change: No, and I think we're doing a lot to minimize the variability if we do another study. I think we understand a lot. We've learned a lot

Joe Hulihan: What's really critical in the study like this is that we have patients who for lack of a better are seizing through their medications at a steady state. There isn't an acute acceleration or worsening of their symptoms which would tend to set yourself up for failure just in the disease is progressing whether or not any therapy can kind of acutely address that. So I think you know I give Joe all the credit in the world that he really stuck to our guns and kept our enrollment criteria at more than eight seizures per month.

Speaker Change: from the RAYS study, obviously, in terms of what endpoints to look at, and patient selection, and Scott mentioned stratification. We want to make sure that we get a representative population, a population that's likely to respond in another study.

Scott Braunstein: I think that we've learned an incredible amount from Ray's, and that'll pay off when it comes time to do another study.

Scott Braunstein: And I think, Doug, the big thing that we want to really discuss with the FDA is...

Joe Hulihan: And I think that's a critical factor for minimizing placebo rate. You can imagine that if a patient was allowed to enroll with only four seizures per month and there was natural variability the placebo response could be 25% if they went from four to three. So Joe was really instrumental in driving the team and keeping us at eight seizures per month which is higher than what you see in multiple seizure studies. But again, our view is how do we minimize placebo rate to maximize success.

Scott Braunstein: We certainly saw very strong signals, as Joe has talked about, with EEGs and the differences between EEGs of patients with Gonaxalone and who receive placebos. Certainly every SAB member, every expert we've shared that data with, feels unequivocally powerful that we should be discussing this and pushing for approval with the FDA. It's very nice to have their support.

Scott Braunstein: You know, what is the right endpoint? We certainly saw very strong signals. Joe is...

Joe Hulihan: powerful that we should be discussing this and pushing for approval with the FDA. It's very nice to have their support. I recognize the reality of what we agreed upon with the FDA, but I think we have other very clear measures of

Scott Braunstein: I recognize the reality of what we agreed upon with the FDA, but I think we have other very clear measures of durability in this study. We'll share those at the NCS meeting, but you can imagine thinking about how many drugs and escalation of care being a logical one, right? So I think we really feel there is durability in this data set that is clearly differentiated from placebo. Unfortunately, in alignment with the agency, the agency never specifically demanded durability defined by avoidance of IV anesthesia.

Joe Hulihan: So I think you know controlling for placebo is going to be critical for us. You know look my experience from talking to our investigators and that we're getting a group of patients a little bit older many of who have gone through surgery many have gone through multiple medications. I think it's a very classic phenotype in this population. Certainly that's what Lisa's market research is showing. And I again to this discussion I think just the high seizure burden really will minimize placebo effect.

Joe Hulihan: durability in the study. We'll share those at the NCS meeting. But you can imagine thinking about how many drugs and escalation of care being a logical one, right? So I think we really feel there is

Joe Hulihan: in this data set that is clearly differentiated from placebo. Unfortunately, the alignment with the agency...the agency never...

Scott Braunstein: And I think we need to have a discussion with them about what other durability measures they would agree to. And I think we have several that we think are objective and are really the key piece of this puzzle, I think, more than site variability. And I think we won't really even talk about that per se at our FDA meeting. Okay, if I can ask one quick question on TSC, in terms of the long-term extension, are you really seeing any discontinuations once patients are able to sort of tolerate the drug for some amount of time, and what is the continuation rate in the long-term extension so far? Well, we are very fortunate that one of our investigators is going to be presenting the long-term extension data that's been submitted for AES. But it hasn't been accepted as yet, right?

Joe Hulihan: So yeah when you ask this I think we feel good about the efficacy. We feel very good about placebo rates not only because of baseline seizure type but where we went or countries we we we we really enrolled in our mind folks that if you go back to the GW study the placebo rate was about 25%. Poland was the second largest in roller in that study. We had a very unfortunate experience in Poland with TDK L5 that was a very high placebo rate.

Joe Hulihan: specifically demanded.

Joe Hulihan: defined by avoidance of IV anesthesia. And I think we need to have a discussion with them of what other durability measures they would agree to. And I think we have several that we think are objective and is really the key piece of this puzzle. I think more than

Joe Hulihan: site variability, and I think we won't really even talk about that per se at our FDA meeting.

Speaker Change: Okay, if I can ask you one quick question on TSC in terms of the long-term extension. Are you really seeing any discontinuations once patients are able to sort of tolerate the drug for some amount of time and the continuation rate in the long-term extension so far?

Joe Hulihan: Certainly the GW study suggested a high placebo rate. So we chose to stay out of Eastern European countries to minimize the risk of high placebo. So between that and the eight years per month we feel very good about the placebo rate coming in somewhere in the high single digits you know no more than low double digits which gives us the best chance to win. Joe you want to comment on additionally on seizure types or anything else that we've seen in the blood data in the three in terms of seizures that give you comfort.

Speaker Change: Well, so we are very fortunate that one of our investigators is going to be presenting the long-term extension data that submitted it for AES. It hasn't been

Scott Braunstein: It's a little early, but we expect a presentation. We'll share that top-line data with you all at our analyst day in September. We are really encouraged that the durability that we see across disease states is really quite robust, and we really believe the pan-extrasynaptic activity of finaxolone is something very unique.

