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spk13: 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 lesson-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 palm key. And now it is my pleasure to introduce your host, Sasha Damouni, Vice President of Corporate Affairs and Investor Relations. You may begin.
spk00: Thank you, and good morning, everyone. With me from Marinus are Dr. Scott Bronstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, Kimberly McCormick, Senior Vice President of Regulatory Affairs, Christy Schaefer, Chief Commercial Officer, and Steve Fancil, 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. I will now turn the call over to our CEO, Scott Braunstein.
spk09: Thank you, Sasha, and welcome to our call. Today marks a historic milestone for Meredith's CDD patients, their families, and caregivers. following the FDA's approval of oral Ganaxalone, which will be commercially known as Zetalme. Zetalme 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. Zetalme 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 Ganaxalone across a range of seizure disorders and positions us well in our evolution to a commercial stage company. The approval of Zetami 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. We are humbled by the opportunity to make a difference in the lives of patients suffering with CDD. Shortly, our Chief Commercial Officer, Christy Schaefer, will detail how we plan to support access for patients who are prescribed Zetalmy through our patient assistance efforts, including the Zetalmy One program. She will also discuss our commercial strategy, launch preparedness, and pricing. 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. 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. In addition, we believe that there is a broader global opportunity for the Ganaxalone franchise, and we are exploring the potential for additional ex-U.S. strategic partnerships to expand Ganaxalone's 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 TSC 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's success and particularly the role of Anaxalone in significantly reducing seizures, most commonly seen in the refractory TSC population. We gained a tremendous amount of insight from our Phase II trial and used that to inform the Phase III 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. 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 Houlihan, our chief medical officer, in his prepared remarks. Turning to the IV development program, we believe that Ganaxalone 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. 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 three 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 IV Ginex 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 US 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 timelines. 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 Ganaxalone 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. We expect that our phase one new formulation work will be completed by mid-2022. 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. 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. 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 Abbott Therapeutics to license patents and patent applications in the U.S. and E.U., related to the use of Ganax Loan for the treatment of CDKL5 deficiency disorder. The OVID patents originated from a provisional patent application that was filed on August 11, 2016. 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.
spk08: Thanks, Scott, and good morning, everyone. We're extremely pleased to have received our first product approval. Citalmi, 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, difficult-to-control seizures, and severe neurodevelopmental impairment. It's 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. 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 CDD. The approval of Zetalmy and CDD is based on data from a single Phase III double-blind placebo-controlled trial, the Marigold Study, which randomized 101 patients to either Zetalmy or placebo. Those treated with Cytomine showed a median 30.7% reduction in 28-day major motor seizure frequency compared to a median 6.9% reduction for those receiving placebo, achieving the trial's primary endpoint with a p-value of .0036. As a reminder, patients entering the Marigold trial had failed an average of seven prior antiepileptic therapies. In the open-label extension study, there were 48 patients treated with Citalmi 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, Citalmi showed a favorable safety and tolerability profile, and there was a low discontinuation rate. The most common adverse event was somnolence. However, it didn't lead to any patients discontinuing treatment. As we prepare for the near-term launch of Zetalmy and CDD, 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. Conaxolone's unique mechanism of action, its pharmacokinetic and pharmacodynamic properties, and most importantly, 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 meetings in the second half of 2022. Now I'd like to discuss our second-generation Ganaxalone formulations. We've identified Lennox-Gastaut syndrome as the lead indication for a reformulated oral Ganaxalone, 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 I 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 two trial in LGS in the second half of this year. LGS is a rare epileptic epilopathy that can result from many structural or genetic causes. 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 in this difficult to treat disorder. Since the seizure types in LGS are much like those in CVD, we believe Ganaxalone is a promising candidate for development in this syndication. We previously presented a case series of patients co-diagnosed with CVD and Lennox-Gastaut from the Marigold study, the results of which support the rationale for developing Ganaxalone in this syndication. 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 I results and initiate the trial in the second half of this year. Our ProDrug 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 advantages relative to both our current oral and IV programs. The first compound shows a blunted C-max that could potentially allow for once-daily dosing and improved tolerability. The second compound, we believe, could be specifically targeted for an IV formulation. We expect to initiate preclinical testing by the middle of this year. Now let me update you on the Phase III TRUST TSC trial in tuberous sclerosis complex. 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 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 participant seizures. 