MRNS - Marinus Pharmaceuticals Inc. (MRNS) Q1 2023 Earnings Call Transcript

2023-05-11 13:58:03 ET

Marinus Pharmaceuticals, Inc. (MRNS)

Q1 2023 Results Conference Call

May 11, 2023 08:30 AM ET

Company Participants

Sasha Damouni Ellis - Vice President of Corporate Affairs and Investor Relations

Scott Braunstein - Chairman and Chief Executive Officer

Christy Shafer - Chief Commercial Officer

Alex Aimetti - Chief Scientific Officer

Steven Pfanstiel - Chief Financial Officer and Chief Operating Officer

Michael Dougherty - Director

Conference Call Participants

Andrew Tsai - Jefferies

Charles Duncan - Cantor Fitzgerald

Brian Abrahams - RBC Capital Markets

Joseph Thome - TD Cowen

Douglas Tsao - H.C. Wainwright

Brian Skorney - Baird

Joon Lee - Truist Securities

Mark Goodman - SVB Securities

Jay Olson - Oppenheimer

Michael Higgins - Ladenburg Thalmann

Presentation

Operator

Greetings and welcome to the Marinus Pharmaceuticals’ First Quarter 2023 Financial Results and Business Update Call. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a question-and-answer session.

And now it is my pleasure to introduce your host, Sasha Damouni Ellis, Vice President of Corporate Affairs and Investor Relations. You may begin Ms. Damouni Ellis.

Sasha Damouni Ellis

Thank you and good morning. With me from Marinus Pharmaceuticals are Dr. Scott Braunstein, Chairman and Chief Executive Officer; Christy Shafer, Chief Commercial Officer; Dr. Alex Aimetti, Chief Scientific Officer; and Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer.

Before we begin, I would like to remind everyone that some of the statements we are making today are Forward-Looking Statements under the securities 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.

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

Scott Braunstein

Thank you, Sasha and welcome to our call. During the first quarter of 2023, we made important progress advancing our oral and IV Ganaxolone programs further establishing Marinus as a leader in the development of innovative treatment options for patients with rare genetic epilepsy and refractory seizure disorders.

We continue to make considerable strides with the launch of ZTALMY, are pleased with our first quarter sales of $3.3 million and are on-track to meet our previously stated full-year 2023 guidance of $15 million to $17 million. Christy Shafer, our Chief Commercial Officer will be reviewing some of the key initiatives for 2023 that we believe will support the continued growth of ZTALMY.

We have also made significant progress in our commitment to bring Ganaxolone to more patients around the world. Let me start with an update on our European PVV marketing authorization application. As part of the day 195 assessment report, the European Medicines Agency communicated that the major objection related to the choice of regulatory starting material has been resolved. We expect to receive the CHMP opinion prism calming in CDD by the end of May and are confident with the progress that we have made to-date.

As a reminder, in August of 2021, we entered an exclusive agreement with Orion Corporation for the commercialization of Ganaxolone in Europe and have been collaborating with them to prepare for the potential launch. We look forward to sharing the formal CHMP opinion with you later this month.

Furthermore, we are pleased to have entered into an exclusive distribution and supply agreement with Biologics with ZTAMLY in several markets in the Middle East and North Africa. Biologics is a multinational pharmaceutical company based in Dubai. We hope to have ZTALMY available for patients in the MENA region in early 2024.

In parallel, we are working closely with Tenacia, our partner in China and expect them to file a new drug application by the end of this year. We are engaged in active discussions with several strategists, who are interested in bringing our products to market in Japan. Our current and future ex-U.S. partnerships are essential part of our commitment to reach the global patient community.

Moving to our clinical pipeline, we are excited to announce our plans to conduct an interim analysis for the Phase III RAISE trial in refractory status epilepticus later this year. Alex will discuss the process in more detail shortly.

But if the results meet the predefined stopping criteria, we expect to report interim top-line data in the second half of this year. Our leadership continues to prepare for a potential RSE filing, including a growing effort from our commercial, regulatory, CMC and medical science teams.

Additionally, we are gratified that physicians across the U.S. are requesting the use of IV Ganaxolone for their most severe super refractory patients and some have seen important clinical improvements.

We are actively recruiting for the Phase III TrustTSC trial in the U.S., Europe, and Canada, and expect the vast majority of clinical sites will be ready to enroll patients by mid-year, including new sites in Israel, Italy, Belgium, Australia, and China.

Due to administrative and regulatory delays in certain EX-U.S. countries, many of these which have now been resolved, we expect top-line data no later than the middle of 2024. Importantly, we learned with CDD efficacy and tolerability are key attributes to success in the refractory epilepsy population, and we are confident that the current protocol design maximizes our opportunity for a clinically meaningful outcome.

Let me conclude with a few additional business updates. We continue to advance our IP portfolio and recently received a notice of allowance from the U.S. Patent and Trademark Office for a new method of use patent for Ganaxolone in TSC.

When granted, the term of this patent will run through 2040, we have spent considerable time and energy broadening our patent portfolio and look forward to the final issuance of both this new method of use patent for the oral franchise and TSC, and an additional dosing method of use patent for our IV franchise in the treatment of RSE. We believe that there are additional opportunities to expand our patent portfolio based on our scientific advancements in the next several years.

We look forward to our upcoming Phase III data readouts and the clinical progress in our second generation platforms. We expect the number of additional milestones before the end of the year, including enrolling our first patient in the RAISE II trial and completing enrollment of the first cohort of patients in the RESET trial in established status epileptic.

We believe our second generation formulations have the potential to be the future of Ganaxolone franchise and are planning to initiate a multiple ascending dose study with our first new formulation in the third quarter with preliminary results expected by year-end.

If these results are consistent with the single ascending dose modeling, this formulation would be utilized in a future trial in Lennox-Gastaut syndrome with the clinical program designed, expected to be finalized in the first quarter of 2024.

Finally, we are pleased to welcome Marvin Johnson to our Board of directors. Marvin has over 34-years of diverse commercial operations experience at Merck and will be invaluable in supporting this ZTALMY commercial efforts while preparing for potential hospital launch of IV Ganaxolone.

Now, I would like to turn the call over to our Chief Commercial Officer, Christy Shafer.

Christy Shafer

Thank you Scott and good morning. I’m pleased to provide you with an update on our continued progress as we execute on the U.S. commercial launch of the ZTALMY. Today, I would like to focus on three topics, how does ZTALMY launch is progressing? What we are doing to accelerate growth and adoption of this important new medicine? And how we are preparing for a potential IV launch of Ganaxolone in the hospital and an expanded indication in TSC.

Net sales as a ZTALMY in the U.S. in the first quarter were 3.3 million with approximately 100 commercial patients active on therapy by the end of the quarter. We continue to see a steady build of treatment naive commercial patients with prescriptions coming from a growing and diverse prescriber base of over 100 unique physicians.