Speaker Change: accepted as of yet, right? It's a little early, but we expect

Speaker Change: presentation. We'll share that top-line data with you all at our Analyst Day in September. We are really encouraged that the durability that we see across disease states

Joe Hulihan: Yeah, well, a lot of things. One, I mean, you mentioned seizure types. The vast majority of the patients coming into the phase three have full onset seizures, where we expect to see good efficacy, and less variability in the response in the patients with focal onset seizures, then we saw, say, with atonic seizures. Still, still a good effect size, and I'm talking about CDD. Still a good effect size, but there was the variability is less than the patients with focal seizures, and to just tag on to what Scott said about patients coming in, it's really eliminating those patients with very few seizures.

Speaker Change: is really quite robust, and we really believe the pan-extrasynaptic activity of the maxillofacial

Scott Braunstein: And time and time again, when we do our market research, it's not only about initial response rates; it's about durability, and it's about safety, as Lisa talked about, and ability to play nicely in the sandbox with other drugs. So I think when we go into this TSC launch, we will have a lot of talking points, a lot of measures of durability, and certainly you see that with other drugs, but I think in particular we've seen it in some disease states that you just wouldn't expect to see it in, right, comparing a little bit of apples and oranges, that we've really tackled what I think are two of the most refractory seizu So we think it's going to be an important message, and we're looking forward to sharing all that data with you guys at analyst day. Thanks Doug. Thank you.

Lisa: It's something very unique and time and time again, when we do our market research, it's not only about initial response rates, it's about durability, and it's about safety, as Lisa talked about, and ability to play nicely in the sandbox with other drugs.

Speaker Change #100: I think when we go into this TSC launch, we will have a lot of talking points.

Joe Hulihan: It's not really linear in terms of seizure frequency, the bigger the number of baseline, the more response you get, but it's really just those patients with very low seizure numbers, that there's that kind of mathematical problem with not being able to get much better. But once you get beyond eight or ten seizures a month, the response doesn't differ that much depending on baseline seizure rate, higher or better, but just really eliminating the very low patients.

Speaker Change #101: A lot of measures of

Speaker Change #101: durability

Speaker Change #102: And certainly you see that with other drugs, but I think in particular we've seen it in some disease states that you just wouldn't expect to see it in, right? Comparing a little bit of apples and oranges.

Speaker Change #101: that we, you know, we really tackled what I think are two of the most refractory...

Speaker Change #101: seizure disorders out there. So, we think it's going to be an important message, and we're looking forward to sharing all that data with you guys at the Analyst Day. Thanks, Doug.

Joe Hulihan: The other thing I'll mention too, it gives it, well, a couple of things. One is we want to make sure the patients had disease stability coming in so that they didn't have, you know, progression to the mean when they came into the study. So we want them to have seizures in each of the two months at a certain frequency, and no more than one week seizure-free during those months to make sure the disease is stable when they come into the baseline. And the other thing too is the somalance. The lower, you know, the titration rate and the lower discontinuation due to somalance, we saw this odd relationship between somalance, higher somalance and lower efficacy.

Marc Goodman: Our next question is from Marc Goodman with Lyrinc. Please proceed with your question. Can you talk about any off-label use you've seen with Ganaxalone?

Speaker Change #103: Thank you.

Speaker Change #104: Our next question is from the line of Mark Goodman with Lyrinc. Please proceed with your question.

Scott Braunstein: And secondly, you mentioned eligibility for milestones. Can you elaborate a little bit on that for this year? Thanks. Marc, I'm sorry, I missed the first question I was going to ask. I'm happy to help all of you. Yeah, I'm sorry.

Mark Goodman: Can you talk about any off-label use you've seen with Ganaxalone and secondly you mentioned eligibility for milestones. Can you elaborate a little bit for this year? Thanks.

Speaker Change #106: Mark, I'm sorry, I missed the first question on Connexion.

Joe Hulihan: And so by reducing the somalance, that also gives me optimism about the efficacy we're going to see in phase three.

Steve Pfanstiel: You know, I'm having a little interference. Steve, do you want to take the test? Do you want to take those questions? I'll off-label you.

Speaker Change #107: I'm happy to answer any more of your questions.

Unknown Executive: Our next question. Let's go to the next question.

Speaker Change #108: Yeah, I'm sorry, you know, I'm having a little interference. Steve, do you want to take those questions?

Steve Pfanstiel: Yeah, sure. I can jump in here, I think. Marc, maybe I'll answer the second one first.

Mark Goodman: Off-label use.

Unknown Executive: Thank you.

Steve Pfanstiel: Yeah, sure. I can jump in here, I think. Mark, maybe I'll answer the second one first. You mentioned milestones.

Steve Pfanstiel: You mentioned milestones. So the nearest-term milestone that we've talked about is a €10 million payment from Orion that would be due upon commercialization of CDD. So that happens when they launch in two of the major markets or no later than 18 months after their first market. There's a similar type of payment associated with TSE commercialization. And then we also have commercialization payments with China through our Tenacia partnership. Those are a little further out and not quite to the same magnitude, but a nice amount as well.

Speaker Change #109: So the nearest term milestone that we've talked about is a 10 million euro payment from Orion that would be due upon Commercialization of CDD so that happens when they launch in two of the major markets or no later than 18 months after their first market There's a similar type of payment associated with TSE commercialization

June Lee: Our next question is from the line of June Lee with truest. Please just see with your question.