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, to connect to a placebo added to their existing anti-seizure medications. We expect to include 60 sites, predominantly in the US, Western Europe, Canada, and Israel, and we'll continue to evaluate sites in other countries. As was the case in phase two, the phase three study will enroll patients receiving a genitor and epidiolex, 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 two study that have led to modifications in the phase three protocol. These include an adjustment to the titration schedule for all study participants which we believe will improve tolerability of Kinexolone when added to the medications patients are currently receiving for the treatment of TSC, leading to better efficacy outcomes. 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 U.S. sites and plan 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 three RAISE trial is designed to demonstrate a rapid onset of action and durable SE cessation, the latter 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. we expect to restart enrollment in the RAISE trial in May with new batches of the existing iVEG and Exelon formulation. For background context to our announcement in February, during visual inspection as part of routine stability testing, visible particulates of aluminum phosphate were seen in the drug solution, resulting in a reduction of shelf life. The current formulation with that shorter shelf life will be used to restart the trial. Longer term, We expect to reformulate iVegan Axolone, the new buffer that does not contain the phosphate salts that interact with the aluminum from the glass bottles. 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're on track to put the new formulation on stability in the fall, which will support our NDA filing. Our second status trial is the RESET trial, and in contrast to the RAISE trial, which is focused on refractory SE, RESET is focused on established status epilepticus, which occurs earlier in the status continuum. 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 RAISE 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 SE trial, RAISE-II, 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 iVEGAN-X alone in the US 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 closing, 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 of Regulatory Affairs.
spk15: Thank you, Joe. It is great to be here to speak with you today. With this regulatory approval of Zotomi, we now have our first commercial product. The Zotomi label indication is for patients two years of age and older, with no formal laboratory monitoring required, such as hepatic or hematologic testing, no REM program, and a favorable risk-benefit profile that is well-tolerated when used in combination with other anti-seizure medications. Cetamine is expected to be commercially available following the scheduling as a controlled substance by the U.S. Drug 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 Ganoxone CBD 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 process. We're actively working to prepare the response to the question raised at day 120. As Scott mentioned, we expect the CHMP opinion on the MIA by year end 2022. Now I would like to highlight some of the key outcomes of our end of phase two study interactions with the regulatory agencies in the US and Europe for TSC. As a reminder, we have received orphan drug designation in the US and in Europe for this indication and we believe we have overall alignment on the Phase III TRUST-TSC clinical trial design. Based upon feedback from these regulatory interactions, 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. In terms of the IV can accident development program, 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 III RAISE trial in status epilepticus while we resolved this issue. We subsequently provided the FDA with a full assessment of our strategy to resupply clinical trial material and our projected timing to resume enrollment. To support clinical trial expansion, we are targeting submission of a clinical trial application in Canada by the end of second quarter. Before I turn the call over to Christy, I want to take a moment to thank the entire Mariners 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 two 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 Christy Schaefer, our Chief Commercial Officer.
spk14: Thank you, Kim. The commercial team couldn't be happier about the approval of ZTOMI, the first and only FDA-approved treatment for seizures associated with CBD in patients two years of age and older. CITOMI 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 Marinus, our mission is to dramatically improve lives affected by rare epilepsy, and CITOMI is the first neuroactive steroid GABA-A receptor modulator specifically approved for patients with CBD, an extremely rare disorder. 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 Zatomi to reflect the value it brings to the underserved patient population while balancing our commitment to access and sustainable innovation. Zatomi wholesale acquisition costs 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. Expected gross to net discounts, including mandatory government discounts, are projected to be in the low 20% range. 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 Zatomi requires us to be equally innovative in offering customized access solutions to meet the many needs of our patients. To support the CDD community, Marinus plans to launch the Zatomi One program, a comprehensive patient services program to provide assistance with product access, ongoing support to patients, caregivers, and their medical teams, and financial support to eligible patients. Our goal is to ensure patients have seamless access from prescription through fulfillment. These programs are expected to launch simultaneously with the commercial launch of Zotami in July. Over the past several months, our Master 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 TALME 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. 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. 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. Expanded Access Program to commercial product and treatment initiation for new patients. Our goal is to ensure comprehensive patient access and formulary coverage of Zotomi. Our efforts to secure near-term access will be one of targeted payer and PBN 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. 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 CBD patients and where the centers of excellence are located. 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 Fanstiel, who will provide you with a financial update.
