Q4 2021 Marinus Pharmaceuticals Inc Earnings Call

Operator: Greetings and welcome to the Marinus Pharmaceuticals approval for quarter and full year 2021 financial results and business update call. At this time, all participants are in a listen-only mode.

Greetings and welcome to the Marinus Pharmaceuticals approval fourth quarter and full year 2021 financial results and business update call.

Operator: After this speaker's presentation, there will be a question and answer session. If you'd like to ask a question during this time, press star followed by the number one on your telephone keypad. If you'd like to withdraw your question, press the pump.

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

After the speaker's presentation, there will be a question and answer session.

If you'd like to ask a question. During this time press star followed by the number one on your telephone keypad, if you'd like to withdraw your question press the pound key.

Operator: And now it is my pleasure to introduce your host, Sasha Damouni, Vice President of Corporate Affairs and Investor Relations. You may begin. Thank you and good morning everyone.

And now it is my pleasure to introduce your host Sasha that Boni, Vice President of corporate Affairs, and Investor Relations you may begin.

Sasha Damouni: With me for Marinus are Dr. Scott Braunstein, Chief Executive Officer, Dr. Joe Hulihan, Chief Medical Officer, Kimberly McCormick, Senior Vice President of Regulatory Affairs, Kristi Shafer, Chief Commercial Officer, and Steve Pfanstiel, Chief Financial 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 laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development program's 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-K.

Thank you and good morning, everyone with me for Meredith are Dr. Scott Braunstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, Kimberly Mccormick Senior Vice President of regulatory Affairs Christi, Schaefer, Chief Commercial officer, and Steve <unk> Chief Financial Officer.

Before we begin I would like to remind everyone that some of the statements. We're making today are forward looking statements under the securities laws. These forward looking statements involve substantial risks and uncertainties that could cause our clinical development programs future results performance or achievements to differ significantly from.

Those expressed or implied by such forward looking statements.

These risks and 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.

Scott Braunstein: I will now turn the call over to our CEO, Scott Braunstein. Thank you, Sasha, and welcome to our call. Today marks a historic milestone for Marinus, CDD patients, their families, and caregivers following the FDA's approval of oral Ganaxolone, which will be commercially known as Zitalmin. Zotomy is the first and only approved treatment for seizures associated with CDKL5 deficiency disorder, or CDD, a rare form of genetic epilepsy in patients two years and older.

I will now turn the call over to our CEO Scott Braunstein.

Thank you Sasha and welcome to our call today marks a historic milestone for Meredith C. D D patients their families and caregivers following the fda's approval of oral <unk> alone, which will be commercially known as <unk> told me to tell me the first and only approved treatment for seizures associated.

She did with C D Gayle <unk> deficiency disorder, where C. D D. A rare form of genetic epilepsy in patients two years and older.

Scott Braunstein: Zitalmi is expected to be available in July following scheduling as a controlled substance by the U.S. Drug Enforcement Administration. We believe this approval further validates our clinical development plans for Ganaxolone across a range of seizure disorders and positions us well in our evolution to a commercial stage company. The approval of ZITOMI would not have been possible without the support of patients, families, caregivers, and investigators who participated in the clinical studies to develop this new treatment option, as well as an unwavering commitment of our Marinus employees.

The told me is expected to be available in July following scheduling is a controlled substance by the U S. Drug enforcement administration. We believe this approval further validates our clinical development plans for <unk> alone across a range of seizure disorders and positions us well in our evolution to a commercial stage company.

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The approval of the Tommy would not have been possible without the support of patients families caregivers and investigators who participated in our clinical studies to develop this new treatment option as well and we bring commitment of our emeritus employees.

Scott Braunstein: We are humbled by the opportunity to make a difference in the lives of patients suffering with CDD. Shortly, our Chief Commercial Officer, Kristi Shafer, will detail how we plan to support access for patients who are prescribed Zytomy through our patient assistance efforts, including the Zytomy One program. She will also discuss our commercial strategy, launch preparedness, and pricing.

We are humbled by the opportunity to make a difference in the lives of patients suffering with C. D D.

Shortly our chief commercial officer, Christy Shaper will detail, how we plan to support access for patients who are prescribed the call me through our patient assistance efforts, including does it tell me one program. She will also discuss our commercial strategy launch preparedness and pricing.

Scott Braunstein: The approval also enables the potential for significant non-diluted funding in the near term to execute on our business strategy and invest in our future. We have been awarded a rare pediatric disease priority review voucher by the FDA, which we plan to monetize to bolster our financial position. The approval also enables us to draw an additional $30 million in funding under the existing Oak Tree Credit Agreement. Steve will discuss both of these in greater detail during his prepared remarks.

The approval also enables the potential for significant non dilutive funding in the near term to execute on our business strategy and invest in our future. We've been awarded a rare pediatric disease priority review voucher by the FDA, which we plan to monetize to bolster our financial position. The approval also enabled.

As to draw an additional $30 million in funding under the existing Oaktree credit agreement.

Steve will discuss both of these in greater detail during his prepared remarks as a reminder, in the European Union. The marketing authorization application for <unk> is being evaluated for the treatment of seizures associated with T. D D with the CH M. P opinion expected by year end 2022.

Scott Braunstein: As a reminder, in the European Union, the Marketing Authorization application for Ganaxalone is being evaluated for the treatment of seizures associated with CDD with a CHMP opinion expected by year-end 2022. We have been collaborating extensively with Orion, our European strategic partner, as they prepare Ganaxalone's commercial readiness. We remain committed to identifying opportunities throughout the world to improve the lives of patients suffering with CDD, including our ongoing commitment to the European Expanded Access Program.

We have been collaborating extensively with Orion, our European strategic partner as they prepare <unk> commercial readiness, we remain committed to identifying opportunities throughout the world to improve the lives of patients suffering with TDD, including our ongoing commitment to the European expanded access program.

Scott Braunstein: In addition, we believe that there is a broader global opportunity for the Ganaxalon franchise, and we are exploring the potential for additional ex-U.S. strategic partnerships to expand Ganaxalon's global footprint. Regarding our Lead Stage Oral Program, let me discuss our commitment to the tuberous sclerosis complex community. We are actively screening patients in the U.S. for the Phase 3 TRUST-TSC trial and expect to have the majority of U.S. sites initiated and actively enrolling in the second quarter.

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In addition, we believe that there is a broader global opportunity for the good excellent franchise and we are exploring the potential for additional ex U S strategic partnerships to expand <unk> global footprint.

Regarding our late stage oral program, let me discuss our commitment to the tuberous sclerosis complex community.

We are actively screening patients in the U S for the Phase III Trust TSB trial and expect to have the majority of U S sites initiated and actively enrolling in the second quarter. We have added several critical new elements to the phase III design that provide us with high confidence in the trial success and particularly the ROE.

Scott Braunstein: We have added several critical new elements to the Phase 3 design that provide us with high confidence in the trial's success and particularly the role of Benaxylone in significantly reducing seizures most commonly seen in the refractory TSC population. We gained a tremendous amount of insight from our Phase 2 trial and used that to inform the Phase 3 protocol. We expect top-line data in the trial during the first half of 2024 and we continue to work with our sites to improve these timelines.

Index alone and significantly reducing seizures, most commonly seen in the refractory PSC population, we gained a tremendous amount of insight from our phase II trial and use that to inform the phase III protocol, we expect topline data in the trial during the first half of 2024 and we continue to.

To work with our sites to improve these timelines.

Scott Braunstein: Dr. Ian Miller, a highly regarded pediatric epileptologist who joined the organization last year, is playing an important leadership role in this trial. I will leave further comments to Joe Hulihan, our chief medical officer, in his prepared remarks.

Dr. Ian Miller, a highly regarded pediatric epilepsy apologists, who joined the organization last year is playing an important leadership role in this trial.

I will leave further comments to Joe Houlihan, our Chief Medical officer in his prepared remarks, turning to the IV development program. We believe that <unk> can dramatically improve outcomes for patients suffering from status epilepticus and prevent the escalation of treatment to IV anesthetics and a significant number of patients the comes.

Scott Braunstein: Turning to the IV development program, we believe that Gonaxalone can dramatically improve outcomes for patients suffering from status epilepticus and prevent the escalation of treatment to IV anesthetics in a significant number of patients. The company continues to press ahead with our IV clinical trials, despite setbacks as a result of the impacts from COVID-19 and an unexpected interruption in clinical supply material experienced in the first quarter of this year. We are adding new trial sites and are moving closer to the resupply of our clinical trial materials.

<unk> continues to press ahead with our IV clinical trials. Despite setbacks as a result of the impacts from COVID-19, and then unexpected interruption and clinical supply material experienced in the first quarter of this year, we are adding new trial sites and are moving closer to the resupply of our clinical trial.

Materials as a result of several coordinated internal efforts within Meredith and our contract manufacturing organizations. We are now expecting to reach supply our clinical trial sites and resume recruitment for the phase III <unk> trial in refractory status epilepticus in may of this year a month earlier than <unk>.

Scott Braunstein: As a result of several coordinated internal efforts within Marinus and our contract manufacturing organizations, we are now expecting to resupply our clinical trial sites and resume recruitment for the Phase III RAISE trial in refractory status epilepticus in May of this year, a month earlier than previously announced. At the same time, the manufacturing team is making significant efforts to improve the shelf life of Ibogainex loan to 24 months or greater. As of today, 52 centers are activated and ready to enroll when supply is made available in May.

Previously announced at the same time the manufacturing team is making significant efforts to improve the shelf life of boddington ex loan to 24 months or greater.

As of today 52 centers are activated and ready to enroll when supply is made available in may we are confident in our ability to proceed with this trial given that current hospital resources are less strained by COVID-19, our key U S sites are activated and we have recently seen growing interest from several new sites that <unk>.

Scott Braunstein: We are confident in our ability to proceed with this trial given that current hospital resources are less strained by COVID-19, our key U.S. sites are activated, and we have recently seen growing interest from several new sites that previously declined participating in the trial. Additionally, we have received encouraging feedback via our scientific advisory board and have recently implemented a minor protocol amendment that will broaden the entry criteria. We currently expect top-line results in the second half of 2023 and will continue to do all we can to improve these timers.

<unk> declined participating in the trial.

Additionally, we have received encouraging feedback via our scientific advisory Board and have recently implemented a minor protocol amendment that will broaden the entry criteria. We currently expect top line results in the second half of 2023, and we will continue to do all we can to improve these timelines I am.

Scott Braunstein: I am proud that our team has shown the ability to adapt to the challenges raised by the pandemic with a diligent focus on advancing this critically important program. Now turning to what we believe will be the future of the Ganaxalon franchise, our second-generation oral formulation. The goal of this initiative is to deliver an improved pharmacokinetic profile, including better bioavailability, lower variability, and more predictable drug exposure.

Proud that our team has shown the ability to adapt to the challenges raised by the pandemic with a diligent focus on advancing this critically important program.

Now turning to what we believe will be the future of the <unk> franchise, our second generation oral formulations. The goal of this initiative is to deliver an improved pharmacokinetic profile, including better bioavailability lower variability and more predictable drug exposure, we expect that our phase.

<unk> new formulation work will be completed by mid 2022.

Scott Braunstein: We are simultaneously focusing research efforts on developing a modified release version of this new formulae. We currently believe that we have a second formulation candidate ready for clinical evaluation in the second half of this year and this candidate may not require any additional modified release technology to offer twice daily dosing options. Finally, both formulation programs have novel intellectual property.

We are simultaneously focusing research efforts on developing a modified release version of this new formulation. We currently believe that we have a second formulation candidate ready for clinical evaluation in the second half of this year and this candidate may not require any additional modified release technology to offer twice daily.

Dosing options finally, both formulation programs have novel intellectual property.

Scott Braunstein: As a reminder, if studies of the new oral formulation demonstrate the expected PK profile, which would be very consistent with historical animal models, we plan to move quickly to a trial in Lennox-Gastaut syndrome and would expect to begin that study in the second half of 2022. Predictable PK of the new formulation would allow us to perform dose ranging studies to assess both efficacy and tolerability. This is something that has never been thoroughly assessed with oral Ganaxalone and we hope that such evaluations can add to its clinical utility in future indications.

As a reminder, if studies are the new oral formulation demonstrate the expected PK profile, which would be very consistent with historical animal models. We plan to move quickly to a trial in Lennox <unk> syndrome, and would expect to begin that study in the second half of 2022.

Predictable PK of the new formulation would allow us to perform dose ranging studies to assess both efficacy and Tolerability. This is something that has never been thoroughly assessed with Oregon ex loan and we hope that such evaluations can add to its clinical utility and future indications.

Scott Braunstein: Additionally, we've made some exciting progress in our pro-drug program, which Joe will discuss in detail shortly. Beyond our preclinical work and our ongoing clinical studies, we are making great strides strengthening our intellectual property and bolstering our advocacy efforts. This month, Marinus entered an exclusive license agreement with Ovid Therapeutics to license patents and patent applications in the U.S. and EU related to the use of Ganaxolone for the treatment of CDKL5 deficiency disorder. The Ovid patents originated from a provisional patent application that was filed on August 11, 2016.

Additionally, we've made some exciting progress in our prodrug program, which Joe will discuss in detail shortly.

Beyond our preclinical work in our ongoing clinical studies.

We're making great strides strengthening our intellectual property and bolstering our advocacy efforts. This month Meredith entered an exclusive license agreement with <unk> therapeutics to license patents and patent applications in the U S and EU related to the use of <unk> for the treatment of <unk> deficiency disorder.

The avid patents originated from a provisional patent application that was filed on August 11 2016.

Scott Braunstein: With regard to our advocacy efforts, our view is that every patient matters, particularly in the rare and orphan disease area. Our goal is to help educate, engage, and empower patients, their families, and caregivers, and to maintain strong and transparent relationships with the advocacy community. Now I would like to turn the call over to Joe for additional updates on our clinical program. Thanks, Scott. Good morning, everyone.

With regard to our advocacy efforts our view is that every patient matters, particularly in the rare and orphan disease area. Our goal is to help educate engage and empower patients their families and caregivers and to maintain strong and transparent relationships with the advocacy community now I would like.

To turn the call over to Joe for additional updates on our clinical programs.

Thanks, Scott and good morning, everyone.

Joe Hulihan: We're extremely pleased to have received our first product approval. So tell me, a neuroactive steroid that acts as a positive allosteric modulator of the GABA-A receptor, is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5-deficiency disorder, or CDD, in patients 2 years of age and older. As a reminder, CDD is a serious and rare genetic disorder, characterized by early onset difficulty control seizures and severe neurodevelopmental impairment, is caused by a mutation of the CDKL5 gene located on the X chromosome, which is responsible for producing a protein essential for normal brain development and function.