Joe Hulihan: Good morning. This is awesome one for June. Thanks for taking the questions. Just curious what the timing on the type team meeting with the FDA is and what scenarios you think could come out of the meeting. And then I know this is mentioned on the call, but she'll want to be sure what the discontinuation rate due to somalance was in the phase three trust TSC trial and what that number was in the phase two trial.

Speaker Change #110: And then we also have commercialization payments with China with our Tenacia partnership. Those are a little further out and not quite to the same magnitude, but a nice amount as well. In terms of off-label, I know we've got Lisa on. Lisa, do you want to touch on kind of off-label use with Connexion?

Lisa Lejuwaan: In terms of off-label, I know we've got Lisa on. Lisa, do you want to touch on any kind of off-label use with Connexion? Absolutely. Thank you, Steve. We've got about 15% of our patients on therapy that do not have a CBD diagnosis, and they're affected by other DEEs. I'll just add that most payers are covering the drug for these patients, acknowledging a significant unmet need here. I couldn't hear you, but the thing I'll add is I think, you know, we've heard a lot of back and forth about the GW launch in TSE.

Joe Hulihan: Thank you. Thanks, just to start backwards, we've only reported the total discontinuation rate of 26% in the phase two vast majority of those were related to tolerability issues. And certainly the other piece of that puzzle is more than 70% of the patients in the phase two required dosing adjustments. So they were patient for really struggling with the dosing and it was really something we didn't become aware of until very effectively until the trial was completed.

Lisa: Absolutely, thank you Steve. We've got about 15% of our patients on therapy that do not have a CBD diagnosis and they're affected by other DEEs. I'll just add that most payers are covering the drug for these patients, acknowledging a significant unmet need here.

Lisa Lejuwaan: And I think, you know, we have several GW team members as part of the Marinus team between their expanded access program and the overlap with LGS. I think they went into their TSE launch with a substantial number of patients already on the drug. I think we can confidently say there are close to no patients currently that I'm going to ask you today that are being reimbursed with the diagnosis of TSE, or certainly that we don't, we do not know of any in terms of those developments in cephalopathy. So we really feel like the entire TSE market is open for us from day one, and it's certainly not a big part of our business today. Thanks.

Speaker Change #111: I couldn't hear you, but the thing I'll add is I think we've heard a lot of back and forth about the GW launch and TSC.

Speaker Change #112: And I think, you know, we have several GWT members as part of the Mariners team. And between their expanded access program and the overlap with LGS, I think they went into their TSC launch.

Joe Hulihan: One of the physicians who will be at our analyst day, I'm quite excited about because she was in our phase two and really struggled with the patients on the phase two dosing regimen. I took a lot of personal convincing from our medical team and myself to get this position to participate in the phase three and I think I'll share with you at the analyst day. What a good response that he's had at least in a blinded fashion from the phase three thus far.

Speaker Change #112: with a substantial number of patients already on drugs.

Speaker Change #113: I think we can confidently say there are close to no patients currently, I'm gonna ask someone today, that are being reimbursed with the diagnosis of TSC, or certainly that we don't, we do not know of any.

Speaker Change #113: in terms of those developmental encephalopathy. So, we really feel like the entire TSC market is open for us from day one and there's certainly not a big part of our business today.

Joe Hulihan: To you and I really apologize, I forgot your first question. Oh, I was just curious about the timing on the type team meeting with the FDA, and I was curious if you could come out of that. Thanks. Absolutely, yeah. So, Jo, Alex, the regulatory team has been working incredibly hard, putting to, you know, going through the IB data set and really understanding that data. There's no question, you know, to Jo's comment, we are quite convinced that the drug was highly efficacious and had a durable effect.

Speaker Change #113: Thanks.

Jason Butler: The next question is from the line of Jason Butler with JMP. Please proceed with your question. Hey, it's Roy on behalf of Jason.

Speaker Change #114: Thank you.

Speaker Change #114: The next question is from the line of Jason Butler with JMP. Please receive your question.

Scott Braunstein: Just a quick one, and maybe you already answered this, but for TAMI, you should mention the key initiatives over a thousand patients ID'd and patients who might have CDD but not a diagnosis. I guess what proportion of the patients today do have a diagnosis? Let me kick it off, then I'll flip it over to Lisa, Jason.

Roy: Hey, it's Roy on for Jason. Just a quick one, and maybe you just answered this, but for the TAMI, you should mention the key initiatives, over a thousand patients ID'd, and patients who might have a CDD, but not a diagnosis. I guess what proportion of the patients today do have a diagnosis, I guess?

Scott Braunstein: Remember, you know, the two major advocacy groups, IFCR and the Lulu Foundation in the U.S., fought very hard for a CDKL5 code that went into effect a little bit more than a year before we launched, so roughly three and a half years ago. To kind of put that in perspective, Right, and we expect about 100 newborns a year. And in the last three, three and a half years, they've gone from zero to 200 to 400 to now roughly 1,000 unique patient codes for CDKL5.

Speaker Change #116: Let me kick it off, then I'll flip it over to Lisa, Jason. Remember, you know, the two major advocacy groups, IFCR,

Joe Hulihan: I think unfortunately, the end point that we chose had a great deal of variability and did not really reflect the durability of the drug. It really reflected what we believed. It's more physician practice. And that's unfortunate. That's really counterintuitive to what we were told going into the study time and time again by the biomedical community and the experts that we talked to. So our real goal for this, the meeting with the FDA is really the real line on end points that we think are much more objective that we can define the durability of the product.