spk04: 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. Before going into that, I'll first touch on the impact of the Priority Review Voucher an Oak Tree 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. 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 Oak Tree 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 2023. We expect the PRV and Oak Tree 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. I'll now move to our financial results. In 2021, we recognize revenues of 1.5 million and 15.3 million for the three and 12 months ended December 31st, 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 barter revenues of 1.5 million and 6.4 million for the three and 12 months ended December 31st, 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. This total amount of $9 million was booked upon signing in Q3 2021. Research and development expenses increased to $18 million and $73.5 million for the three and 12 months ended December 31st, 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 TSC, 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. The primary drivers of the change were increased headcount and 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. Separately, for the full year 2021, a one-time 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 31st, 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 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. 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 Tree Credit Facility are projected to extend our cash runway into the second half of 2023. For the fiscal year 2022, we are projecting barter 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. Now, I'll turn the call back to Scott, who will provide concluding remarks.
spk09: Thanks, Steve. This is an extremely exciting time for our company, and we are hard at work to ensure seamless patient access to Zytomi. 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. 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 CDD 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 TAMI, embodies what Marinus has built on and continues to drive our work every day, commitment, community, and innovation. 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?
spk13: Thank you. At this time, I would like to remind everyone in order to ask a question, press start, then the number one on your telephone keypad. Your first question comes from Joseph Tom with Cohen and Company. Please go ahead.
spk03: Hi there. Good morning. Thank you for taking our questions and congratulations on the approval. Maybe first on the TALMI, 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 the pivotal trial had seen about an average of seven AEDs for their disease. I guess now that there is a specific agent approved, where do you see the Ptolemy kind of falling in the treatment paradigm? Do you think pairs 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 CDKL5? Thanks.
spk09: Thanks, Joe. And nice to hear from you this morning. Joe Houlihan, 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 side.
spk08: Thanks. Hi, Joe. Yeah, I think 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 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'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 it to be earlier than that. But that's, you know, 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 AEDs. But maybe I'll turn it over to Christy for her perspective.
spk09: 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. We opened that up to open label extension, 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. 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 we're looking quite burdensome, 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 significant number of patients already on drugs. But Christy, let me turn it over to you for your expectations. Post to Salesforce and DEA scheduling.
spk14: Yeah, thanks, Scott, and good morning, Joe. Yeah, to the points that Joe and Scott have already made, the Salesforce 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 bolus 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. 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.
spk03: Perfect. That's very helpful. And maybe just one more quick one, if I can. On the second-generation oral therapy, kind of what are you looking for in the Phase 1 update mid-year to give you confidence to go into the Phase 2 for LGS? Is it really just safety and that you're hitting the predicted PK, or is there anything else that you're looking for in that data set? Thanks.
spk08: Yeah. Scott, I can take this one. Yeah. No, we're looking for... Yeah, it's mainly safety and, well, mainly PK and safety. The profile for the PK looks good. 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. We have the prodrug in development, and one of the aspects of the prodrug is potentially 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.
spk09: 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 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. So, you know, to Joe Houlihan'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 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.
spk03: Perfect. Thank you, and congratulations again. Thanks, Joe.
spk13: Your next question comes from Mark Goodman with SVD Laring. Please go ahead.
spk07: Yes, good morning. Scott, can you talk about the RSC protocol amendments and just give us an understanding of when you first mentioned this problem with the batches last month and where we are today, what have you figured out and what is still yet to figure out as far as your confidence in meeting this new timeline? Thanks.