We're extremely pleased to have received our first product approval.

So Tommy a neuro active steroid that acts as a positive allosteric modulator of Gaba a receptor.

As indicated for the treatment of seizures associated with cyclin dependent.

Slide five deficiency disorder or CBD in patients two years of age and older.

As a reminder, CBD is a serious and rare genetic disorder.

Characterized by early onset difficult to control seizures, and severe neuro developmental impairment.

It's caused by a mutation in the <unk> five gene located on the X chromosome.

Which is responsible for producing a protein essential for normal brain development functions.

Joe Hulihan: This is one of the most refractory forms of epilepsy, making the condition particularly challenging for patients and families. Until now, there have been no approved therapies indicated specifically for the treatment of seizures associated with CD. The approval of Zitolamine and CDD is based on data from a single, phase 3, double-blind, placebo-controlled trial, the Marigold, which randomized 101 patients to Ivermectomy or Plastic Surgery. Those treated with cetamine showed a median 30.7% reduction in 28-day major motor seizure frequency compared to a median 6.9% reduction for those receiving placebo.

This is one of the most refractory forms of epilepsy, making the condition, particularly challenging for patients and families.

Until now there have been no approved therapies indicated specifically for the treatment of seizures associated with CBD.

Okay.

The approval of the Tommy in CBD is based on data from a single phase III double blind placebo controlled trial the Marigold study.

Which randomized 101 patients to why there's a tall mirror placebo.

Those treated with <unk> showed a median 37% reduction in 28 day major motor seizure frequency compared to a median of six 9% reduction for those receiving placebo.

Joe Hulihan: Achieving the trial's primary end point with a p-value of 0.0036. As a reminder, patients entering the Marigold trial had failed an average of seven prior antipoleptic therapy. In the open label extension study, there were 48 patients treated with citalomy for at least 12 months, and they experienced a median 49.6% reduction in the frequency of major motor seizures. In addition to the efficacy demonstrated in the Marigold trial, Sitalmi showed a favorable safety and powerability profile, and there was a low discontinuation. The most common adverse event was somnolence.

Achieving the trial's primary endpoint with a P value of 0.0036.

As a reminder, patients entering the Marigold trial and failed an average of seven prior anti epileptic therapies.

And the open label extension study there were 48 patients treated with <unk> for at least 12 months.

They experienced a median of 49, 6% reduction in the frequency of major motor seizures.

In addition to the efficacy demonstrated in the Marigold trial.

Ami showed a favorable safety and Tolerability profile and there was a low discontinuation rate.

The most common adverse event was <unk>. However, it didn't lead to any patients discontinuing treatment.

Joe Hulihan: However, it didn't lead to any patients discontinuing treatment. As we prepare for the near-term launch of Zotomi and CBD, we already have a fully-staffed medical science liaison team in place. We're also developing a comprehensive publication strategy with multiple manuscripts in development, that will focus on key themes and knowledge gaps related to CDD. Connexaline's unique mechanism of action, its pharmacokinetic and pharmacodynamic properties, most important.

As we prepare for the near term launches at Tommy and CBD, we already have a fully staffed medical science liaison team in place.

We're also developing a comprehensive publication strategy with multiple manuscripts in development that will focus on key themes knowledge gaps related to CBD.

<unk> unique mechanism of action its pharmacokinetic and Pharmacodynamic properties, most importantly, key safety and efficacy data.

Joe Hulihan: Key Safety and Efficacy Data. We expect the primary manuscript from the Marigold Study to be published shortly in a peer-reviewed journal. Additionally, we still have a significant number of patients enrolled in the ongoing Marigold Open Label Extension and plan to present data from this part of the study at a major medical meeting later this year. We intend to engage with the medical community at upcoming conferences, such as the Neurocritical Care Society and American Epilepsy Society meeting in the second half of 2022. Now, I'd like to discuss our second generation in that Sloan formulation. We've identified Linux, Kestos, and Rome as a lead indication for a reformulated world in Axelone.

We expect the primary manuscript Marigold study to be published shortly in a peer reviewed journal.

Additionally, we still have a significant number of patients enrolled in the ongoing Marigold open label extension and plan to present data from this part of the study at a major medical meeting later this year.

We intend to engage with the medical community at upcoming conferences, such as the neuro critical care Society American Epilepsy Society meetings in the second half of 2022.

Now I'd like to discuss our second generation <unk> formulations.

We've identified Lennox guests dose enrollment as the lead indication for a reformulated, Oregon acts alone.

Joe Hulihan: And we'll also evaluate additional indications in epilepsy and potentially other therapeutic areas. We've made substantial progress and are on track to report phase one results for one of the two formulations in development by mid-year. As Scott mentioned, if clinical data are supportive, we expect to initiate a Phase II trial in LGS in the second half of this year. LGS is a rare epileptic nephelopathy that can result from many structural or genetic causes.

And we will also evaluate additional indications in epilepsy and potentially other therapeutic areas.

We've made substantial progress and are on track to report phase one results for one of the two formulations in development by mid year.

As Scott mentioned the clinical data are supportive we expect to initiate a phase III trial in lgs and the second half of this year.

Lgs is a rare epileptic encephalopathy that can result for many structural or genetic causes.

Joe Hulihan: It's highly treatment refractory, and we believe it's critical to study this indication with the new oral formulation to provide more consistent and predictable exposure to Ganaxolone, which would allow better dose individualization and this difficult to treat disorder. Since the seizure types in LGS are much like those in CDB, we believe can act alone as a promising candidate for development in this indication. We previously presented a case series of patients co-diagnosed with CBD and Lenox-Gastaut from the Marigold study, the results of which support the rationale for developing Ganaxalone in the syndication.

It's highly treatment refractory and we believe it's critical to study this indication with the new oral formulations to provide more consistent and predictable exposure that can ask alone.

Which would allow better dose individualization in this difficult to treat disorder.

Since the seizure types in lgs are much like those in CBD. We believe can exelon is a promising candidate for development.

Yeah.

We previously presented a case series of patients co diagnosed with CBD and lung Scottsdale from the Marigold study.

The results of which support the rationale for developing <unk> in this indication.

Joe Hulihan: The Phase I study will enroll two cohorts in a crossover design that will evaluate several doses of the new formulation and compare its pharmacokinetics to the current oral suspension. We plan to finalize the design of the Clinical Development Program based on the Phase I results, and initiate the trial in the second half of this year. A pro-drug program also continues to advance.., and we've identified two compounds that we believe are strong candidates for IND enabling studies, and which may offer some unique advantage, relevant to both our current oral and IV program. The first compound shows a blunted C-max that could potentially allow for once-daily dosing and improved tolerability, second compound, we believe could be specifically targeted for an IV formulation.

The phase one study will enroll two cohorts in a crossover design that will evaluate several doses of the new formulation and compare its pharmacokinetics to the current oral suspension.

We plan to finalize the design of the clinical development program based on the phase one results.

And initiate the trial in the second half of this year.

A pro drug program also continues to advance and we have identified two compounds that we believe are strong candidates for IND, enabling studies and which may offer some unique advantages relative to both our current oral and IV programs.

The first compound shows a blunted C Max.

Potentially allow for once daily dosing and improved Tolerability.

The second compound, we believe could be specifically targeted for an IV formulation.

Joe Hulihan: We expect to initiate preclinical testing by the middle of this year. Now, let me update you on the phase 3, trust TSC trial in tuberous sclerosis com. [inaudible] We're partnering closely with the Epilepsy Consortium, a group of scientific investigators from academic medical research centers who are dedicated to accelerating the development of new therapies in epilepsy and optimizing clinical trial methodology. Specifically, we're working to ensure the consistency and accuracy of seizure, and that there is dialogue between the consortium and study sites to gather clinical and diagnostic test data relevant to the assessment of study participants' seizures.

We expect to initiate preclinical testing by the middle of this year.

Now let me update you on the Phase III Trust TFC trial in tuberous sclerosis complex.

Were partnering closely with the epilepsy consortium a group of scientific investigators from academic medical research centers, who are dedicated to accelerating the development of new therapies, and epilepsy and optimizing clinical trial methodology.

Specifically, we are working to ensure the consistency and accuracy of seizure counts.

And that there is dialogue between the consortium and study sites to gather clinical and diagnostic test data relevant to the assessment of study participants seizures. Some of our key scientific Advisory Board members believe this played a critical role in the success of the Marigold trial.

Joe Hulihan: Some of our key scientific advisory board members believe this played a critical role in the success of the Marigold trial. The TRUST-TSC study will randomize approximately 162 patients one-to-one, pick an axolone or placebo, added to their existing anti-seizure medication. We expect to include 60 sites, predominantly in the U.S., Western Europe, Canada, and Israel, and we'll continue to evaluate sites in other countries.

The Trust PSC study will randomize approximately 162 patients one to one to can exelon or placebo added to their existing anti seizure medications.

We expect to include 60 sites predominantly in the U S Western Europe , Canada and Israel.

And we will continue to evaluate sites in other countries.

Joe Hulihan: As was the case in phase 2, the phase 3 study will involve patients receiving a finitour and epidialis, making this the first registration study to evaluate the efficacy of an AED in TSC-associated seizures when it's added to those medications. We've gleaned many important insights from the results of our Phase 2 study that have led to modifications in the Phase 3 protocol. These include an adjustment of the titration schedule for all study participants, which we believe will improve tolerability of Ganaxolone when added to the medications patients are currently receiving for the treatment of PSC, leading to better efficacy outcomes.

As was the case in phase two the phase III study will enroll patients receiving a tour and at the dialects, making this the first registration study to evaluate the efficacy of an AAV <unk> associated seizures, when it's added to those medications.

Many important insights from the results of our phase III study that have led to modifications in the phase III protocol.

These include an adjustment to the titration schedule for all study participants, which we believe will improve tolerability of <unk> when added to the medications patients are currently receiving for the treatment of PSC, leading to better efficacy outcomes.

Joe Hulihan: In addition, we're going to stratify enrollment based on whether patients are taking Epidiolex, a commonly prescribed cannabidiol formulation used to treat TSC. As Scott mentioned, we've begun initiating our US sites and plan on adding Western European centers by the middle of the, Now turning to our IV development. We currently have two trials of refractory status supplements, and phase 3 race trial is designed to demonstrate a rapid onset of action and durable S.E. cessation the laver indicated by prevention of progression to IV anesthesia, which is associated with high rates of morbidity and mortality. 52 sites are now open and we continue to activate new ones.

In addition, we're going to stratify enrollment based on whether patients are taking up the pilots.

Commonly prescribed can add the dial formulation used to treat PSC.

As Scott mentioned, we've begun initiating our U S sites.

Then on adding western European centers by the middle of the year.

Now turning to our IV development program.

We currently have two trials in refractory status epilepticus.

The phase III <unk> trial is designed to demonstrate a rapid onset of action and durable cessation. The ladder indicated by prevention of progression to IV anesthesia, which is associated with high rates of morbidity and mortality.

52 sites are now open and we continue to activate new ones.

Scott Braunstein: We expect to restart enrollment in the RAISE trial in May with new batches of the existing iVegan Axelon formulation, background contacts to our announcement in February, during visual inspection as part of routine stability tests. Visible particulates of aluminum phosphate were seen in the drug solution, resulting in a reduction in shelf life, current formulation with that shorter shelf will be used to restart the trial. Longer term, we expect to reformulate Ivegan-Axelone, a new buffer that does not contain the phosphate salts that interact with the aluminum from the glass bottle.

We expect to restart enrollment in the rave trial in May with new batches of the existing IV can excellent formulation.

For background context to our announcement in February .

Adding visual inspection as part of routine stability testing visit.

Visible particulars of aluminum phosphate, we're seeing the drug solution, resulting in a reduction of shelf life.

Current formulations without shorter shelf life will be used to restart the trial.

Longer term, we expect to reformulate IV can actual new buffer it does not contain the phosphate salts that interact with the aluminum from the glass bottles.

Scott Braunstein: We currently have two potential buffer solutions that could be viable alternatives. We expect the future clinical supply and commercial launch will utilize the new formulation with a shelf life of at least 24 months. Based on published FDA guidance, it's our understanding that replacing a buffer in a new formulation only requires that a company identifies and characterizes the differences and provides information demonstrating that these do not affect the safety or efficacy of the proposed drug product.

We have two potential buffer solutions that could be viable alternatives.

We expect the future clinical supply and commercial launch will utilize the new formulation with a shelf life of at least 24 months.

Based on published FDA guidance, it's our understanding that replacing a buffer and a new formulation only requires that accompany identifies characterizes the differences and provides information demonstrating that these did not affect the safety or efficacy of the proposed drug product.

Scott Braunstein: We're on track to put the new formulation on stability in the fall, which will support our NDA plan. Our second status trial is the reset trial (inaudible). And in contrast to the RAISE trial, which is focused on refractory, Reset is focused on established status epilepticus, which occurs earlier in the status continuum.

We're on track to put the new formulation on stability in the fall, which will support our NDA filing.

Our second status trial as the reset trial and in contrast to the raise trial, which is focused on refractory SC.

Reset is focused on established status epilepticus, which occurs earlier in the status continuum.

Joe Hulihan: We anticipate U.S. enrollment to begin in the second half of 2022, at several sites who are eager to participate in both the RESET and RAISE trials, spanning care from the ER to the neural ICU. And we will use this interest to our strategic advantage while enrolling these two distinct studies. In our third Phase 3 SE trial, Phase 2, we anticipate patient enrollment to begin in the first half of next year. This trial will not only serve as a critical piece of the European approval strategy, but has the potential to broaden the use of iVeganAxolone in the U.S. patient population. Our focus today is resolving both our short and long term supply requirements before the initiation and completion of the RAISE II study. As always, in close.

We anticipate U S enrollment to begin in the second half of 2022.

We have several sites who are eager to participate in both the reset and raised trials spanning care from the ER to the neuro ICU.

And we will use this interest to our strategic advantage while enrolling these two distinct studies.

In our third phase III <unk> trial raised two we anticipate patient enrollment to begin in the first half of next year.

This trial will not only serve as a critical piece of the European approval strategy.

But has the potential to broaden the use of <unk> in the U S patient population.

Our focus today is resolving both our short and long term supply requirements before the initiation and completion of the raised two study.

Okay.