Speaker Change #117: and Lulu Foundation in the U.S. fought very hard for a CDKL5 code that went into effect a little bit more than a year before we launched, so roughly three and a half years ago. To kind of put that in perspective...

Speaker Change #118: Right, and we expect about a hundred newborns a year, and in the last three, three and a half years, they've gone from zero to 200 to 400 to now roughly a thousand unique patient codes for CDKL5.

Scott Braunstein: So what we expected, as we've always talked about, is roughly 2,000 patients below the age of 21, and certainly another 3,000 adult patients, but many of those adult patients won't be genetically tested. Certainly, some are being tested, and some are being treated with tatami. So I think we have a good line of sight on roughly 2,000 patients, a lot less line of sight on the other 3,000. So I think we estimate probably more than 2,500 patients are out there with a diagnosis or with symptoms that haven't yet been diagnosed. And we're clearly seeing this exponential growth in the use of the ICD-10 code. And we know there are not more than 100 newborns a year, right?

Joe Hulihan: That will be the critical piece in really thinking about a study design. And certainly, we're going to share our data set with the FDA and have what we hope is a very robust discussion. Our hope and goal is to get the filing in by the end of the month. And a typical type C meeting is the 90 day review. So our hope is to have that meeting in the early part of the fourth quarter.

Speaker Change #118: So

Speaker Change #118: What we expected, as we've always talked about, is roughly 2,000 patients below the age of 21 and certainly another 3,000 adult patients, but many of those adult patients are

Speaker Change #118: won't be genetically tested. Certainly some are being tested and some are being treated with tatami. So I think we have good line of sight of roughly 2,000 patients, a lot less line of sight of the other 3,000. So I think we estimate.

Joe Hulihan: And I think, you know, we really understand the data. And it said Joe's done an amazing job looking at the G data set looking at practice patterns. And unfortunately, you know, I think we're learning an ICU study where physicians believe after 12 hours new physicians come in. It's just we've just seen a lot of practice patterns, which are disheartening to me as a physician, but certainly it's helping us rethink how to best show the efficacy of this drug.

Speaker Change #118: probably more than 2,500 patients are out there, you know, with a diagnosis or with the symptoms that haven't yet been diagnosed. And we're clearly seeing this exponential growth in the use of the ICD-10 code.

Scott Braunstein: So it's just physician recognition of the code, advocacy groups pushing for the code, reimbursement around the code. All of those pieces of the puzzle are leading physicians to use the code. But we also know, even as of a year ago, we had some centers of excellence that were not using the code appropriately.

Speaker Change #119: And we know there's not more than 100 new boards a year, right? So it's just physician recognition of the code.

Speaker Change #119: The advocacy groups pushing for the code reimbursement around the code

Joe Hulihan: I mean, there's nothing in this study that gave us pause for the efficacy of this drug. I think the other thing that, you know, we'll really align yet with the FDA is how we should think about enrolling this population. We saw some variability in terms of differences and patient outcomes. And we want to align on on a stratification strategy with the FDA to make sure that there are no significant imbalances. And we can really show the value crop of the drug.

Speaker Change #119: all of those pieces of the puzzle are leading positions to use the code. But we also know, even as of a year ago, we had some centers of excellence that were not using the code appropriately. So, it's a little bit of the education around code.

Scott Braunstein: It's a little bit of education around the code, but I think we feel pretty good about the fact that there are already more than 1,000 patients that have a code so we can find these patients. We don't really feel like the 200 or so patients that are currently on therapy, close to 300 patients who have tried therapy or have been prescribed are the only patients out there. I think we feel very good about finding additional patients to keep growing the business.

Speaker Change #120: But I think we feel pretty good the fact that there is already more than 1,000 patients that have a code that we can find these patients. We don't really feel like the 200 or so patients that are currently on therapy, you know, close to 300 patients who have...

Scott Braunstein: I'll finally, I'll just, you know, last note is we'll be presenting the vast majority of this data at a medical meeting in October, the NCS meeting. And it will be a platform presentation. So folks will really get to see all of all of what we've seen in terms of the efficacy and the tolerability of the drug. And certainly we're going to share all of that with the FDA as well. Thanks. Thanks for the question.

Speaker Change #120: tried therapy or have been prescribed are the only patients out there. I think we feel very good about

Scott Braunstein: And certainly, I think we're really focused on that. And Lisa, you can talk about that more. And I think we're gonna have to make this the last question operator. We've gone over about 10 minutes. Lisa, anything else you wanna add? I think you've covered it nicely.

Lisa: finding additional patients to keep growing the business. And certainly, I think, you know, we're really focused on that. And Lisa, you can talk about that more. And I think we're going to have to make this the last question, operator. We've gone over about 10 minutes. Lisa, anything else you want to add?

Lisa Lejuwaan: I'll just add that, you know, one thing that we've done is shift our strategy towards a more data-driven approach because we have so many more HCPs utilizing the code over the past four years. The code has only been available for four years, and we've seen an increase in that data from 200 to 1,000 patients over time identified. There's also been an increase in general genetic testing, you know, with the support of the American Epilepsy Society, who really are putting it out there that every physician should genetically test patients who are seizing and have an unidentified underlying etiology for their disease.