spk09: 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. 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 re-engage and the world is in a better place and we have a meaningful number of sites up, managing the supply 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 actually making a fresh batch. We originally thought that batch would take an order of three to four months, and we've been able to cut that down to now less than three months. And, you know, potentially we're looking to do even better than that. So that supply will be back in the clinic. 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 is coming from the glass vial itself. We never saw this in the phase two supply. 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 two. But what the team has already realized that if we change the buffer system, then we will not have this particulate formation. 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 was unusual to us all. And I really am proud of how quickly the team has responded. It's interesting. I had never seen this problem before in my career, Mark. 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 we're looking to improve upon on the margin help enrollment. But Joe, do you want to talk about the amendments that we've already put in place?
spk08: sure sure scott yeah um i mean as scott said we've spent a lot of time talking to investigators um one-on-one calls and um 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 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 feedback we'd gotten from the investigators, particularly off hours, 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 getting an EEG overnight, which is critical to assessment of status and our 30-minute endpoint status cessation within 30 minutes. Instead of having to have all the EEG techs come in, this rapid EEG can be placed with, 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. 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, you know, regather the investigators, the impact, the major impact by far was COVID. 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 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.
spk17: Thanks.
spk12: Your next question comes from June Lee with Truth Securities.
spk13: Please go ahead.
spk05: Hi. Thanks for taking our questions, and congrats on the approval of the TAMI. You know, on the IV program, were any of the RSC patients dosed with the material past the quote-unquote new expiration date given the unexpected shorter shelf life? 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? And I have a follow-up. Thank you.
spk09: Yeah, well, let me take a few pieces of it, and then I'll turn a little bit over to Joe as well, June. Thanks for the question. So for the RSC trial, for RAISE, that trial has been only U.S. So Eastern Europe, and certainly the supply 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. 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, if we do not see another variant that does unusual things to the hospital, then we should be in very strong shape moving forward. From a resource allocation standpoint, there are still some challenges with nurse coordinators leaving their posts and a shortage overall, but 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 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. So, you know, I put on my medical hat and, you know, I think the risk of thromboembolic 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, you know, give the FDA comfort on safety there.
spk08: Yeah. Yeah, we've been very transparent with the FDA about the particulate issue. We don't see any safety concerns in terms of the patients who received the drug. 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?
spk05: Yes. That's very helpful. I mean, I guess more pertinent for me was any expectations that potency might have declined as the particulates form.
spk09: Oh, no. Let me take that, Joe. Yeah. Particulates are independent of either Ganaxilone or Captizole. So we feel very confident about the potency of the drug. And that Naxolone and, you know, Captozol were in their normal state. This was purely a function of a metal leaching from the glass vial and bonding with a buffer. And because it was a metal, the particulate was, it was a bit of a glistening particulate. So Not sure had it not been a medal that it ever would have been seen, but we feel very comfortable that Naxal in itself was completely intact. Joe, anything else you want to add?
spk08: 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 concerns. Great.
spk05: 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. I'm 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, anything you've heard from the payers. on that. Thank you.
spk14: Hi, June. This is Christy. 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.
spk05: Thank you. And congrats again on the approval. Thank you.
spk09: Thanks, June. Appreciate your support.
spk13: Your next question comes from Douglas Sao with HC Wenright. Please go ahead.
spk11: 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, 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 the TAMI should fit in within the treatment paradigm? And obviously, it's very differentiated. It's the only one with the labeled indication for CDD. Thank you.
spk09: Doug, let me kick it off, and then I'll maybe turn it over to Joe and Christy. So remember, because CDD is such a significant neurological disorder. These kids are all 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 and have less than a 15% 1.5 responder rate over the course of one year. 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. And let's not also forget that the CDK Alliance and The other alliance groups that work with CDK families are very active and also a big supporter and helpful in giving advice to families. So maybe I'll stop there. Joe, anything you want to add on the treatment paradigm before we turn over to Christy?
spk08: Yeah, we've talked about the double-blind data. The patients had a 30.7% reduction in seizures. The patients who stayed on it for at least a year, that reduction was 49.6%. So just about half the patients are just about 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 kind of specific to this condition is the patients have a honeymoon period with the drugs. They start on the drug and they tend to have a very limited duration of efficacy. So I think, 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 physicians 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 Christy, see if you have any comments.