As always in closing I'd like to thank the patients families medical professionals and advocacy groups.

Kimberly McCormick: I'd like to thank the patients, families, medical professionals, and advocacy groups who are so supportive of our efforts. Now I'd like to turn the call over to Kim McCormick, our Senior Vice President for Regulatory Affairs. Thank you, Joe. It is great to be here to speak with you today. With this regulatory approval of the Tommie, we now have our first commercial product. The ZITOMI label indication is for patients 2 years of age and older, with no formal laboratory monitoring required such as hepatic or hematologic testing, no REMS program, and a favorable risk-benefit profile that is well-tolerated when used in combination with other anti-seizure medications.

So supportive of our efforts.

Kimberly McCormick: The tommy is expected to be commercially available following scheduling as a controlled substance, by the U.S. Child Enforcement Administration, which is expected to occur within 90 days of approval. Based on our assessment of the preclinical clinical data on Ganaxone and its mechanism of action, we expect to receive a Schedule IV by the DEA, which is similar to other epilepsy treatments. As far as the Genaxum CDD, European Marketing Authorization application, we announced in February that the MAA will convert to a standard review and that we have reached an agreement with the European Medicines Agency to extend the day 120 clock stop by three months to allow sufficient time to respond to questions received as part of the review. We're actively working to prepare the response to the questions raised at day 120. As Scott mentioned, we expect to see HMP opinion on the MAA by year-end 2022.

Now I'd like to turn the call over to Ken Mccormack, Our senior Vice President regulatory Affairs.

Thank you Joe it's great to be here to speak with you today.

With this regulatory approval like autonomy, we now have our first commercial product.

Is it from enable indication is for patients two years of agent order with no formal laboratory and margin required just to Patty or as you mentioned logic testing no Rems program and a favorable risk benefit profile that is well tolerated when used in combination with other anti seizure medications.

<unk> is expected to be commercially available following scheduling as a controller.

But the U S. Chinese Horstmann administration, which is expected to occur within 90 days.

Based on our assessment of the preclinical clinical data on <unk> and its mechanism of action, we expect to receive a scheduled four by the DEA, which is similar to other epilepsy treatments as.

As far as it can ackman Edd European marketing authorization application.

In February at the <unk>.

<unk> will convert to a standard review and that we have reached an agreement with the guarantee.

<unk> should extend the day 120 clock stops by three months to allow sufficient time to respond.

<unk> is part of the review process.

We are actively working to prepare the response to the question Dave.

Dave on 'twenty.

Scott mentioned.

Back to see HMP opinion on the MAA by year end 2022.

Kimberly McCormick: Now I would like to highlight some of the key outcomes of our End of Phase 2 study in Iraq, with the regulatory agencies in the U.S. and Europe for TSC. As a reminder, we have received orphan drug designation in the U.S. and in Europe for this indication, and we believe we have overall alignment on the phase three TRUST-TSC clinical trial design. Thanks for coming to see you back to meet Reggie Tormino-Ross.

Now I would like to highlight some of the key outcome of our indicate steady interaction with the regulatory agencies in the U S and Europe for TSV as.

As a reminder, we have received orphan drug designation in the U S and in Europe .

Occasion, and we believe that overall line on the phase III <unk> clinical trials right.

Based upon feedback from these regulatory interactions we've made several adjustments to the crackle as Joe walked through earlier.

Kimberly McCormick: We've made several adjustments to the protocol as Joe walked through earlier. We believe that a single pivotal study should support registration in both the U.S. and Europe. Transmute IV Connexion Development Program.

We believe that a single pivotal study should support registration in both the U S and Europe .

Change in the IGN Askmen development program, we have notified the FDA and the circumstances around the clinical supply material interruption as well as the fact that we are proactively paused the phase <unk> trial in status epilepticus.

Kimberly McCormick: We have notified the FDA of the circumstances around the clinical supply material interruption, as well as the fact that we have proactively paused the phase three RAISE trial in status epilepticus while we resolve this issue. We subsequently provided the FDA with a full assessment of our strategy to resupply clinical trial material and our projected timing to reach the minimum. To support clinical trial expansion, we are targeting submission of a clinical trial application in Canada by the end of second quarter.

Resolve this issue.

It's going to provide the FDA with a full assessment of our strategy to re supply clinical trial material and our projected timing to resume enrollment.

To support clinical trial expansion, we are targeting submission of a clinical trial application and can at the end of second quarter.

Kimberly McCormick: Before I turn the call over to Kristi, I want to take a moment to thank the entire Marinus team that supported the NDA submission and approval, as well as the FDA for their role in bringing this important treatment to the CDD community. As a reminder, prior to the end of Phase 2 meeting five years ago, the treatment of seizures associated with CDD was not recognized as a standalone indication. Throughout the entire process, our collaboration with the FDA has been a productive one, and we look forward to continuing to partner with them to bring treatments to patients with significant unmet medical needs. Now, I'll hand it over to Kristin Shafer, our Chief Commercial Officer. Thank you, Kim.

I turn the call over to Christine I wanted to take a moment to thank the entire <unk> team.

The NDA submission and approval as well as the FDA for their role in bringing this important treatment to the CBD community as.

As a reminder, prior to the end of phase two meeting five years ago. The treatment of seizures associated with <unk> was not recognized as a standalone indication.

The entire process our collaboration with the FDA has been a productive line and we look forward to continuing to partner with them.

Patients with significant unmet medically now I'll hand, it over to Kristy Schaffer, our chief commercial officer.

Kristi Shafer: The commercial team couldn't be happier about the approval of Zotomi, the first and only FDA approved treatment for seizures associated with CBD in patients two years of age and older. The Tommy is expected to be available in the US through an exclusive specialty pharmacy in July of this year following scheduling by the US Drug Enforcement Administration. At Marinus, our mission is to dramatically improve lives affected by rare epilepsies, and Satomi is the first neuroactive steroid GABA-A receptor modulator specifically approved for patients with CBD, an extremely rare disorder.

Thank you Ken.

Commercial team couldn't be happier about the approval of the Tommy the first and only FDA approved treatment for seizures associated with CBD in patients two years of age and older.

The Tommy is expected to be available in the U S through an exclusive specialty pharmacy in July of this year following scheduling by the U S drug enforcement administration.

At Maranatha, our mission is to dramatically improve lives affected by rare epilepsy, and so tell me if the first narrow active steroid Gaba a receptor modulator, specifically approved for patients with ABB and extremely rare disorder.

Kristi Shafer: We believe that the pediatric patient population is the most addressable based on high diagnostic rates and treatment proximity to pediatric epileptologists and therefore estimate that the U.S. CDD market is around 2,000 pediatric patients. We have worked hard to simplify access to therapy and to provide accessibility through seamless prescription management, affordability, and patient adherence. With that in mind, we have developed a transparent weight-based pricing strategy for Zitalme to reflect the value it brings to the underserved patient population, while balancing our commitment to access and sustainable innovation.

We believe that the pediatric patient population is the most addressable based on high diagnostic.

And treatment proximity to pediatric epilepsy, allergists, and therefore estimate that the U S. CBD market is around 2000 pediatric patients.

We have worked hard to simplify access to therapy and can provide accessibility for seamless prescription management affordability and patient adherence.

With that in mind, we have developed a transparent weight based pricing strategy for the Tommy to reflect the value it brings to the underserved patient population while.

Balancing our commitment to access and sustainable innovation.

Kristi Shafer: The Tommy wholesale acquisition cost will be $2,425 for a 110 ml bottle. The average patient is projected to be approximately four and a half years old and weigh 16 kilograms. These age and weight estimates are based on our clinical experience in the Marigold trial, as well as additional market research. This translates to an average annual wholesale acquisition cost of approximately $133,000.

The Tommy wholesale acquisition cost will be $2425 for a 110 ml bottle.

The average patient is projected to be approximately four and a half years old and wait 16 kilograms. These.

These age and weight estimates are based on our clinical experience and the Marigold trial as well as additional market research.

This translates to an average annual wholesale acquisition cost of approximately $133000.

Kristi Shafer: Expected gross to net discounts, including mandatory government discounts are projected to be in the low 20% Importantly, we are committed to maintaining this price through the end of 2023. We believe taking this responsible, transparent approach, as well as working together with payers, providers, and patient advocacy organizations, we will help CDD patients benefit most from this critical medication in their treatment regimen. Pioneering therapeutic advances like Zotomi requires us to be equally innovative in offering customized access solutions to meet the many needs of our patients.

Expected gross to net discounts, including mandatory government discounts are projected to be in the low 20% range. Importantly, we are committed to maintaining net price through the end of 2023.

We believe taking this responsible transparent approach as well as working together with payer providers and patient advocacy organization.

Hum CBD patient benefit most from this critical medications in their treatment regimen.

Pioneering therapeutic advances like the Tommy requires us to be equally innovative and offering customized access solution to meet the many needs of our patients.

Kristi Shafer: To support the CDD community, Marinus plans to launch the Zotomi One program, a comprehensive patient services program to provide assistance with product access, ongoing support to patients, caregivers, and their medical team, and financial support to eligible patients. Our goal is to ensure patients have seamless access from prescription to fulfillment. These programs are expected to launch simultaneously with the commercial launch of Zotomi in July.

To support this ADB community Meredith plans to launch does the Tommy one program.

Comprehensive patient services program could provide assistance with product access ongoing support to patients caregivers and their medical team and financial support to eligible patients.

Our goal is to ensure patients have seamless access from prescription trade fulfillment.

These programs are expected to launch simultaneously with the commercial launch of the Tommy in July .

Kristi Shafer: Over the past several months, our Masset Access team has been actively engaging with government and commercial payers, as well as priority pharmacy benefit managers to raise awareness around the significant impact of seizures associated with CDD on patients, their families, and caregivers. With this approval, the team will be evolving those pre-approval information exchange presentations to include positioning of the PTALMY clinical economic value proposition for this CDD patient population. We will be onboarding a seasoned sales force of 16 representatives with deep epilepsy and rare disease experience for 16 geographies.

Over the past several months our market access team has been actively engaging with government and commercial payers as well as priority pharmacy benefit managers to raise awareness around the significant impact of seizures associated with feeding data on patients their families and caregivers.

With this approval the team will be evolving the tree approval information exchange presentation to include positioning of the Tommy clinical economic value proposition for this patient population.

We will be Onboarding, a seasoned sales force of 16 representatives with deep at Biloxi and rare disease experience for 16 geographies.

Kristi Shafer: These representatives will be joining the team between now and mid-April and we will use the next 90 days to bring them fully up to speed so they're ready to hit the ground running once we receive scheduling.

These represented ends will be joining the team between now and mid April and we will use the next 90 days to bring them fully up to speed. So they are ready to hit the ground running once we receive scheduling.

Kristi Shafer: Our initiatives will include driving healthcare provider awareness with a focus on eight distinct CBD centers of excellence and 40 key national epilepsy centers. Additionally, we will be supporting the transition of patients participating in the Marigold Open Label Extension. The U.S.

Our initiatives include driving health care provider awareness with a focus on eight distinct CBD centers of excellence and 40 K national epilepsy centers.

Additionally, we will be supporting the transition of patients participating in the Marigold open label extension.

Kristi Shafer: Expanded Access Program to Commercial Product and Treatment Initiation for New Patients. Our goal is to ensure comprehensive patient access and formulary coverage of the telomeres. Our efforts to secure near term access will be one of targeted payer and PBM segmentation and a coverage review process that will evolve over the next several quarters. We expect approximately 60% of the CDD patient population will access coverage through both fee-for-service and managed Medicaid, with the remaining 40% being managed commercially and the top PBMs covering the most U.S. lives.

The U S expanded access program to commercial product and treatment initiation for new patients.

Our goal is to ensure a comprehensive patient access and formulary coverage of the Tony.

Our efforts to secure near term access will be one of targeted payers and pbms segmentation and our coverage of our new process that will evolve over the next several quarters.

We expect approximately 60% of the CDB patient population will access coverage. They both fee for service and managed Medicaid with the remaining 40% being managed commercially and the top pbms covering the most U S lives.

Kristi Shafer: Our comprehensive marketing, advocacy, and educational plans include engagement with all payers and HCP stakeholders. Our initial priority will be on the 22 states that include the largest concentration of CDB patients and where the Centers of Excellence are located.

Our comprehensive marketing advocacy and educational plans include engagement with all Payors and HCP stakeholders.

Our initial priority will be on the 22 states that included the largest concentration of CBD patients and where the centers of excellence are located.

Kristi Shafer: We are excited about our first commercial launch, the strong foundation we've built, and what this approval means for the future of Marinus and the CBD community. We look forward to continuing to work with patients, caregivers, physicians, and payers over the coming months and providing you with updates on our progress over the coming quarters. I would like now to turn the call over to our CFO, Steve Pfanstiel, who will provide you with a financial update. Thanks Kristi and good morning to everyone.

We are excited about our first commercial launch the strong foundation, we've built and what this approval means for the future of Meredith and the CBD community we.

We look forward to continuing to work with patient caregiver.

And payers over the coming months and providing you with updates on our progress over the coming quarters.

I would like now to turn the call over to our CFO , Steve <unk>, who will provide you with a financial update.

Steve Pfanstiel: I am pleased to be able to share our financial results for the fourth quarter and full year 2021 as well as provide initial guidance for 2020. Before going into that, I'll first touch on the impact of the Priority Review Voucher and Oak Creek Credit Facility that Scott mentioned earlier. As a result of the approval for CDD, we were awarded a rare Pediatric Disease Priority Review Voucher. We intend to monetize the Priority Review Voucher, and we have seen recent voucher sales in excess of $100 million.

Thanks, Christy and good morning to everyone I am pleased to be able to share our financial results for the fourth quarter and full year 2021, as well as provide initial guidance for 2022.

For going into that I'll first touch on the impact of the priority review voucher and Oaktree credit facility that Scott mentioned earlier.

As a result of the approval for CVD, we were awarded a rare pediatric disease priority review voucher, we intend to monetize the priority review voucher and we have seen recent voucher sales in excess of $100 million.

Steve Pfanstiel: Additionally, with the approval of CDD, we are now eligible, through the end of 2022, to draw an additional $30 million of credit under our existing agreement with Oaktree Capital. We have previously drawn $45 million from the Oak Tree Credit Facility, and the agreement has the potential to provide up to a total of $125 million in funding through 2020.

Additionally, with the approval of <unk>, we are now eligible through the end of 2022 to draw an additional $30 million of credit under our existing agreement with Oaktree capital.