Lisa: I think you've covered it nicely. I'll just add that, you know, one thing that we've done is shift our strategy towards the more data-driven approach because we have so many more

Andrew Sight: Our next question is from the line of Andrew Sight with Jeffries. Please just see with your question. Hey, thanks. Good morning. Thanks for taking my question. And so on top of the RSC, thanks for sharing all those tidbits.

Lisa: HCP is utilizing the code over the past four years. The code has only been available for four years, and we've seen an increase in that data from 200 to 1,000 patients.

Scott Braunstein: If you had to run another study after the FDA meeting, how would you design it to not only succeed, but also have it done, say within one or two years? Is there anything you can think of to ensure? Thanks. Well, I think Andrew, first and foremost, thanks for the question. I think we, you know, we're going to be very, very thoughtful about this trial design. I think, you know, once we got through our protocol amendments and, um, and our product issues, you know, we're called, we had some manufacturing issues that we were able to resolve.

Speaker Change #121: over time identified. There's also been an increase in general in genetic testing you know with the support from the American Epilepsy Society who really are putting it out there that every physician should genetically test

Scott Braunstein: And we now have great stability and shelf life of the product. So once we got through those issues, we were screening about 15 patients per month. And quite honestly, you know, all of those patients of the vast majority would be eligible for what we think is the right patient population to study in a future study. So I don't worry a tremendous amount about the enrollment. I think we know which sites are very powerful. I think they're eager to be involved in another study.

Speaker Change #121: patients who are seizing and have an unidentified underlying etiology for their disease. So that combination has really driven up the CDKL5 diagnosis in general, and we are very confident in the patients that are out there left for us to still introduce tatami to.

Lisa Lejuwaan: So that combination has really driven up the CDKL5 diagnosis in general, and we are very confident in the patients that are out there, less for us to still introduce tatami to. Thanks, Lisa. Operator, I think we're going to take one more call. We have Charles Duncan on the line. Yes, that's correct. Please go ahead, Mr.

Speaker Change #122: Thanks, Liz. Operator, I think we're going to take one more call. We have Charles Duncan on the line.

Charles Duncan: Yes, thanks for taking the follow-up, Scott. I'm going to make the simplifying assumption that TrustTSC works out well and that SNDA is filed and approved. I guess the question that I have is relative to manufacturing capacity at the end of 2025. I assume that you'll be able to get there. And yeah, so that's the key question that I had to follow up with you on.

Speaker Change #123: Yes, that's correct. Please go ahead, Mr. Duncan.

Charles Duncan: Thanks for taking the follow-up, Scott. I'm going to make the simplifying assumption that TrustTSC works out well and that SNDA is filed and approved.

Charles Duncan: I guess the question that I have is relative to manufacturing capacity at the end of 25. I assume that you'll be able to get there and yeah, so that's the key question that I had to follow up with you on.

Scott Braunstein: But I think to be honest, we really have to think about the financial impact of that to the company and where we want to want to place our resources. But fortunately, we have multiple strategic set. We started engaging for the data, the vast majority of those strategics are still in our data room talking to us regularly, really curious. I think about the FDA outcome. We're still in conversations with BARDA. BARDA unequivocally wants this product available commercially so that in the unfortunate case, and let's hope there never is a nerve gas attack within the United States.

Scott Braunstein: I think we feel very good about our current manufacturing capabilities and our partner, who will effectively dedicate much of their resources to helping us with Ganaxalone. We're very fortunate the API has a five-year shelf life. We've only been growing the shelf life of our Brandon's Ptolemy.

Scott Braunstein: Oh sure, Charles. I think we feel very good about our current manufacturing capabilities and our partner who

Speaker Change #124: effectively will dedicate much of their resources to helping us with Ganaxalone. We're very fortunate the API has a five-year shelf life. We've been only growing the shelf life of our branded Ditalme.

Speaker Change #124: We're hoping to expand that shelf life as well, so we really have the ability to...

Scott Braunstein: We're hoping to expand that shelf life as well, so we really have the ability to continue to manufacture the Ptolemy. And once we kick off these global launches to really start preparing for the TSC launch, but certainly, by our internal expectations, we're going to need additional supply certainly by 27. And by our internal expectations, additional supply in 29. I think we feel very good about the opportunity for TSC in the U.S., and we really believe that a market that's at least five times and potentially as large as 10 times, the CDD market, is very realistic. And Lisa will share some of those numbers with everyone during Analyst Day.

Speaker Change #124: continue to manufacture the Ptolemy and once we kick off these global launches to really start preparing for the TST launch.

Scott Braunstein: They would have access to an excellent for that. And so we are really thinking hard about ways to finance another trial with the help of another party. And certainly I think getting alignment with the agency thinking about the size of the trial, which I think we're thinking right now roughly in the 150 plus or minus patient range is really quite doable within a two year window.

Speaker Change #124: but certainly by our internal expectations.

Speaker Change #124: We're going to need additional supply, certainly by 2027.

Speaker Change #124: and by our internal expectations, additional supply in 2029.

Speaker Change #124: I think we feel very good about the opportunity in TSC in the U.S.