Total payer coverage for ZTALMY increase to approximately 225 million lives, including both commercial and government programs. ZTALMY has received favorable coverage determinations from over 40 payers, representing approximately 130 million commercial lives and Medicaid access has been confirmed in all U.S. states as well as Washington, DC and Puerto Rico representing approximately 95 million lives.

We have received meaningful uptake in all CDKL5 centers of excellence with encouraging trends persisting in surrounding areas where patients are managed routinely for ongoing treatment.

Using sophisticated data sources we have seen an uptick in the usage of the ICD-10 code G 40-42 and continue to see this trend rising with educational efforts and awareness campaigns with over 700 unique patients since 2020.

We are evolving our commercial efforts in response to what we have learned. This includes investments in higher quality data sources, more sophisticated analytics, new educational materials around genetic testing and training in ultra rare market dynamics.

Understanding the crucial role of the caregiver, we continue our commitment to providing ongoing support to the CDKL5 community. Recently, we hosted an educational webinar featuring Dr. Raj Rajaraman, a prominent pediatric neurologist from UCLA, ACBD Center of Excellence, and Dr. Alex Aimetti, Marinus’s Chief Scientific Officer to address questions received from the community.

Additionally, we are in the process of shifting off our caregiver engager program to educate patients and families by sharing experiences of families who have initiated treatment with ZTALMY and what that experience has meant for them and their loved ones.

These stories will be incorporated into our branded promotion for CDD and will also include healthcare providers who can speak to the clinical profile of ZTALMY. We continue to plan for and are making significant progress as we look to expand our oral franchise and build out our acute care franchise in preparation for a potential hospital launch of IV Ganaxolone.

For our expansion efforts the remainder of 2023 will be focused on building on our robust and comprehensive understanding of the U.S. TSC market. These efforts will include initiating an emotional and functional patient journey market research project, treater identification analyses, and a U.S. TSC landscape assessment to identify leverage points, existing behaviors and beliefs to create a brand strategy that enables the optimization of the introduction of ZTALMY to the U.S. TSC market.

For IV our commercial planning investments are ramping up significantly with priority on strategies that we believe will drive early launch success. To maximize the total market potential we are in the final stages of an innovative data project that is first of its kind as it relates to the identification and tracking of status epilepticus patients.

Leveraging data across four distinct claims providers to generate patient progression through each episode resulted in a sophisticated and comprehensive look at inpatient pathways and outcomes associated with usual care. These key findings and insights deepen our understanding of the specific unmet needs as patients progress along the status continuum and will shape our commercial strategy.

Finally, we are preparing to address the inherent challenges with inpatient reimbursements and complex DRGs, and do plan to pursue an NTAP is one component of our access and reimbursement strategy.

As a reminder, the NTAP or the new technology add-on payment designation enables additional payment to hospitals above the standard Medicare severity diagnosis related group payment amount.

Under this policy, for eligible technologies, Medicare pays the applicable MS DRG payment rate up to an additional 65% of the cost of the approved new technology. The team is closely monitoring CMS proposed changes to filing requirements, while also determining an optimal filing approach that allows our hospital customers to maximize the NTAP period post approval.

We look forward to providing more details in our Investor and Analyst Day in September which Sasha will discuss in more detail at the end of the call. We feel there are many opportunities to continue to grow our brand and are committed to supporting CDD families in new and meaningful ways, while expanding our commercial infrastructure in-line with our clinical development programs.

I will now hand the call over to our Chief Scientific Officer, Alex Aimetti, to discuss our ongoing development program.

Alex Aimetti

Thank you, Christy, and hello, everyone. I’m pleased a step in for Dr. Joe Hulihan, our Chief Medical Officer to provide an update on our clinical programs today. Joe is currently in China meeting with our strategic partner to further strengthen our R&D collaboration.

He will be participating in a local CDD Advisory Board, attending a TSC Investigator Meeting and connecting with doctors around the country, who have expertise in CDD, TSC and status epilepticus.

I will now provide an update on our clinical programs. As a reminder, the TrustTSC trial is 162 patient, double-blind, placebo controlled trial in patients experiencing a minimum of eight countable seizures per month, despite adequate treatment with existing therapies, including recently approved anti-seizure medications. This is a highly refractory pediatric and adult population and we believe the estimated number of patients with refractory seizures to be between 25,000 and 40,000 patients in the U.S.

Based on our observations from the Phase II open-label TSC trial where we saw a higher rate of reported somnolence than our Marigold study we developed a new titration schedule for this Phase III study.

The new titration schedule is designed to slowly increase the dose early on and increase more rapidly towards the end of the four week schedule to successfully titrate TSE patients to target doses. We believe that, slower titration initially will optimize tolerability and lead to improved efficacy.

The low discontinuation rate observed in the TrustTSC study to-date gives us increased confidence that the changes we made to the Phase III dose titration are having the desired effect. We continue to actively enroll patients in the TrustTSC trial at sites in the U.S., Europe and Canada.

Due to administrative and regulatory delays getting certain ex-U.S. sites up and running, we now anticipate top-line data 2024. The team has been working hard to overcome these country specific delays and we are confident that the vast majority of sites in the trial will be ready to enroll by the summer.

We expect to begin enrolling patients at new clinical sites in Israel and China this quarter with additional site activations planned in Italy, Belgium and Australia by mid-year. With these new initiations, we expect to see increased enrollment across our global sites. To further support study recruitment and enrollment, Marinus has sponsored two educational webinars in the U.S. and Europe, featuring prominent key opinion leaders.

The first was held in April for U.S. families and hosted by the TSE Alliance, and the second one will be hosted by the TSE Association with a European focus, and will be recorded later this month as we continue to build and strengthen our relationships with global TSE Advocacy Groups.

Now, I would like to provide an update on our clinical programs in status epilepticus. Our Phase III RAISE trial studying intravenous or IV Ganaxolone in refractory status epilepticus continues to advance.

We have dedicated considerable cross-functional resources to prioritize site engagement and scientific education and are confident that it has had a positive impact on enrollment and overall study awareness.

Today, we announced that we are planning to conduct an interim analysis in the second half of the year. The RAISE study protocol provides for a pre-specified interim analysis to evaluate the co-primary endpoints of status epilepticus cessation within 30 minutes and no progression to IV anesthesia for 36-hours, when two-thirds of the patients or approximately 82 patients have completed the trial.

The interim analysis is more than 90% power to show a 40% treatment effect. We continue to enroll patients in the RAISE d trial that are representative of the Phase II patient population, which gives us strong confidence in a robust and clinically meaningful treatment effect that can be observed at the interim analysis.

We expect that successful achievement of the co-primary endpoints would serve as the basis for submission of a regulatory filing in the U.S. I would like to review the process of the interim analysis. Upon completing enrollment of 82 patients with plan to clean and lock the database and an unblinded statistician will supervise the running of tables and quality check to maintain integrity of the data.