We have previously drawn $45 million from the Oaktree credit facility and the agreement has the potential to provide up to a total of $125 million in funding through 2023.

Steve Pfanstiel: We expect the PRV and Elk Creek facility to significantly bolster our balance sheet in the near term and fund our ongoing operations. These transactions are projected to extend our cash runway into the second half of 2022. I'll now move to our financial results. In 2021, we recognized revenues of $1.5 million and $15.3 million for the three-and-twelve months ended December 31, 2021, respectively, as compared to $1.5 million and $1.7 million in each of the same periods in the prior year.

We expect the PIV and Oaktree facility to significantly bolster our balance sheet in the near term and fund our ongoing operations.

These transactions are projected to extend our cash runway into the second half of 2023.

Steve Pfanstiel: These figures include BARDA revenues of $1.5 million and $6.4 million for the three-and-twelve months ended December 31, 2021, respectively, as compared to $1.5 million and $1.7 million in each of the same periods in the prior year. The 2021 revenue totals also include $9 million of revenue related to our licensing agreement with Orion. Total amount of $9 million was booked upon signing in Q3 2021.

I'll now move to our financial results.

In 2021, we recognized revenues of $1 5 million and $15 3 million for the three and 12 months ended December 31, 2021, respectively, as compared to $1 5 million and $1 $7 million in each of the same periods in the prior year.

These figures include BARDA revenues of $1 5 million and $6 4 million for the three and 12 months ended December 31, 2021, respectively as compared to $1 5 million and $1 7 million in each of the same periods in the prior year.

The 2021 revenue totals also include $9 million of revenue related to our licensing agreement with Orion.

Total amount of $9 million was booked upon signing in Q3 2021.

Steve Pfanstiel: Research and development expenses increased to $18 million and $73.5 million for the three and 12 months ended December 31, 2021, respectively, as compared to $13 million and $51.1 million for the same periods in the prior year. The change was due primarily to costs associated with increased R&D headcount, clinical trial activity including RSC and PSE, and drug development activities for both the oral and IV formulation. General and administrative expenses increased to $10.6 million and $37.3 million for the three-and-twelve months ended December 31, 2021, respectively, as compared to $6 million and $18.5 million for the same periods in the prior year.

Research and development expenses increased to $18 million and $73 5 million for the three and 12 months ended December 31, 2021, respectively, as compared to $13 million and $51 1 million for the same periods in the prior year.

The change was due primarily to costs associated with increased R&D head count clinical trial activity, including RSC and PSC and drug development activities for both the oral and IV formulations.

General and administrative expenses increased to $10 6 million and $37 3 million for the three and 12 months ended December 31, 2021, respectively, as compared to $6 million and $18 5 million for the same periods in the prior year.

Steve Pfanstiel: The primary drivers of the change were increased headcount in support for scale-up of the company's operations and commercialization preparations. For the full year 2021, total operating expenses inclusive of R&D and SG&A were $110.8 million, which was at the bottom of our guidance range of $111 to $116 million.

The primary drivers of the change were increased head count in support for scale up of the Companys operations and commercialization preparations.

For the full year 2021, total operating expenses inclusive of R&D and SG&A were $110 8 million, which was at the bottom of our guidance range of $111 million to $116 million.

Steve Pfanstiel: Separately, for the full year 2021, a one-time cost-up collaboration expense of 1.5 million was recorded related to our licensing agreement with Orion. Total amount was booked upon signing in Q3 2021. The company reported net losses of $28.3 million and $98.8 million for the three-and-twelve months ended December 31, 2021, respectively, as compared to net losses of $17.5 million and $67.5 million for the same periods in the prior year. These totals include non-cash stock-based compensation expense of $3 million and $13.9 million for the 3 and 12 months ended December 31, 2021, respectively, as compared to $2.1 million and $7.6 million for the same periods in the prior year. Cash used in operating activities was $55.5 million for the 12 months ended December 31, 2021 as compared to cash used in operating activities of $60.9 million for the same period in the prior year.

Separately for the full year 2021, a onetime cost of collaboration expense of $1 5 million was recorded related to our licensing agreement with Orion. This total amount was booked upon signing in Q3 2021.

The company reported net losses of $28 3 million and $98 8 million for the three and 12 months ended December 31, 2021, respectively as compared to net losses of $17 5 million and $67 5 million for the same periods in the prior year.

These totals include noncash stock based compensation expense of $3 million and $13 9 million for the three and 12 months ended December 31, 2021, respectively as compared to $2 1 million and $7 6 million for the same periods in the prior year.

Cash used in operating activities was $55 5 million for the 12 months ended December 31, 2021, as compared to cash used in operating activities of $60 9 million for the same period in the prior year.

Steve Pfanstiel: As a note, the 2021 operational cash flow figure includes the $29.6 million of upfront proceeds from the Orion Collaboration Agreement signed in 2021. As of the end of December 2021, we had cash and cash equivalents of $122.9 million. We believe this balance is sufficient to fund our operations and maintain the minimum cash balance required under our debt facility into the fourth quarter of 2022. As stated earlier, additional funds expected from the PRV and our Oak Creek credit facility are projected to extend our cash runway into the second half of 2020.

As a note the 2021 operational cash flow figure includes the $29 6 million of upfront proceeds from the Orion collaboration agreement signed in 2021.

As of the end of December 2021, we had cash and cash equivalents of $122 $9 million. We believe this balance is sufficient to fund our operations and maintain the minimum cash balance required under our debt facility into the fourth quarter of 2022.

As stated earlier additional funds expected from the <unk> and our <unk> credit facility are projected to extend our cash runway into the second half of 2023.

Steve Pfanstiel: For the fiscal year 2022, we are projecting BARDA revenues to be in the range of $7 to $10 million and our GAAP Operating Expense Estimate, inclusive of G&A and R&D expenses, to be in the range of $152 to $157 million, which includes approximately $17 million of non-cash, stock-based compensation.

For the fiscal year 2022, we are projecting barter revenues to be in the range of $7 million to $10 million and our GAAP operating expense estimate inclusive of G&A and R&D expenses to be in the range of $152 million to $157 million, which includes approximately $17 million of noncash stock based compensation.

Scott Braunstein: Now, I'll turn the call back to Scott, who will provide concluding remarks. Thanks, Steve. This is an extremely exciting time for our company, and we are hard at work to ensure seamless patient access to Zytomix. Additionally, we are pleased to announce that we have joined the Rare Disease Company Coalition and will be joining forces with other rare disease companies and the rare disease communities at large. Along with our partners, we plan to play an important role in establishing and implementing policies to accelerate access and adoption for patients and their families.

Now I will turn the call back to Scott, who will provide concluding remarks.

Steve This is an extremely exciting time for our company and we are hard at work to ensure seamless patient access to this Tommy. Additionally, we are pleased to announce that we have joined the rare disease company coalition and will be joining forces with other rare disease companies in the rare disease communities at large along.

And with our partners, we plan to play an important role in establishing and implementing policies to accelerate access and adoption for patients and their families.

Scott Braunstein: Before I turn the call over for questions, I want to take a moment to thank all those involved in making this approval a reality. This momentous achievement would not have been possible without the hard work of our dedicated Marinus employees, the support of CDB families, advocacy partners, regulators, and study investigators. We also thank our shareholders for their support and encouragement. This critical milestone, the FDA approval of the Ptolemy embodies what Marinus has built on and continues to drive our work every day. Commitment, community, and innovation.

Before I turn the call over for questions I want to take a moment to thank all those involved in making this approval a reality. This momentous achievement would not have been possible without the hard work of our dedicated marinus employees to support our CDB families.

<unk> partners regulators and study investigators we also thank our shareholders for their support and encouragement.

This critical milestone the FDA approval of the Tommy embodies what Marin. This was built on continues to drive our work everyday commitment community and innovation. We look forward to keeping you up to date on our commercial and regulatory progress and development milestones over the coming months operator can you now open the call.

Operator: We look forward to keeping you up to date on our commercial regulatory progress and development milestones over the coming months. Operator, can you now open the call to questions? Thank you. At this time, I would like to remind everyone that in order to ask a question, press star, then the number one on your telephone keypad. Your first question comes from Joseph Thome with Cohen and Company. Please go ahead. Hi there.

Two questions.

Thank you at this time I would like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad.

First question comes from Joseph Thome with Cowen and company. Please go ahead.

Scott Braunstein: Maybe first on Ptolemy, the launch: is it your sense that there's sort of a warehousing or bolus of patients that are ready to go on therapy once the therapy becomes commercially available? And then second on that, you emphasize that patients enrolled in a pivotal trial have seen about an average of seven AEDs for their disease. Now that there is a specific agent approved, where do you see the Ptolemy kind of falling in the treatment paradigm?

Hi, there good morning, Thank you for taking my questions and congratulations on the approval.

Maybe first on the Tommy the launch is it your sense that there's sort of a warehousing or bolus of patients that are ready to go on therapy once.

<unk> therapy becomes commercially available and then second on that you emphasized that patients enrolled in the pivotal trial has seen about an average of 780 <unk> or their disease. I guess now that there is a specific agent approved where do you see the tell me kind of.

Falling in the treatment paradigm do you think payers would still want some other AED tourist or could this be kind of a first or second line drug once the patients diagnosed with retail side. Thanks.

Scott Braunstein: Do you think PARES would still want some other AEDs first or could this be kind of a first or second line drug once a patient's diagnosed with CDTL5? Thanks. Thanks, Joe. And nice to hear from you this morning.

Joe Hulihan: Joe Hulihan, do you want to talk a little bit about what your expectation is for patients and when they're going to present for therapy? And then maybe we'll turn it over to Christy to talk a little bit about her expectations from the commercial. Oh, thanks. Hi, Joe.

Thanks, Joe and nice to hear from you. This morning, Joe who hand do you want to talk a little bit about what your expectation is for patients and when theyre going to present for therapy, and then maybe we'll turn it over to Kristy to talk a little bit about.

Her expectations from the commercial side.

Joe Hulihan: Yeah, I think that the study was done as an adjunctive study. So I'd anticipate, at least certainly not yet, it would be first line. They'll start in addition to other drugs. I know the commercial team has modeled, you know, the average age, not necessarily the number of prior drugs, but with the specific indication, I would anticipate fairly early, add on, but obviously we'll see. I don't think it would be the, I mean, this is just my clinical impression, it would be the sixth or seventh drug I'd expect to be earlier than that. But that's, you know, until it gets out there, you know, these things tend to start a little bit later and advance in the treatment sequence as time goes on. That is the new AD.

Thanks, Hi, Joe.

Yes, I think.

The study was done as an adjunct to study.

I would anticipate at least certainly not yet it would be first line they'll start in addition to other drugs.

The commercial team has modeled.

The average age not necessarily the number of prior drugs, but with the specific indication.

I would anticipate a fairly early.

Add on but obviously, we will see I don't think it would be the I mean this is just my clinical impression it would be the sixth or seventh drug unexpected would be earlier than that.

But that's.

Until it gets out there these things tend to start a little bit later and advance in the treatment sequence as time goes on.

That is the new <unk>.

Scott Braunstein: But maybe I'll turn it over to Kristi for, you know, her perspective. Christy, before you start, let me just give Joe some of the numbers, too, so he has a better sense from a warehouse perspective. Joe, just as a reminder, the clinical trial was 100 patients, and we opened that up to open-label extension.

But maybe I'll turn it over to Christopher.

Her perspective.

Christy before you start let me just give Joe some of the numbers too. So he has a better sense from a warehouse perspective, Joe just as a reminder, the the.

The clinical trial was a 100 patients we open that up to open label extension.

Scott Braunstein: And we've reported that we have about half of those patients still on drug. Remember, that was a global study, so about half of those patients are U.S.-based. So the number of patients in the Phase III clinical is now about, in the U.S. specifically, less than 25 patients. We haven't given the numbers for our EAP program, but those numbers are less.

And we've reported that we have about half of those patients still on drug remember that was a global study so.

About half of those patients are U S based so the <unk>.

Number of patients in the phase III clinical now about in the U S. Specifically less than 25 patients we havent given the numbers for our EAP program, but those numbers are less we have fewer patients in the EAP then the clinical trial trial program, we've talked to you in the past a little bit about the EAP and some.

Scott Braunstein: We have fewer patients in the EAP than the clinical trial program. We've talked to you in the past a little bit about the EAP and some of the difficulties we've had, the requirements for an IND, and the clinical requirements that were met, quite burdensome for particularly for small centers with a limited number of patients and during COVID that was difficult. So you shouldn't think about this being a disease state where there's a lot of a significant number of patients already on drug. But Christy, let me turn over to you for your expectations. Posted Salesforce and DEA, Yeah, thanks, Scott. And good morning, Joe.

The difficulties we've had the requirements for an IND.

The clinical requirements.

We're <unk>.

Quite burdensome for particularly for small centers with a limited number of patients and during COVID-19 that was difficult. So.

You Shouldnt think about this being a disease state where there is a lot.

A significant number of patients already on drug, but Christy let me turn it over to you for your expectations.

The sales force and DEA scheduling.

Kristi Shafer: Yeah, to the points that Joe and Scott have already made, the sales force will certainly be supporting the efforts of our clinical operations team to transfer those patients from our open label and EAP patients program, excuse me, over to commercial drug. However, because of the small number of patients, the ultra rare nature of the disease, we do not expect a traditional bullet of patients. Additionally, during this early period, without formulary and inclusion criteria present with payers, we will see a lot of off formulary medical necessity requests that will be worked through.

Yeah, Thanks, Scott and good morning, Joe yet to the point that Joe and Scott have already made the Salesforce world certainly be supporting the efforts of our clinical operations team to transfer those patients from our open label and EAP patients.

Program excuse me over to commercial drug however, because of the small number of patients the ultra rare nature of the disease, we do not expect a traditional bulletins patients. Additionally, during this early period without formulary and inclusion criteria present with pay.

Sure.

We will see a lot of off formulary medical necessity requests that will be worked through.

Kristi Shafer: Moving through prescription management, this will take a little bit of time in our early quarters, and we'll certainly have another bit of a ramp up period into 2023. Perfect, that's very helpful. Then maybe just one more quick one if I can.

Moving through the prescription management this will take a little bit of time, and our early quarters and you'll certainly have another bit of a ramp up period into 2023.

Perfect. That's very helpful. And then maybe just one more quick one if I can.

Scott Braunstein: On the second generation oral therapy, kind of what are you looking for in the phase one update mid-year to give you competence to go into the phase two for LGS? Is it really just safety in that you're hitting the predicted PK or is there anything else that you're looking for in that data set? Thanks. Yeah, it's got to take this one.