Scott Braunstein: But again, I think from a resource allocation standpoint, we're going to we put almost all our resources behind the oral program. We really want to see a future for the IB program, but we also have to recognize that it has to be a smart financial investment. And so we'll see how the meeting goes with the FDA. I think we're very optimistic. We can get to an alignment on some of these key elements.

Speaker Change #124: really believe that a market that's at least five times and potentially as large as ten times the CDD market is very realistic, and Lisa will share some of those numbers with everyone.

Scott Braunstein: And I think equally important, we're expecting strong volumes across Europe, very strong volumes in China, and expanding volumes throughout the world. And so we're getting prepared and doing it in a very stepwise and staged fashion. And certainly, we think it's critical to have a second unique manufacturing site to minimize risk.

Lisa: during the Analysts' Day. And I think equally important, we're expecting strong volumes across Europe, very strong volumes in China.

Lisa: volumes throughout the world.

Scott Braunstein: We then feel we can really run the study in a reasonable amount of time and we'll figure out the best way to finance that study with shareholder interest certainly in mind. So that's kind of where we stand and I think we'll be able to walk away with this from our interaction with the FDA with a relatively clear path forward. I think that we think the solution is relatively simple. I think the agency has been a great thought partner.

Lisa: stepwise in stage fashion, and certainly we think it's critical to have a second unique manufacturing site.

Scott Braunstein: And in that process, we've made the investment for the equipment. The room build out will start shortly. And we want to make sure that in 2027, we have more than enough product. So those plans are in place, and we feel really good about the way we're preparing for that. And fortunate, look, it was a very hard decision for us to let some people go in June and restructure the organization. But as we've said all along, we've always had high confidence in the TSC launch. We think it can drive profitability, and we have not shortcut or shortchanged the oral franchise at all.

Speaker Change #125: to minimize risk and you know that process we've made the investment for the equipment the room build out will start shortly and we want to make sure that in 2027 we have more than enough product.

Speaker Change #125: So those plans are in place, and we feel really good about the way we're preparing for that.

Scott Braunstein: So we're looking forward to meeting them and getting this room to market. I think it's, you know, a critically important resource for physicians to have. But we recognize the hospital environment is one that we have to be able to show the value and that's our plan.

Speaker Change #125: it was a very hard decision for us to let some people go in June and restructure the organization. But as we said all along,

Speaker Change #125: We've always had high confidence in the TSC launch, we think it can drive profitability, and we have not short-cut or short-changed the Oral franchise at all. And obviously, you know, Christine's been a great...

Scott Braunstein: So that's how we're going to move forward and we will be really excited to share those plans with you in the coming months.

Scott Braunstein: Thanks for the question. Appreciate it.

Scott Braunstein: And obviously, Christine's been great. She is a great chief commercial officer. You can hear from this call that Lisa is incredibly qualified as well. We've got great leadership in place. We're thinking about manufacturing. We're thinking about the global regulatory strategy.

Unknown Executive: Thank you.

Douglas Tsao: Our next question is from the line of Douglas Tsao with H.C.

Douglas Tsao: Wayne, right?

Scott Braunstein: Please just see a third question. Hi, good morning, thanks for taking the questions. Just in terms of the analysis of the IV program, Scott, obviously we've seen, you know, there were challenges in terms of its addition behavior. I'm just curious if you have a chance to look at results by sites, by individual sites, with their particular sites that really sort of deviated from your expectations and what your sort of expectation and understanding of treatment patterns would be, especially in terms of advancing patients to IV anesthesia, or was it really just a broader phenomena that you saw in the study?

Christine: She is a great chief commercial officer.

Christine: You can hear from this call that Lisa is incredibly qualified as well. We've got great leadership in place. We're thinking about the manufacturing.

Scott Braunstein: We are going to be quite ready to execute post this data. So thanks so much for the call, Charles. I really appreciate it. Thanks, everyone. I really appreciate you joining the call. We're about 15 minutes over, but it was great to share some of our thoughts, and we look forward to seeing you at the analyst event in September. And thanks again for dialing in. This will conclude today's conference. May I disconnect your lives at this time? Thank you for your participation and have a wonderful day.

Christine: We're thinking about the global regulatory strategy. We are going to be quite ready to execute post this data. So thanks so much for the call, Charles. Really appreciate it.

Speaker Change #127: Thanks, everyone. I really appreciate you joining the call. We're about 15 minutes over, but great sharing some of our thoughts, and we look forward to seeing you at the analyst event in September. And thanks again for dialing in.

Speaker Change #128: This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation and have a wonderful day.

Scott Braunstein: Yeah, thanks, Doug. We did look at an analysis of how our larger sites did, and certainly there was a stronger signal for the drug in our bigger sites in our high enrolling sites, and I think quite honestly that was driven as much by the factor that those conditions advance care more commonly. We're not afraid or concerned about moving to IV anesthesia, so as a result, there were lower placebo rates and certainly the Delta was larger than the overall study. I think to be quite fair, that matters a bit, but not necessarily.

Scott Braunstein: I think we would not feel comfortable enrolling another study where our advancement to IV anesthesia is the end point. I think what we learned is that regardless of what physicians told us, which was they would move to IV anesthesia 80% of the time after failing two drugs. Patients who received an excellent in the study typically received three drugs, typically were in and out of status for about a day and a half.