These data would then be provided to the Data Monitoring Committee or DMC to evaluate for efficacy and safety. The DMC would then inform Marinus as to whether or not the study met the pre-specified efficacy stopping boundaries on the co-primary endpoints.

If the study does achieve the pre-specified efficacy stopping rules, the Marinus Leadership Team would then have the opportunity to evaluate the data and share top-line results soon after. If the trial is complete, at the interim analysis, we will continue to enroll new patients in a planned open label extension to collect additional safety data, which we believe would be supportive for regulatory filings.

We also continue to progress our other trials in status epilepticus. Enrollment in our Phase III RAISE II trial in RSC for European registration is anticipated to begin in the second half of 2023.

On a successful interim analysis, we would plan to transition a significant number of our U.S. RAISE II sites to the RAISE II trial in an effort to expedite enrollment. We also expect a complete enrollment of the first cohort of our Phase II reset trial in established status epilepticus before the end of the year.

Finally, we continue to provide IV Ganaxolone to physicians who request it for their severe patients in super refractory status epilepticus under an emergency IND mechanism. To-date, 16 patients with super refractory status have been treated with IV Ganaxolone. Some cases have already been presented at major medical meetings or as case reports in the literature, and we anticipate additional cases to be published in the future.

I would now like to turn to our second generation product development efforts. We have completed our single ascending dose study in healthy volunteers with our new oral formulation. The new formulation exhibited linear pharmacokinetics at single doses of 100 to 1200 milligrams overcoming some of the limitations of the current suspension.

Modeled data suggests effective trough levels can be obtained with BID dosing with this new formulation enabling Ganaxolone to be studied in additional rare epilepsy patient populations. Our multiple ascending dose study is expected to initiate enrollment in the third quarter of 2023 with preliminary data by the end of the year. In parallel, we are aiming to finalize the clinical program design for Lennox-Gastaut syndrome in the first quarter of 2024 pending results of the MAD Study.

Our pro-drug development continues to advance and a lead oral candidate has been selected. We are targeting Phase I data in 2024.On the scientific affairs side of the organization we continue to generate relevant and compelling data aimed at addressing the needs of the medical and caregiver communities.

We are excited about the data sets we have planned to share with you all this year. First, we are planning to share the two year data from the CDD Marigold Open-Label Extension Study at this year’s International Epilepsy Congress in Dublin, and then expanded data at the American Epilepsy Society meeting in Orlando.

In addition, we are planning to present multiple abstracts, including the complete single ascending dose study data, some early real world data on ZTALMY use in the U.S., as well as new preclinical data of IV Ganaxolone in a severe status epilepticus model.

The Marinus Scientific and Medical teams will have a considerable presence at this year’s Neurocritical Care Society, Child Neurology Society, and American Epilepsy Society’s annual meetings as we continue to educate about Ganaxolone and the disease states in which it is being studied in, as well as raise Marinus’ scientific awareness. All in all, I’m excited about the progress we are making on our clinical programs, and it is shaping up to be a very exciting year with multiple data catalysts along the way.

I would now look to turn the call over to our CFO and COO, Steve Pfanstiel, who will provide you with a financial update.

Steven Pfanstiel

Thanks, Alex and good morning to everyone. I’m pleased to be able to share our financial results for the first quarter of 2023. Before going through the details of our financial performance, I want to touch on a few key updates for the business.

We are very pleased to have initiated significant startup work related to our API on shoring initiative. As you may recall, BARDA exercised its option late last year to support this initiative, which included funding of up to 12.3 million.

Importantly, this work is expected to provide a second domestically sourced manufacturing capability for Ganaxolone API and has the potential to drive a greater than 30% reduction in API supply cost, which represents a significant portion of the overall manufacturing cost for Ganaxolone.

We have also been active in our deal making over the past two years, partnering with Orion for the European market, Tenacia for China, and now biologics for MENA. We remain active for further expansion with the current focus on Japan.

As we continue to advance Ganaxolone’s development in ex-U.S. markets such as Europe, we have the potential to see royalty and milestones contributing to our cash inflows in the near-term in addition to ongoing R&D reimbursement.

For the fiscal year 2023, we are maintaining our guidance with U.S. ZTALMY revenues projected to be in the range of $15 million to $17 million and BARDA revenues to be in the range of $8 million to $11 million.

We continue to project our GAAP operating expenses inclusive of SG&A and R&D expenses to be in the range of $165 million to $175 million of which we expect approximately $16 million to be non-cash stock-based compensation.

We expect that our current cash, cash equivalents and short-term investments of $199.2 million will be sufficient to fund our operations into the second half of 2024 inclusive of maintaining the minimum required cash balance of $15 million under our credit agreement.

I will now move into our financial results. For the first quarter of 2023, we recognized product revenues of $3.3 million for the three-months ended March 31, 2023. These revenues consist of ZTALMY product sales which was launched in the third quarter of 2022.

Separately, we recognized BARDA revenues of seven million for the three-months ended March 31, 2023, as compared to 1.5 million for the same period in the prior year. The increase is driven primarily by activity associated with start-up of our API on-shoring initiative and increased RAISE trial activity.

Research and development expenses increased to 27.9 million for the three-months ended March 31, 2023 as compared to 18 million for the same period in the prior year. The change was due to increased costs associated with their API on-shoring effort, increased TSC and RSE clinical trial activity and increased headcount.

As a reminder, the API on-shoring effort is approximately 70% funded by BARDA that the increase in R&D expenses is partially offset by the increased BARDA revenues reflected in the first quarter.

Selling general and administrative expenses increased to 15.2 million for the three-months ended March 31, 2023, as compared to 11.7 million for the same period in the prior year. The primary drivers of the change were increased headcount and commercial support for the U.S. launch of ZTALMY.

Interest expense was 4.1 million for the three-months ended March 31, 2023, as compared to 1.7 million for the same period in the prior year. The increase is driven by drawdown of an additional 30 million of credit under the Oaktree agreement in March 2022, upon FDA approval for ZTALMY and non-cash interest expense related to our revenue interest financing with Sagard.

Interest income was 2.3 million for the three-months ended March 31, 2023 as compared to less than $0.1 million for the same period in the prior year. The increase in interest income was driven by the overall increase in cash, cash equivalents and short-term investments and increased yield on those balances.

The company reported a net loss of 34.7 million for the three-months ended March 31, 2023 as compared to a net loss of 19.4 million for the same period in the prior year. As a note, the 2022 net loss the one-time gain of 12.7 million related to our recognition of a portion of the upfront payment associated with our Orion partnership.

These totals also include non-cash, stock-based compensation expense of 3.7 million for the three-months ended March 31, 2023, as compared to 3.4 million for the same period in the prior year.

Cash used in operating activities was 41.5 million for the three-months ended March 31, 2023, as compared to cash used in operating expenses of 27.7 million for the same period in the prior year.