spk14: 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 will have education surrounding that and certainly surrounding the ICD-10 code, but also just thinking about inclusion criteria failing to prior anti-epileptics. Those being the two major hurdles, looking at Marigold, we think that kids at the age of two years old will have quite a significant opportunity to get on drugs. 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 two anti-epileptics, we believe most two-year-olds will be available for drugs.
spk17: Okay, great.
spk11: And if I can ask a follow-up on the prodrug, I think, Scott, you indicated you have potential prodrug candidates for both the oral as well as IV. I'm just curious, from the IV standpoint, Would that be utilized, or 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.
spk09: Thanks, Doug. I would say our focus would be on the status program first and foremost. Capsazole is great that it makes Ganex so insoluble, but it has limitations. We certainly are limited in the daily dosing. Today, the FDA really allows us as a company to use 50 grams of capsaicin all over 24 hours. So that's our 830 milligram dose in the Phase III RSC trial. Physicians have done EINDs in super refractory status and are treating upwards of 1,000 patients. milligrams of Ganaxolone, which is about 63 grams of Capsazole. 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 Ganaxolone could be quite meaningful and beneficial for those patients. So I would say first and foremost, that's where I'd like to see us go. 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, cap-dissolve slightly slows the gamaxone going to the brain. Now, you see very high blood concentrations very quickly, but theoretically, a Ganexolone product without captozole may actually get to the brain quicker, may increase the opportunities for us to use it in other settings. We know that BARDA, as an example, very interested in IM formulation. So it creates a lot of opportunities for us to do some different things. And, you know, 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 C-max. And I think that really creates a unique opportunity for 24-hour dosing and the ability to use in other therapeutic disease states that, you know, require chronic dosing. So we'll be keeping a close eye on that. 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, even the first pro-drug program for newer opportunities on the oral side.
spk17: So let me stop there. Okay, great. Thank you.
spk12: Your next question comes from Andrew Tse. With Jeffries, please go ahead.
spk01: Okay, thanks. 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? 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 as well. Thanks.
spk09: Joe or Kim, do you want to talk about the label?
spk17: And then I'll turn it over to Christy. Kim, do you want to start?
spk12: Sure.
spk15: So I think the label, actually, we were very pleased with the label that we ended up with. I think it was 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 showed the FDA's collaboration with us moving forward, and I think we're very pleased with the label.
spk08: Yeah, I mean, I was pleased as well. I think, as Kim mentioned, we've had very transparent and productive discussions with the FDA all the way along.
spk17: I think it's a very solid label, and we're very pleased. Chris, do you want to talk about the market opportunity?
spk14: Sure. It's a great question, Andrew, 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 going to 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 the long-term care facility settings. which creates another host of challenges for a commercial team to address those patients. 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 adult epilepsy community. But today, we believe that most diagnostic rates and treatment centers are going to be surrounded around the pediatric patient.
spk09: Thanks, Chrissy. 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 2 to 21. 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 the seizures associated with CDKL5 deficiency. 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. 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 21, 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 efforts.
spk01: Got it. Thanks. And thanks for the caller. And will prescriptions be trackable on Ikevia or Symfony?
spk09: I think the answer is going to be no because we're going to have a single specialty distributor. Okay. Very good. Thank you, guys. Thank you.
spk13: Your next question comes from Jay Olson with Oppenheimer. Please go ahead. Go ahead.
spk10: Oh, hey. Congrats on the Zitalium 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.
spk08: Sure. Yeah, this is Joe. 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. So we're going to have a good presence at meetings. Feedback on the posters has been very positive. I think 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 RAISE study and other neurocritical care specialists and neurologists interested in status epilepticus.
spk17: So it was an extremely productive meeting.
spk10: 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? And finally, what is your estimated valuation for the PRV and timeline for monetizing that?
spk09: Steve, do you want to take it or you want me to give a little background on OVID or you're good to go?
spk04: Yeah, Scott, if you want to touch on OVID and give background, I'll jump on the PRV next.
spk09: Yeah. So, Joe, as a reminder, the folks at OVID filed patents on the use of CDD, of Ginexilin and CDKL5 deficiency disorder. 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 Gnax 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. I think Ovid was very reasonable in their request for the value of those patents. And we certainly think that we've now in-licensed a new patent for the use of Ganaxilone and 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, Abbott 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. Steve, do you want to take some here?