Scott Braunstein: And even in that scenario, or in this case the control group, physicians were only advancing care 50% at the time. And that may have been changing EEG patterns. It may have been changing physicians. It may have been not necessarily following the behaviors of the EEG, but I think we've just learned that this is too subjective and end point. Regardless of what physicians have told us time and time again. And remember, we did a very big survey.

Scott Braunstein: We specifically went to all our sites. We asked for their practice patterns. And I think yes, we saw much more consistent treatment pattern in our bigger enrolling sites. And I would say a variation in those patterns and sites that enroll to one or two patients. I think by nature, when you have a study and you have sites that are enrolled in one or two patients, you do run the risk of site bias. That is their site behavior influencing the outcome of the study. That certainly played a factor here, but I don't think the biggest factor. Joe, is anything you want to add?

Joe Hulihan: I mean, you don't have much time to say that. Yeah, yeah. No, I don't think there were particular sites as you mentioned, Scott. It was, you know, kind of some patient at each site or not at every site, but no, and I think we're doing a lot to minimize the variability. If we do another study, I think we understand a lot. We've learned a lot from the race study, obviously, in terms of what endpoints to look at and patient selection and Scott mentioned stratification.

Joe Hulihan: We want to make sure that we get a representative population, a population that's likely to respond in another study. So I think that we've learned an incredible amount from raising and that'll pay off when we come time to do another study.

Scott Braunstein: And I think the big thing that we want to really discuss with the FDA is, you know, what is the right endpoint? We certainly saw very strong signals as Joe is talked about with EEGs and the differences between EEGs of patients with an axelone and and who received placebo certainly every SAB member, every expert we've shared that data with feel unequivocally powerful that we should be discussing this and pushing for approval with the FDA.

Scott Braunstein: It's very nice to have their support. I recognize the reality of what we agreed upon with the FDA, but I think we have other very clear measures of durability in the study. We'll share those at the NTS meeting, but you can imagine thinking about how many drugs and escalation of care being a logical one. So I think we really feel there is durability in this data set that is clearly differentiated from placebo.

Scott Braunstein: Unfortunately, the alignment with the agency, the agency never specifically demanded durability defined by avoidance of ibionisnesia. And I think we need to have a discussion with them of what other durability measures they would agree to and I think we have several that we think are objective and is really the key piece of this puzzling more than site variability.

Scott Braunstein: And I think we won't really even talk about that per se at our FDA meeting.

Douglas Tsao: Okay, if I can one quick question on TSC in terms of the long term extension, are you really seeing any discontinuations once patients are able to tolerate the drug for some amount of time and the continuation rate in the long term extension so far? Well, so we are very fortunate that one of our investigators is going to be presenting the long term extension data set submitted for a yes, it hasn't been accepted as of yet, right?

Douglas Tsao: It's a little early, but we expect a presentation will share that top line data with you all at our analyst in September. We are really encouraged that the durability that we see across the Z state is really quite robust and we really believe the pan extra synaptic activity of an excellent is something very unique and time and time again when we do our market research, it's not only about initial response rates.

Douglas Tsao: It's about durability and it's about safety as Lisa talked about and ability to play nicely in sandbox with other drugs. So I think when we go into this TSC launch, we will have a lot of talking points, a lot of measures of durability. And certainly you see that with other drugs, but I think in particular we've seen it in some disease states that you just wouldn't expect to see it in, right?

Douglas Tsao: Comparing a little bit of apples and oranges that we really tackled what I think are two of the most refractory seizure disorders out there. So we think it's going to be an important message and we're looking forward to sharing all that data with you guys at the analyst day. Thanks, Doug.

Unknown Executive: Thank you.

Marc Goodman: Our next question is from the line of Marc Goodman with Learing. Please just use your question. Can you talk about any off-label use you soon with connects alone? And secondly, you mentioned eligibility for milestones. Can you elaborate a little bit for this year, folks? Steve, do you want to take those questions off-label use? Yes, sure. I can jump in here. I think Marc, maybe I'll answer the second one first. You mentioned milestones.

Marc Goodman: So the nearest from milestone that we've talked about is a 10 million euro payment from Orion that would be due upon commercialization of CDD. So that happens when they launch in two of the major markets or no later than 18 months after their first market. There's a similar type of payment associated with TFD commercialization. And then we also have commercialization payments with China with our Tenacious Partnership. Those are a little further out and not quite to the same magnitude, but a nice amount as well.

Marc Goodman: In terms of off-label, I know we've got Lisa on. Lisa, do you want to touch on kind of off-label use with connects alone? Absolutely. Thank you, Steve. We've got about 15% of our patients on therapy that do not have a CDD diagnosis, and they're affected by other DEEs. I'll just add that most payers are covering the drugs for these patients, acknowledging a significant unmet need here. And I'll add a little more.

Marc Goodman: I couldn't hear you, but the thing I'll add is I think, you know, we've heard a lot of back and forth about the GW launch in TSE. And I think, you know, we have several GW team members as part of the Marinist team in between their expanded access program and the overlap with LGS that they went into their TSE launch with a substantial number of patients already on drug. I think we can confidently say there are close to no patients to currently unganassal in today that are being reimbursed with the diagnosis of TSE, or certainly that we do not know of any in terms of those developments on cephalopathy. So we really feel like the entire TSE market is open for us from day one, and there's certainly not a big part of our business today. Thanks. Thank you.