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

Scott Braunstein

Thanks, Steve. 2023 is off to a strong start for Marinus, and we are thrilled to have a strong balance sheet to support a continued positive momentum of ZTALMY launch, the advancement of our two late stage clinical programs and our second generation product development. We are committed to delivering

We are committed to delivering shareholder value and expanding opportunities to serve patients that may benefit from ZTALMY and IV Ganaxolone. I would like to thank our employees for their hard work and dedication to advancing our mission and our investors for their support.

Sasha, I will turn it back to you.

Sasha Damouni Ellis

Thanks, Scott. Planning is underway for an Investor and Analyst Event in September, which we will share more details about in the coming months. We look forward to diving into our commercial planning at RSC and providing color around how we are advancing our strategic goals to prepare for a successful launch.

Operator, can you now open the call to questions?

Question-and-Answer Session

Operator

Thank you. [Operator Instructions] We will take our first question from Andrew Tsai at Jefferies.

Andrew Tsai

Hi everyone, thanks, good morning. I appreciate you taking my questions. I appreciate all the progress as well. So, maybe two questions on RSE today. First question is, I’m just curious, how do you envision the interim top-line release to look like, presumably, it will be quantitative numbers, drug versus placebo on the co-primary endpoints, but it sounds like the DMC may look at safety as well. So would you share safety and would you also share some details on the secondary endpoints as well, so, the bottom line is just trying to gauge how robust of a kind of top-line release we can expect at the end of the day.

And number two. Only to the extent you can share, can you remind us what you are monitoring on a blinded basis in the Phase III, whether it is around the baseline characteristics, making sure you are enrolling the right patients, or maybe even looking at the actual blinded efficacy outcomes or even overall safety, or are you looking at all three? Just any color would be helpful.

Scott Braunstein

Thanks Andrew. Let me take the second question first and then I will pass - what we will provide the DMC. And remember that we have a central EEG reviewer, who is looking at the patient who are enrolling, I think most importantly that EEG reviewer is sharing with us the consistency that the patients being enrolled from a baseline characteristics are hitting the appropriate seizure burden to be enrolled in the study. That is really the only data point that we have access to.

We are really not looking at the overall blinded data sets in any way. Certainly, we want to keep the integrity of the study. So in our minds, it is really about what that baseline EEG looks like, the severity of the patient entering the study. And of course, the other piece of the puzzle that we see regularly are patients who fail screening.

And so we are still seeing about 50% of patients who from first line to second line, who are responding to an anti-epileptic. I mean, interestingly, it can be hours. Sometimes it is eight to 10 hours before a patient is no longer considered a candidate of the study. So that is a number we expected.

I think as we look to the future, particularly with the RAISE II trial, we will really be focusing on that window of seizure resolution compared to standard of care today. So, that is an important measure for us because we want to ensure a low placebo rate. And we think those numbers have been very consistent.

So thanks for the question. Alex, you want to talk a little bit about what we will provide to the DMC and most likely what we will have in our top-line.

Alex Aimetti

Yes, sure. Thanks for the question, Andrew. As mentioned at our interim, we will have pre-specified efficacy stopping boundaries in place for our co-primary endpoints. Also included in our formal statistical testing hierarchy will also include the two key secondary endpoints that look at no progression to IV anesthesia at 72 hours as well as time to status epilepticus cessation.

We would plan to include our key secondary endpoints in our interim top-line data release if that interim does meet the pre-specified stopping boundaries. In regard to the other secondary endpoints we have, those secondary endpoints are all planned to be descriptively analyzed.

And, you know, that includes a lot of various clinical outcomes, functional outcomes, a CGI modified ranking scale, as well as very important healthcare utilization metrics. And our plan at this point would be to present those at upcoming major medical meetings. And then just quickly, yes, absolutely safety will be included in that as well. That is a critical component to our data release at that time point.

Andrew Tsai

Great. Thank you, guys so much. Very clear.

Scott Braunstein

Thanks Andrew.

Operator

We will move next to Charles Duncan at Cantor Fitzgerald.

Charles Duncan

Hey, good morning Scott and team, thanks for all the update and congrats on the progress. Had a couple of questions ex-U.S. and so wondered if you could provide any additional color on the resolution of the objection for the starting material, the regulatory starting material, how was that resolved and, yes, what is the process there and what gives you confidence in the upcoming positive opinion?

Christy Shafer

Thanks. Thanks for the question, Charles. You know, just to remind you and everyone on the call, our process for creating Ganaxolone, creating that API was agreed upon with the FDA about three to four years ago. Oh gosh. Even, maybe even a little bit longer.

And that is the same process that we suggested to the EMA and interestingly, in the last three to five-years, we have made this process incrementally better. So, as an example, when we started making Ganaxolone five, six years-ago, the purity on the API was about 97%. Now it is well north of 99.8%.

And quite honestly, our scientific team and I have learned now more about starting materials than I ever care to really walk me through our process. And we were just having a scientific debate with the EMA I think no, and our rapporteurs.

And we continued to provide the scientific rationale around our starting material, the quality that was associated with it, this very high purity. We tested for multiple impurities. I think most importantly, we really walked back at the agency step by step through the process.

And I think with that we got our rapporteurs and the CHMP comfortable with this starting material in terms of the safety, it was one we always believed in. It was one that I was very willing to escalate if necessary.

But at the end of the day, we are a scientific team. I think both the U.S. and European regulatory bodies are scientific teams, and we were able to come to a conclusion that we believed was the right one and now we have support in multiple regulatory agencies.

So in our minds, that was the biggest issue. There was a lot of other work we had to do, Charles, to satisfy the European authorities that were substantially bigger in scope than the U.S. and we have climbed those down.

So the team of Marinus has put in hundreds of hours to get there and we are incredibly excited with the upcoming opinion, we are enthusiastic about a launch in the near-term and I think this means a tremendous amount to families in Europe, validation of our platform.

And the opportunity really help additional patients in European markets and soon thereafter in MENA markets and soon thereafter in Chinese markets with Ganaxolone initially in CDD and then our expansion. So it is a big milestone. It was a very strong and healthy scientific process and one I’m incredibly proud of our team. So thanks for the question.

Charles Duncan

Congratulations on that process. Let me ask you about incidence and prevalence ex-U.S. You mentioned MENA, you mentioned China obviously EU, I guess I’m wondering how do you see CDD ex-U.S. versus U.S.? Are there any geographic, call it, drivers to increased incidents or even prevalence? And then can you provide any other color on the Japanese partnering process? Are you having ongoing discussions, and could that actually come to fruition yet this year? Thanks.

Scott Braunstein

Thanks. Let me take the second part of the question Charles, and then I will let Alex to answer because Alex is our expert epidemiologists, when it comes to the instance of CDKL5. On the Japanese front, our teams really started the engagement process recently.

We have seen a lot of interest from several companies. I can’t promise you a deal this year only because we have some big data sets coming up, and I could imagine some companies waiting for those data sets.