On the second generation oral therapy kind of what are you looking for in the phase one update mid year to give you a comprehensive go into the phase two for Lgs is it really just safety and.

Youre hitting the predicted PK or is there anything else that youre looking for in that data center.

Thanks.

Joe Hulihan: Yeah, no, we're looking for, yeah, it's mainly safety and, well, mainly P.K. and safety. The profile for the P.K. it looks good.

Yes.

I'd like to take this one.

No we're looking for.

Yes, it's mainly safety and what mainly PK and safety.

The profile for the PK it looks good.

And.

I think one of the main things we're looking for is consistency.

Joe Hulihan: And I think one of the main things we're looking for is consistency, in exposure. And I think that will be one of the main pharmacokinetic parameters we'll be looking at. And tolerability, you know, down the road, you know, there are a number of different profiles we can potentially look at.

In exposure.

And.

I think that will be one of the main pharmacokinetic parameters will be looking at.

And Tolerability down the road.

There are a number of different profiles, we can potentially.

Joe Hulihan: We have the prodrug in development. And one of the aspects of the prodrug is potentially, you know, blunting the C-max effect, and improving tolerability as well. But anyway, I think consistency is the main thing we're looking for. Consistency in delivery and improved bioavailability. I don't know, Scott, if you want to add anything to that. Thanks, Joe.

Look at we have the pro drug in development one of the aspects of the trove pro drug is potentially Lumpiness C. Max effect.

Improving tolerability as well.

But anyway I think consistency is the is the main thing we're looking for consistency in delivery and improve bioavailability.

Scott if you want to add anything to that.

Scott Braunstein: The only thing I'd add to that, Joe, is I think we have, and really this is Joe Hulihan's analysis from the Marigold study, we know where we want to go in terms of a clear therapeutic dose. And so what we see in the phase one study is really the first piece of the equation to then target blood levels in the phase two at 100 nanograms per ml, 150 nanograms per ml, and I think we'd like to be able to really test 200 nanograms per ml as a target blood concentration in patients.

Thanks, Joe the only thing I'd add to that Joe is I think we have and really this is Joe houlihan's analysis from from the Marigold study, we know where we want to go in terms of a clear therapeutic dose.

And so what we see in the Phase one studies is really the first piece of the equation to then target blood levels in the phase two.

100, nanograms per ml or 150 nanograms per ml and.

We'd like to be able to really test 200, nanograms per ml as a target blood counts and <unk> in patients. So.

Scott Braunstein: So, you know, to Joe Hulihan's earlier point, once we see that in the PK, the modeling itself and understanding the dosing should be relatively straightforward, right? I mean this program really benefits from all the work that we've done over the last three years to understand the target blood level concentration. Hopefully, that's going to allow us to really move quickly and see the signal we would expect not only in phase one, but in phase two. Perfect. Thank you, and congratulations again.

Joe Houlihan's earlier point.

Once we see that in the PK modeling itself and understanding the dosing should be relatively straightforward right. I mean this program really benefits from all the work that we've done over the last three years to understand the target blood level concentrations and hopefully that's going to allow us to really move quickly.

And see the signal, we would expect not only in phase one but in phase two as well.

Perfect. Thank you and congratulations again.

Thanks, Joe.

Scott Braunstein: Thanks, Joe. Your next question comes from Marc Goodman with SVB Larynx, please go ahead. Yes, good morning, Scott.

Your next question comes from Marc Goodman with SBB Leerink. Please go ahead.

Yeah.

Scott Braunstein: Can you talk about the RSC protocol amendments? And just give us an understanding of, you know, when you first mentioned this problem with the batches, you know, last month and where we are today, what have you figured out? And what is still yet to figure out as far as you know, your confidence in meeting this new timeline? Thanks. Well, let me start with the supply itself, and then maybe I'll turn to Joe for some of the minor protocol amendments that we made really towards the end of last year. From the supply side, we are very confident that we can use the current formulation.

Yes. Good morning, Scott can you talk about the RFC protocol amendments.

Just give us an understanding of when you first mentioned this.

Problem with with the batches.

Last month, and where we are today, what what have you figure it out.

And what is still yet to figure out as far as your confidence in meeting this new timeline. Thanks.

Well, let me start with the supply itself and then maybe I'll turn to Joe for some of the minor protocol amendments that we made really towards the end of last year from the supply side.

We are very confident that we can use the current formulation.

Scott Braunstein: We just have a shortened shelf life, so we have to manage that through the clinical trial. And now that we know that, that's relatively easy for us to manage. And certainly, I would hope as we reengage and the world is in a better place, and we have a meaningful number of sites up managing the, the, the, clinical supply itself will be less of an issue as we really kick off enrollment. So this is just a function, Marc, to get back into the clinic of of actually making a fresh batch. We originally thought that batch would take in order of three to four months, and we've been able to cut that down to now less than three months.

We just have a shorten shelf life. So we have to manage that through the clinical trial and now that we know that that's relatively easy for us to manage and certainly I would hope as we reengage in the world is in a better place and we have a meaningful number of sites up.

Managing the the <unk>.

Clinical supply itself will be less of an issue as we really kick off enrollment so.

This is just a function mark to get back into the clinic of of actually making a fresh batch. We originally thought that that would take in order of.

Three to four months and we've been able to cut that down to now less than three months in and potentially we're looking to do even better than that so that supply will be back in the clinic. The team is also really done an amazing job to figure out what the issue was in terms of this unusual buffer.

Scott Braunstein: And, you know, potentially, we're looking to do even better than that. So that supply will be back in the lab. The team has also really done an amazing job to figure out what the issue was in terms of this unusual buffer interaction with aluminum that's likely coming from the glass, is coming from the glass vial itself. We never saw this in the Phase 2 supply.

<unk> with aluminum that's likely coming from the glass is coming from the glass vial itself. We never saw this in the phase two supply that was a different glass vial.

Scott Braunstein: That was a different glass vial. So we can't say for sure whether this is a surface area issue or a difference in the glass vial. But this was a new problem we had not seen in the Phase 2. But what the team has already realized that if we change the buffer system, then we will not have this particulate formation.

So we can't say for sure whether this is a surface area issue or difference in the glass vial, but this was a new problem, we had not seen in the phase II, but what the team has already realized that if we changed buffer system. Then we will not have this particular formation.

Scott Braunstein: And so that work is already underway, we're looking at compatibility there, and we have every reason to believe that the new buffer system will be integrated in our new NDA batches over the second half of the summer. So I think we're technically on track for the supply, both in the short term and long term, and the team is really, you know, this is, this was unusual to us all, and I really am proud of how quickly the team has responded.

And so that work is already underway, we're looking at compatibility there and we have every reason to believe that the.

The new buffer system will be integrated in our new NDA batches over the second half of the summer so I didn't work.

Italy on track for the supply both in the short term and long term and the team is really this is this was unusual to us all and I really am proud of how quickly the team has responded.

Scott Braunstein: It's interesting, I had never seen this problem before in my career, Marc, and I think you may have all noticed that Gilead announced some unusual issues with NIV formulation soon after us, so certainly this does happen in the industry, but again, I'm very happy we caught it early and we can fix this both short term and long term, although it's obviously very frustrating from a trial standpoint, but happy that we're close to getting back on track. Maybe I'll turn to Joe for some of the minor protocol amendments that we added at year end, but before I turn it over to Joe, you know, I've said publicly, we've now done a series of advisory boards, and our clinicians unequivocally believe this trial is the right trial design, they believe they have a meaningful number of patients to enroll, very similar to our projections, three to four patients per year per site, and they're all enthusiastic about being a part of the trial, but there are certainly day-to-day issues that they've shared with us that, you know, we're looking to improve upon on the margin health enrollment, but Joe, do you want to talk about the amendments that we've already put in place? Sure, sure, Scott.

Interesting, we I had never seen this problem before in my career, Mark and I think you may have all noticed that gilead announce some unusual issues with an IV formulation soon after us so.

Certainly this does happen in the industry, but again I'm very happy we caught it early and we can fix this both short term and long term.

Although it's obviously very frustrating from a trial standpoint.

I believe that we're close to getting back on track.

Maybe I'll turn to Joe for some of the minor protocol amendments that we added at year end.

But before I turn it over to Joe what I've said publicly we've now done a series of advisory boards and our clinicians unequivocally believe this trial is the right trial design.

They believe they have.

A meaningful number of patients to enroll very similar to our projections three to four patients per year per site.

And they are all enthusiastic about being a part of the trial, but there are certainly day to day issues that they've shared with us that we're looking to improve upon.

The margin help enrollment, but Joe do you want to talk about the the amendments that we've already put in place.

Joe Hulihan: Yeah, I mean, as Scott said, we've spent a lot of time talking to investigators, one-on-one calls, and found some interesting things that, you know, every site has some different kind of standards of practice, and it's really individualized. I think it's taking a lot of contact and coaching with the sites. I think that's going to be a focus. The amendment we put in place at the end of last year addressed some of the key, you know, feedback we've gotten from the investigators, particularly off hours.

Sure Scott.

I mean as Scott said, we've spent a lot of time talking to investigators.

One on one calls and.

Found some interesting things there.

Every site has some different kind of standards.

Standards of practice, and it's really individualized I think it's taken a lot of contact and coaching with the sites I think thats going to be a focus.

The amendment, we've put in place at the end of last year.

Address some of the key.

Feedback, we've gotten from the investigators, particularly off hours.

Joe Hulihan: You know, admissions for status transfers from other hospitals, we're now allowing what's called rapid EEG to be used, not just for screening patients, but also for assessing the initial endpoint in the study at 30 minutes. That would allow, you know, getting an EEG overnight, which is, you know, critical to assessment of status and our 30-minute endpoint status cessation within 30 minutes, instead of having to have all the EEG texts come in, this rapid EEG can be placed, you know, with, it's just, it's called a hairline EEG with a limited electrode array and, We looked at some of the recordings from this and they're very good quality.

Admissions for status transfers from other hospitals.

We're now allowing.

What's called rapid EG to be used not just for screening patients, but also for assessing.

The initial endpoint in this study at 30 minutes.

That would allow you know getting an EEG overnight, which is critical to assessment.

Status and our 30 minute endpoint status cessation within 30 minutes.

Instead of having to have all of the <unk> come in.

This rapid EEG can replace.

With.

It's just it's called a hairline AEG with a limited electrode array and <unk>.

We looked at some of the recordings from this and they're very good quality.

Joe Hulihan: And so we think that's going to be important. We've reduced the burden on the investigators in terms of their data collection for the EEG. And so, you know, one thing about restarting the trial in May, it gives us the opportunity to re-gathered the investigators. The impact, the major impact by far was COVID.

And so we think that's going to be important we reduce the burden on the investigators in terms of their data.

Data collection for the G.

And so.

One thing about <unk>.

Restarting the trial in May.

Gives us the opportunity to you know.

Re gather the investigators the impact the major impact by far with Covid.

Joe Hulihan: And so we want to, you know, re-energize the investigators, hopefully be able to pull them together in a face-to-face meeting, and really, you know, get excitement around the trial now that they're coming out of the worst of COVID and really get the thing going again. And again, as I said, continue to be in touch with sites and educate and coach, and also keep the sites in touch with one another. The coordinators have a lot of best practices to share, so we're facilitating those contacts as well. Your next question comes from Joon Lee with Truce Securities. Please go ahead.

And so we want to.

Reenergize, the investigators hopefully be able to pull them together in a face to face meeting.

And really get it.

<unk> around the trial now that theyre coming out of the worst of Covid and really get the thing going again.

And again as I said continue to be in touch with sites and educate and coach and also keep the sites in touch with one another.

Coordinators have a lot of best practices to share. So we're facilitating those contacts as well.

Okay.

Thanks.

Your next question comes from Joon Lee with Truth Securities. Please go ahead.

Scott Braunstein: Hi, thanks for taking our questions and congrats on the approval of this DOMI. You know, on the IV program, were any of the RSC patients those with the material past the quote-unquote new exploration date given the unexpected shorter shelf life? And how much of this trial delay is CMC related as opposed to enrollment headwinds? Do you have any, for example, do you have any sites exposed to Eastern Europe, for example?

Hi, Thanks for taking our questions and congrats on the approval of the Tommy.

On the IV program, where any of the RSC patients dosed immaterial past.

New exploration date, given the unexpected shorter shelf.

Shelf shelf life and how much of this trial delays CMC related as opposed to enrollment headwinds do you have any for example, do you have any sites exposed to eastern Europe for example, and I have a follow up thank you.

Scott Braunstein: And I have a follow-up. Yeah, well, let me let me take a few pieces of it. And then I'll, I'll turn a little bit over to Joe as well. June, thanks for the question. So, for the RSE trial for raise. That trial has been only US, so Eastern Europe, and certainly the supply is primarily in the US. Our API comes from outside the US, we have several years of API supply on hand, and the actual manufacturing of the API to the IV solution is all done within the US.

Well, let me let me take a few piece of it and then I'll I'll turn a little bit over to Joe as well June thanks for the questions.

So for the RSV trial for raise that trial has been only U S. So eastern Europe and certainly the supply is is primarily.

In the U S. Our API comes from outside the U S. We have several years of API supply on hand, and the actual manufacturing of the API to the IV solution is all done within the U S.

Scott Braunstein: And you asked a little bit about the delay, and I would say we just built into our timelines about half of the delay due to COVID. What we really saw in Q1, which was this material spike in Omicron and ICU admissions peaking, many of our sites not being able to take transfers, that really derailed us in Q1 prior to us having this clinical supply issue. So my expectation is that if we do not see another variant that does unusual things to the hospital, then we should be in very strong shape moving forward.

And.

You asked a little bit about the delay and I would say, we just built into our timelines about half of the delayed due to COVID-19 .

What we really saw in Q1, which was this material spike in omnicom and ICU admissions are peaking many of our sites not being able to take transfers that really.

Derail does in Q1 prior to us having this clinical supply issue. So my expectation if we do not see another variant that does unusual things to the hospital then we should be in very strong shape moving forward.

Scott Braunstein: From a resource allocation standpoint, there are still some challenges with nurse coordinators leaving their posts and a shortage overall, but we certainly feel very good about where we are today in terms of the ICU itself. The particles, the safety issue, I'm going to turn it over to Joe, but just to put this in perspective, these particles are felt to generally be about the size of a red blood cell. So they're extremely small.