spk04: Yeah, Jay, happy to jump in and talk about the PRV. Just as a reminder, it was because of the rare pediatric 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 commoditized products. 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 would anticipate we can execute an agreement in Q2. There is a potential for a 30-day HSR review. It depends on kind of the parties involved and the amounts. But all the recent transactions we've seen, say, over the past, call it 12 to 15 months, have been in the 100 to 110 million range. At the end of the day, it'll be a supply and demand question. But, you know, that's where recent transactions have been.
spk10: Super helpful. Thanks for taking the questions. Thanks, Jay.
spk13: Your next question comes from Brian Scorney with Baird. Please go ahead.
spk02: Hey, good morning, everyone, 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. Just wondering what the gating factor is on these two. Is this just limited to the supply issues, too, or is part of this delay related to European clinical trial site issues?
spk09: Let me take the RAISE questions, and then I'll pass it over to Steve for the first question. 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. 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. 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. And so we're going to use our new batch material for RAISE 2, and that naturally just pushed the timelines out an extra quarter in terms of of creating the CTA and the IMPD for the European study. So it was really just a timing issue so that we could use new supply for RAISE-II, 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.
spk04: Hey, good morning, Brian. 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 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 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 said, hey, at about four and a half years old, that's around 16 kilograms of The actual kind of max weight based on the dosing is actually at 28 kilograms, which is a little over 11 years old. So we would expect over time, as patients are on this chronically, that four and a half year old average will shift up. But 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, three year olds in. So Kind of hard to predict, you know, what percent, you know, will be at over that, you know, that max weight. But I would say, you know, 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 answer your question?
spk02: I think I was actually asking more in four, whatever the child's weight is, how many of them actually get to their top dose on titration?
spk04: Oh, on the titration piece. Sorry.
spk02: Yeah, yeah.
spk04: Yeah, so, yeah, I can provide some color there. When we look 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 generally said that we think it'll be slightly lower, maybe 80%, 85%, just because you're not in a clinical trial. There might be other reasons that they don't titrate up to that full dose. But we think, you know, in general, 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 63. Perfect. Thank you.
spk12: Your next question comes from Jason Basler with JMP Securities.
spk13: Please go ahead.
spk06: Hi, this is Roy 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 the overall duration of therapy and compliance? Any read through from the extension data? You know, we're kind of looking at a different paradigm to 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 expected. Thanks.
spk09: Let me kick it off and then I'll turn it over to Joe or Chrissy if they have some comments. But 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. 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 idea. patients have a response, they're very likely to have a durable response. Not every patient, but the vast majority of patients appear to have a durable response. That was seen in our phase two open label data. We see it in our phase three. We believe the extrasynaptic activity, really the pan-synaptic activity of Ganaxone is likely to be the rationale for it. 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. And when I look at our two-year open-label data and we see about 50% of patients still on therapy, very much in line with what you would expect in terms of a durable response. Joe, Christy, either you want to jump in and make any additional comments?
spk08: I'll just say one thing briefly and then turn it over to Christy if she has any comments. 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. So we were glad to see that. So anyway, I don't know if that helps provide some additional context. So Christy, do you have anything to add?
spk14: 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, as Tomi, a 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 work and then they stopped working and they needed something new. And so what we're very hopeful for is that Zotami, 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 other things.
spk06: Okay, great. Thank you. That's helpful. And then just a kind of technical question, I guess. So, for the pro-drug candidates, is there any preclinical safety work that you need to do, and is that agreed upon already with the FDA?
spk09: 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?
spk15: 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 pro-drug and which candidates identify to move forward with.
spk09: But we feel pretty good about what we know about the structure of the drug, and the risks are pretty low going in. It doesn't hurt. Got it. Thank you.
spk13: And there are no further questions at this time. I will turn the call back over to the presenters for closing remarks.
spk09: Well, thanks, Operator, and thanks, everyone, for jumping on the call this morning. I couldn't, as we've said it before, 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 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 all in the future. Thanks for jumping on the call today.
spk13: This concludes today's conference call. You may now disconnect.
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