That being said, there is, I think, very distinct interest around the orphan part of our disease relative to the hospital side of the disease and certainly. We would love to see a deal done before year-end. That is our corporate goal.

But understanding that sometimes some companies get a little bit nervous in front of datasets. So we are pushing hard. I think we have seen more interest that I would have initially expected, which is exciting.

I think the U.S. revenue trajectory and now the European approval will be very supportive of - from strategic in Japan. I’m going to push our business development team to get something done over the next few months. I’m excited with those prospects.

Alex, how about I turn it over to you to talk a little bit on the epidemiology?

Alex Aimetti

Yes, certainly. We believe that the birth rate or the incidence ex-U.S. is very similar to how we think about it here in the U.S. which is approximately one in 40,000 live births. I think what is a really important driver to think about is the rate and adoption of genetic testing to identify that patient population.

And I really think we are at a really exciting time in the field of epilepsy genetics. And there continues to be increased momentum in the adoption and the realization of the clinical impact of providing a proper etiological diagnosis.

So a lot of the countries in Western Europe for sure have been genetically testing their patients for many years. And we continue to see that rise and we are continuing to see it grow throughout the global regions.

Scott Braunstein

The only thing Charles, we are now seeing the first centers of excellence in several countries throughout Europe. We know there are over 600 patients identified through the CDK the Global CDK Alliance.

In China, we know that there are several patients in United Arab Emirates waiting for the drug. So, we get a lot of inbound calls and nothing that we are seeing from our discussions globally make us believe that the incidence is any different across the globe.

I think the one kicker for me with Japan will be the birth rate. And the lower birth rate in Japan, I think will have an incremental impact of the size of the Japanese orphan disease market, not necessarily status epilepticus cause it is an aging population, but I think on the orphan side, just from a modeling perspective, I think it is a little bit smaller than the U.S. given the birth rates.

Charles Duncan

I appreciate the insights and genetic testing, it makes sense to me. Thanks for taking the questions.

Operator

We will take our next question from Brian Abrahams at RBC Capital Markets.

Brian Abrahams

Hi there good morning, thanks for taking my questions and congrats on all the continued progress. I just had a few questions on IV Ganaxolone. I guess maybe first off, on the mechanics around the interim, wondering if you could expand a little bit more on the gating factors and timelines we should be thinking about forgetting to the 82 patients, cleaning the data and getting to DSMB evaluation. And if this doesn’t hit the stopping criteria, what would be the implications for the program both the RAISE trial and the other studies?

And then lastly, just as a follow-up separately, wondering if you could speak to any learnings or observations you can take away from those 16 EID patients, recognizing that they are in a different stage and using a different protocol. Thanks.

Scott Braunstein

I think, again, I will start backwards and then I will turn it over to Alex where the question started. I think the super refractory patient population is, is increasingly interesting to me. I think I have been pretty transparent with investors that it is a very long road for a Phase III double-blind placebo controlled child.

That being said, we continue to get requests and have incredible outcomes for a patient recently who had been - we had been the last line of resort. They had been transferred to a tertiary care center.

We believe that had they not gotten our drug, they would’ve been discontinued from their ventilator. And that patient was able to be discontinued from anesthesia and left the ICU as a result of IV Ganaxolone.

Our team is working on some new suggestions to physicians when they request EID on dosing. Slightly a different dosing regimen than we are using in RSC. Those regiments are being filed as we speak, so I can’t talk much more about it, but we would expect by the time of AES to talk about that a little bit more.

And I think what we are really thinking about is there, from all these learnings from EIDs, is they are an opportunity for us to do, a single arm study and really help progress the field. So I think it is very exciting and we certainly know this is a population that needs help. It is just the best way how to attack it from an organizational standpoint.

I actually forgot your middle question, Brian. I’m having a little phone service, so I’m not taking notes. So, Alex, why don’t you talk a little bit about the process of data cleaning? The only thing I will say is, you know, really the key point is when we get to that interim number, and that is when we make the decision to lock and load the data set.

And Alex, I will turn it over to you to just talk about those mechanics a little bit more specifically.

Alex Aimetti

Yes, certainly. Thanks for the question, Brian. I think one part of your question was, you know, how do we get to 82 patients? And I can just say that there is again, a lot of significant momentum in our enrollment in this study and really confident in us getting to that number here soon.

Again, we have really dedicated a significant amount of cross-functional resources to really make sure that we are engaging actively with our clinical sites and making sure that all of the key stakeholders within the hospital system have the right amount of information to help identify a potentially eligible raised patient and if eligible, get them enrolled.

A little bit more about mechanics. Once we have the 82nd patient in, there is a 30-day follow up. So about four weeks to continue to collect all of the safety data, from there we think that we can clean and lock the database in potentially three to five weeks.

So call it seven to 10 or so weeks from 82 ^nd patient in that data set will be shared with the DMC. The outstanding question is how long the DMC will take to fully evaluate and assess that data set and provide that information, to Marinus, whether yes, the pre-specified efficacy stopping rules were met or to likely proceed as is on that. And at that point, as mentioned earlier if the stopping criteria is met, then we would look at that for a few days and announce those top-line data.

I will pass it to Scott to answer that last question that you had about, if the interim does not hit.

Scott Braunstein

Yes, thanks. Thanks Alex and Brian, and Sasha for reminding me about that question. So I think, Brian, there is no question that we can still hit statistical significance if we don’t hit the interim. And maybe just to add on to Alex, when we begin that interim process, we will continue to enroll patients in a double blind fashion.

If the DSMB said to continue the study, we can do so. We think that would take a few additional months to complete the study. We still have new sites up and running, and we are allowing new sites to come on board through about the middle of the year.

So I expect to be at 70, 75-ish sites by the June timeframe, a lot of reasons for that, which I can go through. But to your question specifically, we would enroll the study and then unblind the data at 124 patients.

That being said, given the fact that this study has a very high probability of hitting at the interim, should it not, I think the likelihood that we have a clinically meaningful drug at the end of the study, without stopping at the interim, is a low probability.

So I think we generally believe where we set the bar for the interim, and Alex talked about a greater than 90% power to show 40% clinical benefit versus placebo. We think that is where the drug needs to come in to have important clinical outcomes associated with it.

So we are making a very strong bet that this drug is working. We will see a low placebo rate and we will have more than sufficient data to file at the interim. And I think that is where our head’s at today, Brian.

Brian Abrahams

That is really helpful. Scott and Alex, thank you guys so much.

Alex Aimetti

Thanks for the question.

Operator

We will move next to Joseph Thome at TD Cowen.

Joseph Thome

Hi there. Good morning. And thank you for taking our questions. Thanks for walking through all the different steps here. I guess just in terms of what you are going to be telling the street, I guess, what is your disclosure strategy? Will you say, when that 82 ^nd patient is enrolled, will you say when you say when you are taking the interim or we kind of just know once the results of the DMC review are available. And maybe on RSE, as you see it from a CMC and safety database perspective, how are you thinking about timelines of having everything together assuming the positive outcome? Thanks.