From a resource allocation standpoint, there are still some challenges with nurse coordinators, leaving their posts in a shortage overall, but but we certainly feel very good about where we are today in terms of the <unk>.

See you itself.

Particles the safety issue a bit of turn it over to Joe, but just to put this in perspective these particles.

Felt to generally be about the size of a red blood cell. So theyre extremely small so you know I put on my medical had.

Scott Braunstein: So I put on my medical hat and I think the risk of thromboembolic event is extremely small. These are for patients who are dosed with expired material, and Joe, maybe I'll turn it over to you just to talk about how we're going to give the FDA comfort on safety. Yeah, yeah, we've been very transparent with the FDA about about the particulate issue. We don't see any safety concerns in terms of the patients who received the drug.

I think the risk of thrombotic embolic event is extremely small there were patients who were dosed with expired material.

And Joe maybe I'll turn it over to you just to talk about how we're going to.

The FDA comfort on safety there.

Yeah.

Yes, we've been very transparent with the FDA about about the particular issue.

We don't see any safety concerns in terms of the patients who.

Received the drug of course, we're going back over the safety monitoring data obviously, but.

Scott Braunstein: Of course, you know, we're going back over the safety monitoring data, obviously, but we haven't seen anything to suggest that there's any safety issue with patients who've gotten the drug so far. So does that answer your questions? Yes, that's very helpful. I mean, I guess more pertinent for me were any expectations that potency might have declined as the particulates formed. Oh, let me take that, Joe.

They're there.

We haven't seen anything to suggest that there's any safety issue with patients who have gotten the drug so far.

<unk>.

So does that answer your question, yes, thats very helpful.

More pertinent for me was.

Any expectations that potency might have declined as the particulars form.

Joe Hulihan: Yeah, particulates are independent of either gonaxalone or captosol. So we feel very confident about the potency of the, And that Gnaxolone and, you know, Capsazole were in their normal state. This was purely a function of a metal leaching from the glass vial and bonding with a pipe. And because it was a metal, the particulate was, it was a bit of a glistening particulate.

Oh, no let me take that Joe.

Articulatory independent of either going to Exelon for Captisol. So.

We feel very confident about the potency of the drug.

That would be Max loan and Captisol were in their normal state. This was purely a function of.

Our metal leaching from the glass vial and bonding with a buffer.

And because it was the metal the particulate was it was a bit of a glistening particulate. So not sure I had it not been to metal that it ever would have been seen but but we feel very comfortable that an excellent itself was completely intact, Joe anything else you want to add.

Scott Braunstein: So, not sure had it not been a metal that it ever would have been seen, but we feel very comfortable that Canaxone itself was completely intact. Joe, anything else you want to add? No, no, just as you said, there's no reason to expect that there's been any decline in efficacy. And, you know, it's a blinded trial, but we haven't heard anything back from sites about any concern. Great.

No no just.

Just as you said that there's no reason to expect that there isn't any.

Decline in efficacy and.

It's a blinded trial, but we haven't heard anything back from sites about any concern.

Kristi Shafer: And the last question is, your average pricing of $133,000 per patient per year, if I heard that correctly, is materially above what we modeled. Just curious how the conversations with government and private payers have gone as you were preparing to launch, and how that must be reflective of that conversation. So, just any qualitatively, you know, anything you've heard from the payers on that. Thank you. Hi, Joon. This is Kristi.

Great.

The last question.

Average pricing of 133000 per patient per year, if I heard that correctly is materially above what we'd model.

Just curious.

How how the conversations with government and private payers have gone.

As you were preparing to launch and how.

Must be reflective of that.

Conversation, so just any qualitatively.

Anything you've heard from the payers on that thank you.

Okay.

Kristi Shafer: I'd be happy to take that. We started a really deep pricing research project early last year that, quite frankly, suggested we had really significant flexibility and could have priced significantly upwards of where we finally landed. But we felt it really necessary to take a responsible patient-centric approach that reduced the hurdles and supported a smooth access to care. So I hope that you'll feel that that research with both payers and physicians and advocacy groups really support where we've landed. I'll also note that this is completely in line with other anti-epileptics that have come to market most recently. Thank you. And congrats again on the approval. Thank you. Thanks. Thanks, Joon.

Hi, Jan this is christiana I'd be happy to take that.

We started a really deep pricing research project early last year that quite frankly suggested we had really significant flexibility and could have price significantly upwards of why are we finally landed.

But we felt it really necessary to take a responsible patient centric approach and that reduced the hurdles and supported estimated access to care and so I hope that youll feel that.

That research with the payers and physicians and advocacy groups really support where we planned. It I'll also note that this is completely in line with other anti epileptics that have come to market next recently.

Thank you and congrats again on the approval. Thank you.

Thanks June I appreciate your support.

Scott Braunstein: Appreciate your support. Your next question comes from Douglas Tsao with HC Wainwright, please go ahead. Hi, good morning, thanks for taking the questions.

Your next question comes from Douglas Tsao with H C. Wainwright. Please go ahead.

Scott Braunstein: I think in the Marigold study, patients were on between one to four other anti-epileptics. I'm just curious, you know, from your perspective in the early going, where do you think Zotami will sort of fit in, in terms of sort of being used as an adjunctive therapy? And is there sort of a message that you're going to sort of try to relay to clinicians about where Zotami should fit in within the treatment paradigm? And obviously, it's very differentiated.

Hi, good morning, Thanks for taking the questions I think in the.

Marigold study patients were on between one to four other.

Anti epileptics I'm just curious.

From your perspective, and the early go away, where do you think it's autonomy will sort of fit in in terms of sort of being used as an adjunct to therapy and is there sort of a message that youre going to sort of try to relate to clinicians about where the Tommy should fit in.

Within the treatment paradigm and obviously, it's very differentiated as the only one with the labeled indications for CBD. Thank you.

Okay.

Scott Braunstein: It's the only one with the labeled indication for CDD. Thank you. Doug, I'll kick it off and then I'll maybe turn it over to Joe and Kristi.

Doug Let me kick it off and then I'll, maybe turn it over to Joan Christy So you'll remember because <unk> is such a significant neurological disorder. These kids are all all presenting before the age of one with their seizures and or behavioral neuro cognitive deficits and so as a result of that and.

Scott Braunstein: So, you know, remember, because CDD is such a significant neurological disorder, these kids are all presenting before the age of one with either seizures and or behavioral neurocognitive deficits. And so as a result of that and really effectively universal genetic testing, the vast majority are diagnosed before the age of one. The literature is also crystal clear that these kids tend to fail every anti-epileptic and have less than a 15 percent one five responder rate over the course of one year.

Really effectively universal genetic testing the vast majority are diagnosed before the age of one the literatures also crystal clear that these kids tend to fail every anti epileptic and and have less than a 15% one five responder rate over the course of one year.

So very consistent with our phase III trial, our expectation would be fairly by the age of two at a time that our label.

Scott Braunstein: So very consistent with our phase three trial, our expectation would be really by the age of two, by the time that our label is indicated, that these kids would have already failed two, three, four different medications. And so my view, our current label is very appropriate in terms of when we would expect these kids to not only get diagnosed, not only stay on local therapies, but to have already been to either one of the eight centers of excellence or the 40 or 50 larger sites or a pediatric epileptologist who's really going to be caring for a more refractory patient.

As indicated that these kids would have already failed 234 different medications and so my view of this.

Our current label is very appropriate in terms of when we would expect these kids not only get diagnosed done only scale local therapies, but two have already been to either one of the eight centers of excellence, where the 40 or 50 larger sites or.

A pediatric epilepsy apologists who's really.

Going to be carrying for a more refractory patients.

Scott Braunstein: And let's not also forget that the CDK Alliance and the other alliance groups that work with the CDK families are very active and also a big supporter and helpful in giving advice to families. So, maybe I'll stop there.

Let's not also forget that the CDK Alliance and the other alliance groups that work with the CD with CDK families are very active and also a big supporter of Av.

<unk>.

Helpful and giving advice to families. So.

Joe Hulihan: Joe, anything you want to add on the treatment paradigm before we turn over to Christy? Yeah, you know, I just, we've talked about the double blind data, you know, they had a, the patient had a 30.7% reduction in seizures. The patients who stayed on it for at least a year that that reduction was 49.6%.

Maybe I'll stop there Joe anything you want to add on the treatment paradigm before we turn it over to Christie.

I just.

We've talked about the double blind data.

The patient has had a 37% reduction in seizures the.

Ah patients who stayed on it for at least a year that reduction was 49, 6%. So just about half the patients.

Or just about 50% reduction.

We will be presenting the data in more detail.

Joe Hulihan: So just about half the patients, are just about, you know, 50% reduction. And we will be presenting the data in more detail. But patients who have stayed on the drug appear to do very well. One of the things about the disorder that's, The patients have a honeymoon period with the drugs. They start on the drug and they tend to have a very limited duration of after-care. So I think.

But patients who have stayed on the drug appeared to do very well one of the things about the disorder.

It's.

Kind of specific to this condition is the patients have a honeymoon period with the drugs they start on the drug.

Tend to have a very limited duration of efficacy.

I think.

Joe Hulihan: You know, I said that these drugs start at a certain point in the treatment sequence in advance. I think the initial clinical response that the physician see, hopefully, you know, they'll see a good response. And if we see durability of response, that's going to be important. And I think that would drive advancing the treatment sequence. But maybe I'll turn it over to Kristi, see if you have any comments.

You said that these drugs start at a certain point in the treatment sequence in advance I think the initial clinical response that the physicians see hopefully.

They'll see a good response and if we see durability of response, that's going to be important.

And I think that would drive advance in the treatment sequence.

Maybe I'll turn it over to Kristy, if you have any comments.

Okay.

Kristi Shafer: Yeah, from a commercial perspective, we're really thinking about a few things of how we can get patients smooth access to care. And how we've modeled this is really thinking about the prior authorization process and what that will look like. We fully expect that we will need a genetic test for care, and we have fully modeled this out, and we'll have education surrounding that, and certainly surrounding the ICD-10 code. But also just thinking about inclusion criteria failing to prior anti-epileptics. So, those being the two major hurdles, looking at Marigold, we think that, you know, kids at the age of two years old will have quite a significant opportunity to get on drugs.

Yeah from a commercial perspective.

We're really thinking about a few things.

How we can get patients.

You may access to care and how we've modeled that is really thinking about the prior authorization process and what that will look like are we fully expect that we will need a genetic test to four for cure and we have modeled this out and will have education surrounding that and certainly surrounding the.

<unk> 10 code.

But also just thinking about inclusion criteria is failing to prior anti epileptics. So those being the two major hurdles and looking at Marigold, We think that you know.

We can't at the age of two years old will have quite a significant opportunity to get on drug I'm looking that our our marigold patients had failed medications by the time. They got until act genetic tests, which is widely available and utilized right now and failing.

Kristi Shafer: Looking that our Marigold patients had failed six, seven medications by the time they had gotten to us, a genetic test, which is widely available and utilized right now, and failing to anti-epileptics, we believe most two-year-olds will be available for drugs. Okay, great. And if I can ask a follow up on the prodrug, I think, Scott, you indicated, You have potential project candidates for both the oral as well as IV. I'm just curious from the IV standpoint, would that be utilized?

Two anti epileptics, we believe most two year olds will be available for a drug.

Yeah.

Okay, great and if I can ask a follow up.

On the pro drug I think Scott you indicated.

You have potential drug candidates for both the oral as well as IV I'm just curious from the IV standpoint would that be utilized is that something that you think about for the sort of status program or is that something that could be brought into new indications. Thank you.

Scott Braunstein: Is that something that you think about for the sort of status program, or is that something that could be broadened to new indications? Thank you. Thanks, Doug. I would say our focus would be on the status program first and foremost. Captozol is great that it makes Gonaxole soluble, but it has limitations.

Thanks, Doug.

I would say our focus would be on the status program first and foremost.

Scott Braunstein: We certainly are limited in the daily dosing. Today, the FDA really allows us as a company to use 50 grams of captozol over 24 hours. So that's our 830 milligram dose in the phase three RSC trial. Physicians have done EINDs in super refractory status and are treating upwards of 1,000 milligrams of Gonaxolone, which is about 63 grams of captozol.

Captisol is great that it makes good excellent soluble but it has limitations. We certainly are limited in the daily dosing somewhere between you know today. The FDA really allows us as a company to use 50 grams of Captisol over 24 hours. So that's our.

830 milligram dose in the phase III RSV trial physicians have done E. Indeed in Super refractory status and are treating upwards of a thousand.

Milligrams of <unk> ex loan, which is about 63 grams of Captisol, but we've never ask the FDA for that and so I think when we think about the super refractory market in particular higher doses of <unk> could be quite meaningful and beneficial for those patients. So I would say first and foremost.

Scott Braunstein: But we've never asked the FDA for that. And so I think when we think about the super refractory market in particular, higher doses of Ganaxone could be quite meaningful and beneficial for those. So I would say first and foremost, that's where I'd like to see us go.

That's where.

I'd like to see Us go.

Scott Braunstein: Certainly, once we had a new formulation, we could use it for the entire franchise, and that would have potentially long-term financial benefits for us as well, thinking about that 3% to 5% royalty rate that we would pay LIGAND over time. And the third piece I would say is, theoretically, captosol slightly slows the ganaxalin going to the brain. Now, you see very high blood concentrations very quickly, but theoretically, a ganaxalin product without captosol may actually get to the brain quicker, may increase the opportunities for us to use it in other settings.

Certainly once we had a new formulation, we could use it for the entire franchise and that would have potentially long term financial benefit for us as well.

Thinking about that 3% to 5% royalty rate that we would pay like it overtime.

And the third piece I would say is theoretically.

Captisol slightly slows the.

<unk> go into the brain now you see very high blood concentrations very quickly, but theoretically a good Axel <unk> excellent product without Captisol may actually get to the brain quicker maybe may increase the opportunities for us to use it in other settings.

Scott Braunstein: We know that BARDA, as an example, is very interested in IM formulation. So it creates a lot of opportunities for us to do some different things, and we think it's a really interesting program. I'll just jump back on the first pro-drug program, as Joe mentioned. We weren't planning it, but what we've seen is this really nice, blunted CMAG.

We know that part of.

As an example, very interested in I am formulation so.

It creates a lot of opportunities for us to do some some different things.

And we think it's a really interesting program I'll just jump back on the first pro drug program as Joe mentioned, we Werent planning it but what we've seen is just really nice blunted C. Max and I think that really creates a unique opportunity for 24 hour dosing and the ability to use.