Jason Butler: The next question is from one of Jason Butler with JMP. Please just use your question. Hey, it's Roy on for Jason. Just a quick one, and maybe just answered this, but first of all, me. I mentioned that the key initiatives over a thousand patients I need and patients who might have a CDD, but not a diagnosis. I guess what proportion of the patients today do have a diagnosis, I guess.

Scott Braunstein: Let me kick it off, then I'll put it over to Lisa Jason. Remember, you know, the two major advocacy groups, IFC are and Lulu foundation in the US. That's a very hard for a CDKL5 code that went into effect a little bit more than a year before we launched. So roughly three and a half years ago to kind of put that in perspective. Well, and we expect about 100 newborns a year.

Scott Braunstein: And in the last three, three and a half years, they've gone from zero to 200 to 400 to now roughly a thousand of unique patient codes for CDKL 5. So what we expected, as we've always talked about, is roughly 2000 patients below the age of 21. And certainly another 3000 adult patients, but many of those adult patients won't be genetically tested. Certainly some are being tested, and some are being treated to Tommy.

Scott Braunstein: So I think we have good line of sight of roughly 2000 patients, a lot less line of sight of the other 3000. So I think we estimate probably more than 2500 patients are out there, you know, with a diagnosis or with the symptoms that have a gap and diagnose. And we're clearly seeing this exponential growth in the use of the ICD-10 code, and we know there's not more than 100 newborns a year, right?

Scott Braunstein: So it's just physician recognition of the code, the advocacy groups pushing for the code, reimbursement around the code, all of those pieces of the puzzle are leading physicians to use the code. But we also know, even as of a year ago, we had some centers of excellence that were not using the code appropriately. So it's a little bit of the education around the code. But I think we feel pretty good the fact that there is already more than a thousand patients that have a code that we can find these patients.

Scott Braunstein: We don't really feel like the 200 or so patients that are currently on therapy close to 300 patients who have tried therapy or have been prescribed are the only patients out there. I think we feel very good about finding additional patients to keep growing the business. And certainly, I think we're really focused on that. And Lisa, you can talk about that more.

Lisa Lejuwaan: And I think we're going to have to make this the last question operator. We've got over about 10 minutes. Lisa, anything else you want to add? I think you've covered it nicely. I'll just add that you know one thing that we've done is shipped our strategy towards the more data driven approach because we have so many more HCPs utilizing the code over the past four years. The code has only been available for four years.

Lisa Lejuwaan: And we've seen an increase in that data from 200 to a thousand patients over time identified. There's also been an increase in general in genetic testing, you know, with support from the American epilepsy society who really are putting it out there that every physician should genetically test patients who are receiving and have an unidentified underlying etiology for their disease. So that combination has really driven up the CDK-5 diagnosis in general. And we are very confident in the patients that are out there less for us to still introduce to Tommy too.

Operator: Thanks is operator.

Operator: We're going to take one more call.

Charles Duncan: We have Charles Duncan online. Yes, that's correct. Please go ahead Mr. Duncan. Yes, thanks for taking the follow up Scott. I'm going to make this simplifying assumption that trust TSC works out well. And that SNDA is filed and approved. I guess the question that I have is relative to manufacturing capacity at the end of 25. I assume that you'll be able to get there. And yeah, so that's that's the key question that I had to follow up with you on.

Charles Duncan: Oh, sure, Charles. I think we feel very good about our current manufacturing capabilities and our partner who effectively will dedicate much of their resources to helping us with Ganaxelone. We're very fortunate that the API has a five year shelf life. We've been only growing the shelf life of our branded tatalmi. We're hoping to expand that shelf life as well. So we really have the ability to continue to manufacture the tatalmi. And once we kick off these global launches to really start preparing for the TSD launch.

Charles Duncan: But certainly by our internal expectations, we're going to need additional supply, certainly by 27, and by our internal expectations, additional supply in 29. I think we feel very good about the opportunity in TSD in the U.S. And we really believe that a market that at least five times and potentially as large as 10 times the TSD market is very realistic. And we shall share some of those numbers with everyone during the analyst day.

Charles Duncan: And I think equally important, we're expecting strong volumes across Europe, very strong volumes in China, expanding volumes throughout the world. And so we're getting prepared and doing in a very step wise and stage fashion. And certainly we think it's critical to have a second unique manufacturing site to minimize risk. And that process, we've made the investment for the equipment. The room build out will start shortly. And we want to make sure that in 2027 we have more than enough product. So those plans are in place and we feel really good about the way we're preparing for that and fortunate.

Scott Braunstein: You know, look, it was a very hard decision for us to let some people go in June and restructure the organization. But as we said all along, we've always had high confidence in the TSD launch. We think it can drive profitability and we have not a short cut or short change the oral franchise at all. And obviously, you know, Christie's been a great, she is a great chief commercial officer. You can hear from this call that Lisa is incredibly qualified as well.

Scott Braunstein: We've got great leadership in place. We're thinking about the manufacturing, we're thinking about the global regulatory strategy. We are going to be quite ready to execute post this data. So thanks so much for the call, Charles, really appreciate it. Thanks, everyone. I really appreciate you joining the call. We're about 15 minutes over, but great, great chair and some of our thoughts. And we look forward to seeing you at the analyst event in September. And thanks again for dialing in.

Operator: This will conclude today's conference. May disconnect your lines at this time. Thank you for your participation and have a wonderful day.