Scott Braunstein

Yes. Thanks, Joe. I haven’t necessarily made a final decision. We have the team haven’t made a final decision on our communication strategy. I think we have tried to be as transparent with you guys as possible and keep you up to-date. As everyone knows, this is an incident trial and there are great weeks and there are quiet weeks. And then again, it is a complex data set.

So I just want to make sure that, when we communicate, we not only have hit our number of patients, but we have good confidence that we can clean and lock the database, as Alex described. So we are going to -- what we are doing, Joe, is we are doing our best to clean and monitor the data, as it comes through. But it is a big process, these are sick patients.

And I think I will feel very confident by the summertime that the timelines that Alex walked people through, we can hit those and look to exceed them particularly in terms of a data cleaning. So bear with us, give us a few more months, we will get there and we will finalize our disclosure around exactly when we are starting process.

Will you mind repeating the second question?

Joseph Thome

Yes. And the second part was just on the CMC components and potential safety exposure. Is that, I guess, negating to anything or on a positive in a room, would you be ready to go?

Scott Braunstein

Yes, no, great question. Thank you. So CMC, we are super excited. We have filed the amended IND to start using our Citrate buffer. And yes, we are disclosing that the new buffer is citrate today. So all those science peaks you want to look up the solubility of citrate buffers rather than phosphate buffers.

We want to give you something today, We are expecting that, the FDA will basically say, you are free to use that product in the study. We have batches with that ready to go. So we will incorporate that new citrate buffer product into the clinical study within the next few weeks.

We will start RAISE II 100% with that new buffer. But as a good housekeeping measure, as we did with ZTALMY, we will ask for pre-NDA CMC meeting to review the package with the FDA and say, “look, here is what we got and here is our question.” Is this sufficient, is this sufficient?

As an example with ZTALMY, we asked the FDA 10 questions and they said we would like to see more on two of the 10. So we had six to nine-months before the filing to add some additional analytical testing. So we will do the same on the CMC side.

I’m incredibly proud of the progress that the CMC team has made. They have made so much progress. We have added a new formulation bottle size for launch and we will talk about that more in September. It may be a few months after launch, but we think it is going to be really important commercially. So from a CMC perspective, I think we are locked and loaded.

And I’m sorry, Joe, you asked me one other piece beyond CMC that I forgot as well?

Joseph Thome

Just the safety database component?

Scott Braunstein

Yes. No, that is a great question. So I’m not losing sleepover safety. I think any drug has to have an efficacy, safety balance. We know the safety. We have had a DSMB reviewing the Phase III.

We have seen nothing new that we are aware of, nor have been informed by the DSMB. We have got a ton of now open-label data with 20% higher doses in super refractory patients. We have seen nothing unexpected in that population as well.

But to make sure that there is not an issue in terms of patient number, we have every intention of keeping our sites open, rolling probably half of our sites into open label treatment with Ganaxolone.

Again, building the ability for physicians to use the drug in these very sick patients. And of course, we will have additional double blinded data in the several weeks from the time we choose to lock the data to unblinding. Of course, once we unblind the data, we move every site to either open label or to RAISE II

And people ask me a lot, well, why would you cut the study at 82? Well, one, we think we can get there without an issue from an efficacy and outcomes standpoint. And two, we think raise two is a really important add-on to the franchise, and we want to accelerate those time runs as well. So we have a lot of reasons to be enthusiastic about the interim and the future expanded patient number. So I’m not at all losing sleep from an FDA perspective on safety. Thanks for the question.

Joseph Thome

Excellent. Thank you.

Operator

We will go next to Douglas Tsao at H.C. Wainwright.

Douglas Tsao

Hi good morning. Thanks for taking the questions. Scott, maybe first on the second generation product development. I think in the release you said that you are close to advancing or you have a lead oral candidate selected. I’m just curious from the -- I you have talked about developing a pro-drug IV formulation. I’m just curious what the update or how far along what progress you have made on that front?

Scott Braunstein

So, yes, look, we are moving aggressively on the IV side as well. We really do believe that a formulation with no or significantly less - all will have a lot of advantages in the pediatric population and super refractory status.

And of course, if we could substitute the entire franchise, we do have a three to 5% royalty stream with Ligand that was negotiated before our team came to the organization and G&N a great partner to-date. But Captisol is hard work.

We have an IV candidate approach of selected. It looks beautiful in the human cell models. The problem right now is we don’t see normal metabolism of that pro-drug, any other animal model. So we are scratching our heads of how to do the tox work when you don’t have the appropriate animal model. Lots of companies run into this.

I have just run into this problem with another company that I have seen it several times in my career. We are going to talk to a few consultants to figure out how to advance that compound. At the same time, our chemistry team, our chemists are working on new formulations that effectively look and smell like the one we have now, but would also have the same metabolism in animal models for us to do the tox work.

But we know that this, the pro job is 80%, 90% Ganaxolone. We know what that cleaved particle looks like and the safety of that particle. So in my mind there is got to be another way we can overcome this to move this a little bit more rapidly into the clinic.

That being said, we have made tremendous progress in the two years that we have been working on this behind the scenes. And, you know, I’m hopeful we are going to have a lead candidate chosen by year-end, and, you know, then it is about 18-months from lead candidates to INDs.

But once we get to IND, Doug, I mean, similarly to the oral formulation program, we know what blood levels we need to hit and we would expect the pro-drug to behave very similarly to our - Ganaxolone today, IV Ganaxolone. So thanks. Thanks for the question.

Douglas Tsao

Sure thanks. Can I ask one follow up? I think on RSC you mentioned that you’ll continue enrolling, even after, you sort of move ahead with the interim analysis. If you ultimately do read out that study and you have enrolled patients, can you switch those patients into RAISE II? Or do you just sort of continue to follow them as part of the RAISE I data set?

Scott Braunstein

Yes, great question. So let’s just say, you know, day X, we internally decide to, we have hit our 82 patients. We are going to clean that database, that 82 patients are going to be the basis of our filing and what we expect to be in RPI.

But again, to Alex’s point, it will take eight to 10 weeks from the time we choose to unblind to data. And so in that 10-weeks, we will still continue to enroll as a double blinded fashion. And to an earlier question, in case we don’t hit at the interim, then we would just continue to enroll to finish the study.

On the news from the DSMB that we should stop the study because there is a clear efficacy signal. We would then stop all enrollment, no longer enroll double blind, and either enroll those sites into single arm open label Ganaxolone use, or into RAISE II.

And I would guess today it will be 30 plus sites that go into each study. But I think we wouldn’t, those additional patients, let’s say 10 or 15, that are enrolled in this window while we are waiting for data, would just be part of the safety data set for RAISE.