Scott Braunstein: And I think that really creates a unique opportunity for 24-hour dosing and the ability to use in other therapeutic disease states that require chronic dosing. So we'll be keeping a close eye on how this class of drugs work in other disorders, but I think we've talked about not committing to other programs until we really felt like we had the right candidate. And right now I'm pretty excited about this, the first pro-drug program for newer opportunities on the oral. So, let me stop there.

As in other therapeutic disease states that require chronic dosing, so we'll be keeping a close eye on how.

This class of drugs work in other disorders, but I think we we've talked about not committing to other programs until we really felt like we had the right candidate and right now I'm pretty excited about this that the first pro drug program for our newer opportunities on the oral side.

So let me stop there.

Okay, great. Thank you.

Scott Braunstein: Okay, great. Thank you. Your next question comes from Andrew Tsai, with Jeffries, please go ahead. Okay, thanks.

Your next question comes from Andrew Cheng.

With Jefferies. Please go ahead.

Scott Braunstein: Good morning, congrats on the approval. So I kind of want to take a step back on CDD and kind of get your sense on how that label itself compared to your expectations. Was it, you know, better in line or worse?

Okay. Thanks, good morning, congrats on the approval.

So I just kind of wanted to take a step back on CDT and kind of get your sense on how the label itself compared to your expectations and was it better in line or worse, and then secondarily I'm curious how you guys are thinking about patient adoption by age group because you technically have a label.

Joe Hulihan: And then secondarily, you know, I'm curious how you guys are thinking about, you know, patient adoption by age group, because you technically have a label for patients older than two years old. My understanding there is an adult prevalence. So curious if you're going to be marketing into the adult group setting. Joe or Kim, do you want to talk about the label?

Four patients older than two years old now my understanding there is an adult prevalence. So curious if youre going to be marketing into that auto group setting as well.

Okay.

Joe Hulihan: And then I'll turn it over to Kristin. Thank you, we'll start. Sure. So I think the label actually, we were very pleased with the label that we ended up with. I think it was, Better than we anticipated, but I think it reflects the quality of the study and the work that was done. So I think it was, shared the FDA's collaboration with us moving forward and I think it's, We're very pleased with the label. Yeah, I mean, I've, I was pleased as well.

Joe or Kim do you want to talk about the label and then I'll turn it over to Christie.

Tim do you want to start.

Sure.

I think the label actually we're very pleased with the label that we ended up with I think.

It was.

Better than we anticipated, but I think it reflects the quality of the study and the work that was done.

So I think it was.

It shows the update corporation with Us before and I think we're very pleased with the label.

Yes.

Kimberly McCormick: I think, as Kim mentioned, we've had very transparent and productive discussions with the FDA all the way along, and, um, I think it's a very solid label and we're very pleased. Chris, do you want to talk about the market opportunity? Sure. It's a great question, Andrew.

I was pleased as well I think as Ken mentioned, we've had very transparent.

Transparent and productive discussions with the FDA all the way along.

And.

I think it's a very solid label.

And we're very pleased.

Chris do you want to talk about the market opportunity.

Kristi Shafer: And we've talked a lot about the pediatric versus adult population. There's obviously going to be a prevalence of adult patients in the United States. But I'll remind you that genetic testing has only become really widely available and adopted in the past six to seven years. So the diagnostic rate in the adult population is gonna be quite low. We also anticipate that a lot of the adult patients, although they may not be diagnosed with CDKL5 deficiency disorder, they'll also potentially be in a long-term care facility setting, which creates another host of challenges for a commercial team to address those patients.

Sure.

It's a great question, Andrew and we we've talked a lot about the.

The pediatric versus adult population there, there's obviously going to be a prevalence of adult patients in the United States.

But I'll remind you that genetic testing has only they can really widely available and adopted in the past six to seven years.

The diagnostic rate in the adult population is going to be quite low.

Also anticipate that a lot of the adult patients, although they may not be diagnosed with <unk> deficiency disorder, now also potentially being a long term care facilities studying.

Which creates another host.

Challenges for our commercial team to address those patients.

Kristi Shafer: The pediatric patients, again, will be treated in, you know, predominantly in the eight CDD centers of excellence across the United States, as well as the 40 largest epilepsy centers across the United States. And again, they have a really clear line of treatment and diagnostic rates in the pediatric population. As these patients age, that will change, and we will certainly address older teenage patients. And as they age out into the, you know, the adult epilepsy community. But today, we believe that most diagnostic rates and treatment centers are going to be surrounded around the pediatric. Thanks, Chrissy.

P D accurate patient again will be traded and.

Predominantly in the H D D D centers of excellence across the United States as well as the 40 largest.

Epilepsy centers across the United States and again, they have a really clear line of treatment and diagnostic rates in the pediatric population as these patients age that will that will change and we will certainly address older teenage patients and as they age out into the entity the adult.

And our celebrity community, but today, we believe that most diagnostic rate and treatment centers opening piece around there around the pediatric patients.

Scott Braunstein: Andrew, the only thing I'll add is, you know, we're thrilled that the label is two and above, which means we could dose adult patients. And certainly our data from the phase three marital certainly suggests that as the children in the study and teenagers who are higher weight, we saw equal efficacy so that that's not an issue. But we've always guided the investment community to not 5,000 CDD patients in the U.S., but the 2,000 patients that we really see from age two to twenty one. Right.

Thanks, Chris here, Andrew the only thing I'll add is.

We're thrilled that the label is two and above which means we could.

Dose adult patients and certainly our data from the phase III <unk> certainly suggests that as the <unk>. The children in the study and teenagers who are higher weight, we saw equal efficacy. So that that's not an issue.

But we've always guided the investment community to not 5000 TDD patients in the U S. But the 2000 patients that we really see from age two to 'twenty one right, that's where we're going to start that being said, we've had one or two patients from an EAP perspective that were young adults that investigators are interested and intrigued.

Scott Braunstein: That's where we're going to start. That being said, we've had one or two patients from an EAP perspective that were young adults that investigators were interested in treating. And this is the first treatment for the seizures associated with CDKL5 deficiency.

Scott Braunstein: And so, you know, that could change over time. I would just caution our experience or our observation from watching other companies go into the adult population. It's complex because so many of those patients are in chronic care facilities. They're harder to capture.

And this is the first treatment in <unk> and for the.

Seizures associated with <unk> deficiency and so.

That could change over time.

I would just caution or experience or our observation from watching other companies go into the adult population. It's complex because so many of those patients are in chronic care facilities. They are harder to capture there hasnt been genetic testing. So those are the pushes and pulls on how we're thinking of.

Scott Braunstein: There hasn't been genetic testing. So those are the pushes and pulls on how we're thinking off the bat. But my hope would be from an investigator sponsored standpoint, we'd have the opportunity to treat young adults over the age of twenty one, publish some additional data on the efficacy. And we are quite committed to an active investigator sponsored program. So as investigators reach out to us and share their interests with us, we've budgeted resources to help support them with their pursuit of additional research. Got it.

But my hope would be from an investigator sponsored standpoint, we'd have the opportunity to treat young adults over the age of 21 published additional data on the efficacy and we are quite committed to an active investigator sponsored program. So as investigators reach out to us.

And share their interests with us.

We budgeted resources to help support them with their their pursuit of additional research efforts.

Scott Braunstein: Thanks. And thanks for calling in. Will prescriptions be trackable on iQIYI or Symfony?

Got it thanks, and thanks for the color and we'll prescriptions be trackable on Ikea or Symphony.

Scott Braunstein: I think the answer is going to be no, because we're going to have a single specialty district. Thank you guys. Your next question comes from Jay Olsen with Oppenheimer. Please go ahead.

I think the answer is going to be no because we're going to have a single specialty distributor.

Very good. Thank you guys. Thank you.

Your next question comes from Jay Olson with Oppenheimer. Please go ahead.

Joe Hulihan: Oh, hey, congrats on the Zotelme approval and thank you for the updates. You had a number of abstracts at the AES meeting back in December. What kind of feedback have you received from physicians in response to that data? And what are your plans for additional presentations and CME programs at medical meetings this year? And then I had a follow up, if I could, please. This is Joe.

Oh, Hey, Congrats on these are telling me approval and thank you for the update.

You had a number of abstracts at the Aes meeting back in December what kind of feedback have you received from physicians in response to that data and what are your plans for additional presentations and CME programs at medical meetings. This year and then I had a follow up if I could please.

Okay.

Joe Hulihan: We're going to have a good presence at the medical meetings. We have two platform presentations at the American Academy of Neurology meeting, coming up in April. We'll be submitting abstracts to American Epilepsy Society, Neurocritical Care Society. Child Neurology Society meetings, as well as the International Epilepsy Congress happening, in Geneva.

Sure. Yes. This is Joe we.

We're going to have a good presence at the medical meetings, we have two platform presentations at the American Academy of Neurology meeting.

Coming up in April .

We'll see.

We will be submitting abstracts to American epilepsy Society of Neuro critical care Society.

Child, Neurology society meetings as well as the international Epilepsy Congress happening.

Geneva.

Joe Hulihan: So we're going to have a good presence at meetings. Feedback on the posters has been very positive. I think that, you know, one thing we mentioned in our comments is that the primary manuscript from the, Marigold study we anticipate having that in print quite soon so we're particularly excited about that but no we've gotten positive feedback at all the meetings both American Epilepsy Society and as I mentioned last year the Neurocritical Care Society and the Child Neurology Society one thing at the American Epilepsy Society we had a chance to interact with, Quite a few of the investigators in the RAYS study and other neurocritical care specialists and neurologists interested in status epilepticus. So it was an extremely productive meeting. Great, thank you. And then, can you walk us through the rationale behind the OVID agreement and how that fits with your Orion partnership? Is there any overlap?

So we're going to have a good presence at meetings.

Feedback on the posters has been very positive.

One thing we mentioned in our comments is that the primary manuscript from the.

Marigold study, we anticipate having that in print.

Quite soon.

So we're we're particularly excited about that but no we've gotten positive feedback in all the meetings.

Netflix side and as I mentioned last year, the neuro critical care Society, and the child Neurology Society, one thing at the American Epilepsy Society, we have a chance to interact with quite.

Quite a few of the investigators and you raise study.

<unk> and other.

Neuro critical care specialists and neurologists.

Interested in status epilepticus. So it was an extremely productive meeting.

Scott Braunstein: And finally, what is your estimated valuation for the PRV and timeline for monetizing that? Steve, do you want to take it, or do you want me to give a little background on OBIT, or you're good to go? Yeah, Scott, if you want to touch on AVA and give background, I'll jump on the PRV next. Yeah, so Joe, as a reminder, the folks at OVID filed patents on the use of CDD, of gonaxalin and CDKL5 deficiency disorder.

Great. Thank you and then can you walk us through the rationale behind the <unk> agreement and how that fits with your Orion partnership or is there any overlap and finally, what is your estimated valuation for the P. R V and timeline for monetizing that.

Steve you want to take it or you want me to give a little background on all of it or you're good to go Yeah. Scott Scott do you want to touch on oven get background I'll jump on the <unk> next year.

Scott Braunstein: And those patents were filed before the current management team, was involved in the company. And, you know, we really learned of this serendipitously when those patents were granted. We certainly believe that both we and Ovid want to make sure that Canaxilone gets to patients who suffer from this disorder. And we wanted to make sure that there was no potential risk for the company around the launch. I think Ovid was very reasonable in their request for the value of those patents.

Yeah.

So Joe as a reminder, the folks at <unk> are filed patents on the use of CBD.

Excellent and CDK <unk> deficiency disorder.

And those patents were filed before the current management team.

He was involved in the company and we really learned of this serendipitously when those patents were granted.

We certainly believe that both we and others want to make sure that can ask loan gets to patients who suffer from this disorder.

And we wanted to make sure that there was no potential risk for the company around the launch and then Ahmed was very low.

Scott Braunstein: And we certainly think that we've now in-licensed a new patent for the use of Canaxilone in CDKL5 deficiency disorder. So it's very nice to have a method of use patent that takes this franchise to 2038. We're going to use that as one of several really new findings that we've seen. And we've talked publicly that we really believe that our oral franchise has much greater support than in the past. And this has really little interaction with and little to do with Orion. That being said, Ovid did file these patents in Europe, and we wanted to in-license these patents so there would be no risk for our commercial partner in Europe.

Reasonable and in their request for the value of those patents and we certainly think that we have now in license a new patent for the use of <unk> and CDK Alpha deficiency disorder. So very nice to have a method of use patent that takes this franchise to 2038, we're going to use that.

As one of several really new findings that we've seen and we've talked publicly that we really believe that our oral franchise has much greater support than in the past.

And this has really little interaction with little to do with Orion that being said Amit did file these patents in Europe and we wanted to in license. These patents so there'll be no risk for our commercial partner in Europe .

Scott Braunstein: Steve, do you want to take from there, here? Yeah, Jay, you know, happy to jump in and talk about the PRV, you know, just as a reminder, because it was because of the rare PDAT disease designation for CDD that we received the PRV, that was issued as a part of the approval last week, we've been very clear. We're moving forward with, you know, monetizing that PRV. Really, these are a commoditized product.

Steve do you want to take it from there here.

Steve Pfanstiel: The process to sell these is pretty well known; transactions happen pretty regularly. We've seen a lot of these happen over the past few months. I wouldn't anticipate we connect with an execution agreement in Q2. There is a potential for a 30-day HR review; it depends on the kind of the parties involved and the amount.

Yeah, Jay happy to jump in and talk about the priv.

Just as a reminder, because it was because of the rare pediatric disease designation for CVD that we received the <unk> that was issued as a part of the approval last week.

We've been very clear, we're moving forward with monetizing that PRP.

Really these are commoditized product process to Saudis is pretty well known transactions happened pretty regularly we've seen a lot of these happened over the past few months.

Steve Pfanstiel: But all the recent transactions we've seen say over the past 12 to 15 months have been in the 100 to 110 million range. At the end of the day, it will be a supply and demand question, but you know, that's where recent transactions have been. Super helpful. Thanks for taking the question. Thanks, Jay. Your next question comes from Brian Skorney with Baird. Please go ahead. Hey, good morning, everyone.

Anticipate we can execute an agreement in Q2 there.

There is a potential for a 30 day HSR review it depends on kind of the parties involved and the amount, but all the recent transactions we've seen say over the past call. It 12 to 15 months had been in the $100 million to $110 million range at the end of the day it'll be a supply and demand question, but you know that's that's where our recent transactions have been.