We wouldn’t expect it as part of the PI, but we would submit it to the FDA as part of the safety. We have been having a lot of discussions about this, and I think that is the most likely outcome. And the way the agency typically handles, these additional data sets. We have had some discussions like, well, when you look at oncology studies, you can unblind at PFS, but then outcomes and survival later on.

But I think for the purposes of being conservative, we are going to assume that the 82 patients are going to be the basis of the label with additional safety data in those 10 or 15 patients who are in that unique double blind portion while we are unlocking.

Does that make you clear?

Douglas Tsao

Yes, that is very clear. Thank you so much.

Scott Braunstein

Sure. We have had a lot of internal discussions about this now, so, it has kept us pretty busy. Thanks, Doug.

Operator

We will go next to Brian Skorney at Baird.

Brian Skorney

Hey, good afternoon, guys. Thanks for taking the question. I guess two quick ones from me. Sounds like there could be a few months between enrolling the 82nd patient and a response from the DMC during which patients are still going to be enrolling in a double blind fashion. I guess given where enrollment is right now. If you stop at the interim, how many patients do you actually estimate will have randomized data for the submission, it takes three-months for DMC to get back to - do you think you could almost have that study fully enrolled at that point and then

Scott Braunstein

Brian, I just want to be clear we only - what we don’t know is from the time we give that data to the DMC, how quickly they will turn it. We don’t think it will be three-months for them to turn it. It could be a few days, it could be one or two weeks.

But what, let’s say, entire 10 to 12-week process include us following the patient to 30-days, cleaning the database, then giving the data to the DMC. So I’m estimating now, we are estimating one to two weeks for the DSMB to come back to us to say, you should stop the study. I just want to be clear on that point. Sorry.

Alex Aimetti

Yes, sorry. I misspoke. I meant, if it was like up three-months from the 80 second patient enrolled to when the NSE gets back to you?

Brian Skorney

You think could you give us like an estimate in terms of how many patients you think will actually wind up having randomized data from?

Scott Braunstein

I think, look, I think if it is a three-months process, then I think it will be roughly 15 additional patients at as many as 20 potential patients from - so generally we think we will be - and we have said this.

We have talked about this publicly that generally we have been enrolling four to five patients a month and we are still expecting acceleration as we open these new sites. So if it is three-months that those type of enrollment numbers, it will be roughly 15 as many as 20 patients or more.

Brian Skorney

Great. Thanks. And then on the reformulated Ganaxolone, if the profile holds up in this MAD study, I know your next stage is focused on one time test. But I’m wondering, have you explored if there is value to kind of looking into CDD and PSV with this real reformulation and what sort of regulatory requirements you might need if you wanted to kind of reference labels on the current formulation for reformulation?

Scott Braunstein

Yes. No, it is a great question and we met as a strategic team about two-weeks ago in Miami and this was the key topic. I think right now where we believe we will fall out from a regulatory standpoint is for the second generation product, we will reference the current forms of Ganaxolone.

We do believe as of today that, that will allow us to do a single pivotal study for approval. That is our working hypothesis today. Of course, once we do the MAB study, we will go to the FDA and propose a Phase III strategy.

And I’m comfortable saying that, we would see as a single study strategy with an expanded database given that the 900 and 1200 BID formulations today have higher AUCs than our existing formulations, so we want to have additional safety data.

We felt long and hard about what is the right strategy with CDD and TSE, we haven’t come to firm conclusions yet on those programs, but we do think, if there is the potential to show stronger efficacy in those populations as well.

It is logical to think about either studies, switch studies or efficacy studies in those populations so nothing is off the table, at this point in time. I think I have spoken to lots of investors and publicly that we would love to have a strategic involved here.

I mean, my view of this is if we can accelerate this second generation program into multiple indications, we have an incredible opportunity to the second gen product with a much broader, deeper message for the rare refractory populations. And we know that there are lots of them out there that are hungry for drug. We are getting requests every day or several requests for ZTALMY, for these refractory patients.

So we know they are out there and we think right now we are spending more energy and time than anyone else in the space. So, to your question, we think there is a real opportunity to expand this program. We recognize we can only do so many things.

So, so stay tuned and I’m looking forward to sharing that with you. We are a little disappointed about the slowdown, but I think we totally understand that we want this program to run smoothly from here. So thanks for the question.

Brian Skorney

Thanks you.

Operator

[Operator Instructions] We will go next to Joon Lee at Truist Securities.

Joon Lee

Hey, congrats on the quarter and thanks for taking our questions. I apologies if this was asked, but if the study does not stop at interim and goes to full enrollment, what is the timing of the top one data at 124 patients and is there any reason why you are not include fertility?

Scott Braunstein

Yes, I think kind of to earlier folks, Joon, it will obviously depend on the monthly enrollment curves. I would expect by the time we are ready to unblind the study, we are enrolling seven to eight patients per month. So roughly three to four-month window from interim to full dataset.

In the time we elect to do the interim to the full data set. So the full data set should be done, should at least the last patient should be enrolled. I would expect soon after the DMC would come back to us.

Joon Lee

Got it. Thank you.

Operator

We will move next to Mark Goodman at SVB Securities.

Mark Goodman

Good morning. First question is, the off-label usage at all, there are a hundred patients you said were on drug. Are they all CDKL5? I’m just curious on that first.

Scott Braunstein

Christy, do you want to take it or you want me to take it? Whatever you like.

Christy Shafer

Yes.

Scott Braunstein

We have had Christie on the line, there is been no commercial questions. Put the girls to work.

Christy Shafer

Thanks Scott. Yes, I’m happy to take it. You know, as of Q1, we have seen greater than a hundred patients on commercial therapy with the majority of them getting reimbursed. We have about a 90% reimbursement rate right now.

I will say that we have only had a handful of non-CDD indicated patients to-date. The majority of them would be for other [DEE] (Ph) for example, LGS. Again, very minimal at this point, but the majority of our patients do have a CDD diagnosis.

Mark Goodman

And since the drug’s approved, are we seeing an increase in the actual number of patients out there with CDKL5? I’m just curious if all of a sudden now there is more testing and we are finding more patients since you’d mentioned it a year ago.

Christy Shafer

Yes, there is great trends in diagnosis and identification today. At this point, we are still really cornered on that one in 40,000 patients in the 2,000 pediatric patients that we have in our funnel. But to that point earlier here on the launch, there are, you know, really wonderful efforts surrounding genetic testing.

It was probably the number one topic at AES last year in December. We have internal progress made just to continue to identify potential patients that do have other syndromic diagnoses. So we still feel very confident in the numbers that we have communicated, but we continue to uncover patients every single day.

Mark Goodman

And then maybe just quickly, one detail on RAISE. Can you just clarify around the IV anesthesia protocol, are you allowing IV anesthesia use if it was for intubation, or are you allowing it if it was attempted to be used as an anti-seizure medication? I know in the Phase II, like half the patients entered the trial intubated and most of them received IV anesthesia for intubation.

Scott Braunstein

Alex, you want me to take it?

Alex Aimetti

Yes, sure. I can take that. So the inclusion criterion in amendment three is any exposure for IV anesthesia for less than 18-hours. We feel that at that time point, these are still patients that are not in super refractory status epilepticus.

It is critical that these patients are not in super refractory status. With that all said though too, they also have to meet the eligibility criterion of the seizure burden prior to study drug administration. So as IV anesthesia is weaned, again, less than 18 hours of exposure, they still have to meet the electrographic status epilepticus definition of at least 20% seizure burden.

So we feel that these patients, despite any in exposure prior to that, if they are still meeting that electrographic eligibility criteria, and we think that they are eligible patients for Ganaxolone and potentially could respond to Ganaxolone if that was administered. Thanks.

Scott Braunstein

Thanks. And Mark I would add, I think that is very real world, right. Smaller community hospital has a patient in status. They give anesthesia, they intubate, they transfer to a bigger center. Were those bigger centers and we had this two-weeks ago.

The patient didn’t get enrolled, but the center basically got a patient in transfer, lowered the anesthesia and patient had status. And that would be perfect for the trial and for the use of our drug. This case, the patient had a contraindication, so wasn’t eligible cause they were on another drug.

But I think very real world that is, those are patients we really want to capture. And we used an 18-hour cutoff because the literature really defines super refractory status as 24 or more. But we certainly believe that there is a meaningful role for the drug in the acute setting. So I think it would work quite well after 24-hours.

Yes, probably as well. But we wanted to be safe, particularly for the purposes of this trial and not enroll patients that were effectively, you know, super refractory nature not responding to anesthetics. So, I think, yes, I think it is going to help the study a lot. I think it is very helpful for the real world commercial opportunity.

Operator

Well take our next question from Jay Olson at Oppenheimer.

Jay Olson

Hey, congrats on all the progress, and thank you for taking the question. Can you talk about the expected product lifecycle for ZTALMY in the U.S. based on the new patent and any other patents you have pending and then also the timeline for getting an NTAP filed and approved. And how long would the NTAP be in place if it is approved or does that require an annual renewal? Thank you.

Scott Braunstein

Chris, do you want to start with the NTAP, and then I will talk about the patents for ZTALMY?

Christy Shafer

I would be happy to. Much of what we are doing right now is really discussing on maximizing the benefit for our healthcare providers and for the system quite frankly, when we do file for an NTAP. Timing is very specific on how to maximize that.

Current the IPPF has proposed a change to the filing for the NTAP. That change will be, if it goes forward, that will go in August of this year, that decision. And it changes it just by a few months of when you would have to have PDUFA.

So again, we have got quite a few scenarios inline right now again to maximize that benefit, because when you do have a positive opinion through the NTAP filing process, you do have that for three years. And if you don’t have an approved product, you kind of eat into the time that the NTAP is active.

So again, we will be looking at this our patient numbers are enrollment trends to see when we would be filing so that we can file it the exact amount of time that we would need to maximize the benefit.

Scott Braunstein

I had I have to I didn’t answer the question on the PAN. So sorry about that. So quick reminder on the IV side and we now have one method of use patent granted and another one that we expect to be issued.

Well first is granted and issued and the second is granted and pending issuance around the dosing paradigm and the resolution of status epilepticus with this high dosing for $8 to $12. So we feel great about those that kind of use.

On the oral side, of course, we have now method of use patents that we have been licensed from - for CDD that go to 38. We now have this new TSC patent method of use that goes to 40. We also - and we are really excited about the TSC - the new TSC patent.

And we have some additional patents pending around CDD around our new dosing titration schedule. And so we feel very confident about the growing method of use patents for the franchise and many of the unexpected findings that we have learned in the last three-years.

That said, what I’m really excited about as well with our second generation programs is that, that will bring seven-years of orphan drug particularly if we follow that path in LGS. And so in my mind that is just another alternative strategy to really guarantee that our oral franchise has strong IP and market exclusivity for many years to come.

So I really couldn’t be happier with how much progress we have made and the comfort that we have in extending the IV and the oral franchise. And of course if we are successful with pro-drugs that would add even different levels of protection to the franchise. So we are feeling pretty good about the longevity of the franchise all around today.

And again, many of you know, I sat on the other side of this and spent more time than I ever care to on patent cases. And we feel quite strongly that, specific method of use patents are as strong as we can build our franchise and all of them are scientifically driven. So that is what gets me excited.

So thanks for the question. And Michael will take your question. It is got to be our last question. We have run over quite long and folks have to get back to their day jobs.

Michael Dougherty

Yes, I agree. Appreciate it. Thanks, Scott. One is we look ahead to data back after this year or into next year on RAISE. If you have an agreement with the agency to prospectively look at the patients and the outcome based on things like severity of neurological deficits seizure burden in other ways or is this just everyone that is coming in for example, if you really hit on seizure burden of 50%, but you completely missed somehow on 20% or vice versa, can you still advance the program or do you have to hit again on the overall. Thanks.

Scott Braunstein

Yes. The agreement with the agency is that we have to hit each co-primary endpoint at a 0.05. I think we feel extremely confident on both, but specifically when you think about the first primary being resolution within 30 minutes, our Phase II data we saw that in every patient by clinical bedside 14 out of 15 by independent EEG reading. And as a reminder, the independent EEG reader is not how the primary is defined by the clinical bedside read.

The second endpoint, again, avoidance of general anesthesia. We were at a 100% in Phase II. We are giving incrementally a little bit more drug in Phase III, we bump from 713 to 830. So we have 12-hours of high dosing. So we feel very good about these very sick patients, avoiding general anesthesia with the use of our drug. Not going to be perfect, but we would expect efficacy in the 70% to 80% range.

And we feel very confident about a placebo rate in this study. For the first primary being close to zero and the second co-primary being no higher than 20% or 25%. So we expect the delta in both of these co-primaries to be north of 40%. I think, that is our expectation we took was 50% or 60% on the second co-primary.

And I think, our expectation on the first co-primary is that we are at least 50%. So that is our expectation going in. If we don’t hit that, we certainly will look at the data and understand what we have and whether or not there is a path forward.

Of course, we don’t hit that interim. We will go to the full, we will finish the study in its entirety and have a larger data set to review, but that is the way we are thinking about it right now, Michael. So thanks for the question.

Scott Braunstein

And operator, I just want to say thanks to everyone for staying on the call. I apologize that we went 20 minutes over, but we did want to answer your question. I’m sorry we didn’t put Steve to work on this call. But he has done such a great job helping us strengthen our balance sheet. I’m glad those are not issues that we had to tackle today, and appreciate all your time and support and we look forward to catching up live in the future. So thanks, thanks for dialing in.

Operator

And that does conclude today’s conference call. Thank you for your participation. You may now disconnect.

For further details see:

Marinus Pharmaceuticals, Inc. (MRNS) Q1 2023 Earnings Call Transcript