Super helpful. Thanks for taking the questions.

Thanks Jay.

Your next question comes from Brian Kearney with Baird. Please go ahead.

Scott Braunstein: And let me offer up my congrats for the approval as well. Two questions for me, I guess, as we kind of think through pricing in our models. As kids are titrated up, how many children wind up reaching and staying at the maximum dose for their weight in the studies? And then my second question is, it seems like the RAISE restart might be running a little bit ahead of schedule, but maybe the RAISE-2 initiation seems delayed beyond the six-month delay you had discussed last month.

Hey, good morning, everyone and let me offer my congrats for the approval as well two questions for me I guess as we can.

And a think through pricing.

In our models.

As kids were titrated up how many children windup, reaching and staying at the maximum dose for their weight in the studies.

Scott Braunstein: Just wondering what the gating factor is on RAISE-2. Is this just limited to the supply issues, too, or is part of this delay related to European clinical trial site issues? Let me take the raise questions and then I'll pass it over to Steve for the first question.

Then my second question is it seems like the raise restart might be running a little bit ahead of schedule, but maybe the raise to initiation seems delayed beyond the six months delay you had discussed last month, just wondering what the gating factor is on phase. Two is this just limit it to the supply issues to her as part of the story related to European clinical trial site issues.

Let me take the reins questions and then I'll pass it over to Steve.

<unk>.

For the first question. So yeah, we are running.

Scott Braunstein: So, yeah, we are running ahead of our initial expectations for raise. And again, my hope, Brian, is the sooner we get that trial up and running again, the less risk we have of losing momentum from study investigators and excitement about the study. I was certainly worried that if we didn't have supply until July, we'd be rebooting from the get go. And so I'm pretty excited now, knowing that we're going to have supply back in May, that we will not lose that enthusiasm in the trial. And we're still interacting with the sites pretty actively.

Ahead of our initial expectation for res and again my hope Brian is the sooner we get that trial up and running again, the less risk we have of losing momentum from study investigators and excitement about the study I was certainly worried that if we didn't have supply until July we'd be rebooting.

You know from the get go and so I'm pretty excited now knowing that we're going to have supply back in may that we will not lose that enthusiasm in the trial and we're still interacting with the sites pretty actively and we're going to hold a new round of investigator meetings as well to really reboot. The U S study.

Scott Braunstein: And we're going to hold a new round of investigator meetings as well to really reboot the U.S. study. We wanted to make sure, particularly as we have to worry about the limitations of the current supply in terms of the shelf life, it would be much easier to execute a study with a product with longer shelf life. And so we expect that longer shelf life product to be coming out of our new batches in the fall.

We just we wanted to make sure, particularly as we have to worry about the limitations of the current supply and in terms of the shelf life. It would be much easier to execute a study with the product with longer shelf life, and so we expect that longer shelf life product to be coming out of our new batch.

As in the fall and so we're going to use our new batch material for raise too and that naturally just pushed the timelines out an extra quarter in terms of.

Creating the Cta in the NPD for the European study. So it was really just a timing issue. So that we could use new supply for a race to win.

Scott Braunstein: And so we're going to use our new batch material for a raise too. And that naturally just pushed the timelines out an extra quarter in terms of creating the CTA and the INPD for the European study. So it was really just a timing issue so that we could use new supply for a raise too, which we think will just make that study run significantly smoother and less concerned on the supply side. Let me turn it over to Steve for your first question. Hey, good morning, Brian.

Which which we think will just make that study runs significantly smoother.

And less concerned on the supply side, let me turn it over to Steve for your first question.

Steve Pfanstiel: So yeah, I'll give a little color on kind of the age dynamics here. I mean, as we look at this, we think the, you know, the initial kind of patients will be in this two to seven range. That's why we've been saying kind of this four and a half on, you know, age on average. We saw it in Marigold being a median of six, average of around seven years old.

Hey, good morning, Brian So yeah, I'll give a little color on kind of the the age dynamics here I mean, as we look at this we think the you know the initial kind of patients will be in this 2% to seven range. That's why we've been saying kind of this four and a half on age on average.

We saw it in Marigold being a median of six average of around seven years old.

Weight based dosing is obviously a part of what we have here. So we've we said hey, it about four and a half years old that's around 16 kilograms.

Steve Pfanstiel: Weight-based dosing is obviously, you know, a part of what we have here. So we've said, hey, at about four and a half years old, that's around 16 kilograms. The actual kind of max weight based on the dosing is actually at 28 kilograms, which is a little over 11 years old.

The actual kind of Max weight based on you know the the dosing is actually a 28 kilograms, which is a little over 11 years old.

Steve Pfanstiel: So we would expect over time, as patients are on this chronically, that 4.5-year-old average will shift up. But I wouldn't expect we're going to have a majority of patients over that 11, 12-year-old as we're always bringing on younger 2, 3-year-olds in. So it's kind of hard to predict what percent will be over that max weight, but I would say it's 4.5 initially kind of creeping up over time as patients age and stay on the drug longer term.

So we would expect over time as patients are on this chronically that four and a half year old average well will shift up.

But it's I wouldn't expect we're going to have a majority of patients over that kind of 11 12 year old as we're always bringing on kind of younger two to three year olds and so.

Kind of hard to predict what percent will be at at over that.

You know that that Max weights, but I would say yeah, it's four and a half initially kind of creeping up over time as patients age and stay on the drug longer term does that does that answer your question.

Steve Pfanstiel: Does that answer your question? I think I was actually asking more in for whatever the child's weight is, how much how many of them actually get to their top dose on titration? Oh, on the titration piece? Sorry, if I if I Yeah, yeah.

I think I was actually asking more in for whatever the child's waiters, how much how many of them actually to their top dose titration.

Steve Pfanstiel: Yeah. So, um, yeah, I can I can provide some color there. When we look at at marigold, and we call it the mean modal dose, but we were dosing, on average patients to about 92% of that max dose. We've, we've generally said that we think it'll be slightly lower, maybe 80 85%. Just because you're not in a clinical trial, there may be other reasons that they don't titrate up to that full dose.

No titration piece, sorry, if I, if I if I yeah, yeah, yeah. So yeah I can I can provide some color there when we look at at Marigold, and we call. It the mean modal dose, but we were dosing on average patients to about 92% of.

Of that Max dose.

Steve Pfanstiel: But we think, you know, in general, it's, it's going to be call it 80 to 85% of that max dose. I think that's where we've said that milligrams per kilogram per day is like in that 50 to 55 range against a max of 60. Perfect, thank you. Your next question comes from Jason Butler with JMP Securities. Please go ahead. Hi, it's Royan for Jason.

We've we've generally said that we think it'll be slightly lower maybe 80%, 85% just because youre not in a clinical trial there might be other reasons.

That they don't titrate up to that full dose, but we think in general it's going to be call. It 80% to 85% of that Max dose and I think that's where we've said that milligrams per kilogram per day is like in that 50 to 55 range against a Max of <unk> 63.

Perfect. Thank you.

Your next question comes from Jason Butler with JMP Securities. Please go ahead.

Scott Braunstein: Thanks for taking our questions. I guess, following up on the past couple questions, most of them have been answered. But I guess, how should we think about the overall duration of therapy and compliance? Any read through from the extension data?

Hi, it's Roy in for Jason Thanks for taking our questions I guess following up on the past couple of questions most of them have been answered but.

I guess, how should we think about that.

Overall duration of therapy and compliance any read through from the extension data.

Kind of looking at it different paradigm to the existing options that are out there.

How do you convince.

Physicians I guess to keep patients on the drug longer maybe the initial clinical response is it as ideal as expected. Thanks.

Well, let me kick it off and then I'll turn it over to Joe or Christy if they have some covenants but.

Scott Braunstein: You know, we're kind of looking at a different paradigm than the existing options that are out there. You know, how do you convince physicians, I guess, to keep patients on the drug longer if maybe the initial clinical response isn't as ideal as it could be? That's what I expected.

The nice thing about this drug is once you get through the titration period Youre going to see the anti epileptic effect. It's interesting in the open label it was a little bit slower, but still but still present early on.

Scott Braunstein: Thanks. Well, let me kick it off and then I'll turn it over to Joe or Chrissy if they have some comments. But, I mean, the nice thing about this drug is once you get through the titration period... You're going to see the anti-epileptic effect. It's interesting in the open label, it was a little bit slower, but still present early on.

Scott Braunstein: And I think what I particularly like when I put on my medical hat is the risk-reward of the drug in terms of.., safety, tolerability, drug-drug interactions being quite limited across the board. And so it seems that from a risk-reward perspective, where we need to win is at the front end of the equation. The back end kind of plays itself out, and I think our open-label data has supported that, that if patients have a response, they're very likely to have a durable response.

And I think what I, particularly liked.

When I put all my medical had as the risk reward of the drug in terms of.

Safety Tolerability drug drug interactions being quite limited across the board.

So it seems that from a risk reward perspective, its where we need to win as the front end of the equation. The backend kind of plays itself out and I think our open label data has supported that.

If patients have a response they are very likely to have a durable response, not every patient, but but the vast majority of patients appear to have a durable response that was seen in our phase two open label data we've seen in our phase three we believe the extra synaptic activity it really depends genetic activity of <unk>.

Scott Braunstein: Not every patient, but the vast majority of patients appear to have a durable response. That was seen in our Phase II open-label data. We see it in our Phase III. We believe the extra-synaptic activity, really the pan-synaptic activity of Ganaxone is likely to be the rationale for it.

And it's likely to be either the rationale for it.

Scott Braunstein: And I think in general, physicians, what our market research has said is physicians are looking for at least a 20 to 25% reduction in seizures to keep patients on therapy. When I look at our two-year open-label data, and we see that about 50% of patients still on therapy, very much in line with what you would expect in terms of a durable response. Joe Christie, either you want to jump in and make any additional comments?

And I think in general physicians, what our market Research has said is physicians are looking for at least at 20% to 25% reduction in seizures to keep patients on therapy I mean, when I look at our two year open label data and we see the about 50% of patients still on therapy.

Very much in line and what you would expect in terms of a durable response.

Joe Christie, either you want to jump in and make any additional comments.

Joe Hulihan: I mean, one thing, I'll just say one thing briefly, and then turn it over to Christie, she has any comments, but you know, we did see efficacy early, we looked at kind of the response during titration and during maintenance and they were very close and so usually when you titrate a drug, it takes a little while. [inaudible] So we were glad to see that. So anyway, I don't know if that helps provide some additional context.

I mean, one thing I will just say one thing briefly and then turn it over to Kristy. If she has any comments.

We did.

See efficacy early we looked at kind of the response during titration entering maintenance.

They were very close.

So.

Usually when you titrated drug it takes a little while.

So we were glad to see that.

Anyway, I don't know if that helps provide some additional context.

Joe Hulihan: So Kristi, do you have anything to add? Yeah, so we've really used Marigold as a really good foundation to think about, who this drug is going to be most utilized for in the patient population. And so, one of our core launch priorities is to really establish the TALMI as central to comprehensive CDD management, and what that means is knowing that those patients who are going to respond and knowing that they have a durable effect, that's a lot of what these patients have been looking for. In Marigold, these patients had cycled through drugs significantly at a very fast rate because they worked, and then they stopped working. And they needed something new.

So Christy do you have anything to add.

Yeah, So we really need to.

Marigold as a really good foundation to think about who.

This drug is going to be.

Medically utilized tour in that patient population and so.

One of our core launch priorities is to really establish the Tommy are central to comprehensive D. D D management and what that means as knowing that those patients who are going to respond and knowing that they have a durable effect. That's a lot of what these patients have been looking for.

And Marigold these patients had cycled through drug significantly at a very fast rate because they work and then they stopped working and they needed something new and so what were very helpful. For us that the Tommy again will be a foundation on that then with a very strong durable effect from <unk>.

Kristi Shafer: And so, what we're very hopeful for is that the TALMI, again, will be a foundational medicine with a very strong, durable effect, from which patients and caregivers and physicians can then build upon should they ever need to with others. Okay, great. Thank you. That's helpful. And then just this kind of technical question, I guess, so for the program candidates, is there any preclinical safety work that you need to do? And is that agreed upon already with the FDA?

<unk> patients and caregivers and physicians can then build upon should they ever need to with other things.

Okay, great. Thank you that's helpful and then just.

Kind of a technical question I guess for the pro drug candidates.

There any preclinical safety work that you need to do and is that agreed upon already with the FDA.

Yeah.

Kimberly McCormick: You know we'll be spending the next give or take 12 to 18 months of doing all the routine pre-IND work that would be required including safety work. Kim anything you want to add from the pro-drug perspective? No, I think, As you said, all the work will be ongoing to support the future FDA filings and the IND as appropriate, so it all depends on where it comes out of the program and which candidates identify to move forward with. But we feel pretty good about what we know about this. Yeah, about the structure of the drug and the risks are pretty low going in. Doesn't doesn't.

We'll be spending the next give or take 12 to 18 months of doing all of the routine pre IND work that would be required and including safety work Kim anything you want to add from the pro drug perspective.

No I think.

Did you say what other work ongoing to support me on future <unk>.

And the Indy is appropriate so it all depends on where it comes out and which can incentify going forward right.

But we feel pretty good about what we know about this about the structure of the drug in.

The risks are pretty logo and Ams doesn't doesn't hurt.

Got it thank you.

Kimberly McCormick: Got it. Thank you. And there are no further questions at this time. I will turn the call back over to the presenters for closing remarks. Well, thanks, operator. And thanks, everyone, for jumping on the call this morning. Couldn't, as we said earlier, we could not be happier with the opportunity to launch the Ptolemy this summer. It's been amazing working with the CDKL5 community and we'll continue to do so. We are very committed to, I look forward to expanding access for this drug as much as we can globally and look forward to getting our other programs back on track.

And there are no further question at this time I will turn the call back over to the presenters for closing remarks.

Well, thanks, operator, and thanks, everyone for jumping on the call. This morning couldn't as we've said it earlier, we could not be happier.

With the opportunity to launch it is telling me this summer.

It's been amazing working with the city came five community and will continue to do so we are very committed to.

Our expanding access for this drug as much as we can globally and look forward to getting our other programs back on track, we're quite hopeful the last few weeks have been.

Real signs that we can do that and look forward to speaking to you on the future. Thanks for jumping on the call today.

Kimberly McCormick: We're quite hopeful the last few weeks have been real signs that we can do that and look forward to speaking to you all in the future. Thanks for jumping on the call today. This concludes today's conference call. You may now disconnect. [music]

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

[music].