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spk07: Greetings and welcome to the Marinus Pharmaceuticals first quarter 2022 financial results and business update call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. If you would like to remove yourself, please press star 1 again. And now it is my pleasure to introduce your host, Sasha Damouni-Ellis, Vice President of Corporate Affairs and Investor Relations.
spk02: You may begin. Thank you, and good afternoon, everyone.
spk14: With me from Marinus are Dr. Scott Bronstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, and Steve Sandsfield, 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 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 Bronstein.
spk11: Thank you, Sasha, and welcome to our call. This has been an exceptional year for the company.
spk12: marked by the FDA's approval of Zetalny for the treatment of seizures associated with CDKL5 deficiency disorder. We've been diligently preparing to bring our first product to market and are on track to launch Zetalny commercially in the U.S. in July, which Steve will speak to in greater detail. It has also been a busy year on other fronts, specifically advancing our pipeline. We were pleased to announce earlier this month that our phase three double-blind placebo-controlled trial in status epilepticus, the RAISE trial, reinitiated screening and recruitment. Our teams have been working diligently behind the scenes to ensure that sites would be ready to begin screening immediately after we ship new clinical supplies. I could not be more proud of the efforts by the entire Marinus team and the cooperation and dedication of our clinical sites. Moving to our oral Ganexolone program, I'm thrilled to share that we are actively recruiting at U.S. sites for the Phase III TRUST-TSC trial in tuberous sclerosis complex and expect to expand globally over the summer and fall. Site activations continue to advance. We are now planning to expand the trial to include 65 to 75 sites compared to the 60 sites we were initially targeting. in an effort to maximize recruitment and move up study timelines. We are currently planning to focus on sites in the US, Western Europe, Canada, and Israel, and expect top line data in the first quarter of 2024. Now, I would like to give a quick update on our second generation product development efforts before handing it over to Joe for a deeper dive on our clinical activities. The goal of our second generation program is to achieve better bioavailability and expand the therapeutic value of Ganaxalone. We have started phase one dosing of the first next generation oral Ganaxalone formulation and remain on track to announce top line data by the middle of this year. Following the evaluation of the phase one data with the specific goal of achieving more consistent and higher blood concentrations of Ganaxalone, We expect to utilize this novel formulation in a phase two study of Lennox-Gastaut syndrome in the second half of the year. We are excited to follow the progress of the first new formulation of Ganaxolone in over 15 years. I'll leave the details to Joe. Let me conclude my remarks by discussing how we plan on bringing Zitami to patients and families around the globe. We are targeting submitting responses to the EMA's day 120 list of questions for the CDD Marketing Authorization Application, or MAA, by mid-year. With a mid-year submission, we would expect the CHMP opinion by the end of the year. We have been collaborating extensively with Orion, our European strategic partner, as they prepare for commercial launch of Canaxalone should it receive approval by the EMA. In addition, we believe that there is a broader global opportunity and are exploring additional XUS strategic partnerships to expand Ganaxilone's commercial footprint. Our goal is to achieve another strategic partnership by the end of the year. Our organization is committed to expanding global access of the Ganaxilone franchise and helping to improve the lives of more patients suffering from CDD, TSC, and status epilepticus. I'll now hand the call over to Joe for more on our clinical development activities.
spk13: Thank you, Scott, and hello, everyone. I'd like to begin by discussing our IV development programs. We currently have two trials in refractory status epilepticus, or RSE, RAISE and RAISE2. Both Phase III trials are designed to demonstrate a rapid onset of action and durable SE cessation. In the RAISE study, which is ongoing, durability will be measured by prevention and progression to IV anesthesia. which is associated with high rates of morbidity and mortality. In the RAISE-II study for European registration, which is planned to begin in the first half of 2023, durability of effect will be assessed by prevention of any escalation of treatment, IV anesthesia or otherwise, which can also prolong hospital stays and intensive medical care. In addition to demonstration of efficacy, Both studies are designed to allow us to assess the health economic impact of Ganaxalone treatment and its potential benefit on healthcare utilization and cost. As mentioned, we announced earlier this month that screening and recruitment have resumed in the RAISE trial, which we paused after routine stability monitoring showed visible particulates of aluminum phosphate in the IV solution. The chair of the Independent Data Monitoring Committee for the trial, reviewed the clinical safety data, and reported that there were no concerning safety events identified. The study is now utilizing new batches of the current IV formulation. The current clinical trial supply has a shelf life of 12 months, and we are working toward developing a commercial supply with at least two years of shelf life. There are several ongoing strategies to achieve this goal, including modification of the buffer for iVigan Axolone. We don't believe that changing the buffer will require bridging studies, and we anticipate using this improved formulation in our global registration studies. We plan on putting these new batches on stability in the third quarter of this year, with the data from the stability batches included in the NDA filing for status epilepticus. With the resumption of the RAISE study, screening, recruitment, and U.S. site activations continue to advance, with over 50 sites now open. We expect to have over 60 sites activated by the end of the third quarter. Extensive discussions with advisors and study staff have provided insights to inform site-specific approaches to enrollment. Study sites were eager for the trial to resume, and they expressed enthusiasm for continuing to identify and enroll patients to address the considerable unmet need and provide the first high-quality evidence to guide the treatment of refractory status epilepticus. Additionally, a number of sites previously experiencing resource constraints due to COVID-19 have come back to us, expressing their interest in participating in the study. To support recruitment and enrollment, we are expanding the study to include sites in Canada, Israel, and Australia, and we continue to expect top line data in the second half of 2023. Our second ongoing status epilepticus trial, the phase two RESET study, is focused on established status epilepticus, an earlier stage in the status continuum. While the annual incidence of refractory status epilepticus is approximately 35,000, the number of patients presenting with established status epilepticus in the U.S., those failing initial treatment with benzodiazepines, is approximately 75,000 per year. By investigating Ginexalone and established status epilepticus, we have the potential to broaden its utilization in the status continuum. I would note that this broadening to established status is not expected to reduce the eligible population for treatment of RSE with Ginexalone. First, the RESET study is evaluating convulsive status epilepticus, whereas most patients with RSE have non-convulsive status. Additionally, the RESET study will be focused on emergency department treatment, whereas the RAISE trial will predominantly enroll patients from the ICU. The RESET study will investigate Conaxalone as an adjuvant to the standard therapies for established status to determine whether it can shorten the time to onset of effect, as well as improve the overall proportion of patients having complete cessation of status. The study uses a novel sequential cohort design to identify the optimal dose of Ganaxalone in terms of both efficacy and tolerability. The response of each patient cohort will inform the dosing for the next, and the design will provide solid evidence for an optimal dose and duration of infusion to utilize in a double-blind, placebo-controlled study. We're currently working through the community consent process known as exception from informed consent, or EFIC, a pathway for clinical research in patients requiring urgent treatment. We're on track to begin U.S. enrollment in the second half of this year and expect top-line data from the first dosing cohorts by year-end 2023. Patient enrollment in our Phase III RSE trial for European registration, RAISE-2, is expected to begin in the first half of 2023. This trial is designed to serve as a critical piece of the European approval strategy, and we believe it has the potential to further broaden the use of IV Ganaxalone in the US. Moving to our oral Ganaxalone programs, since Scott provided an update on our TRUST-TSE trial in tuberous sclerosis complex, I'd like to spend some more time on our second generation formulations. We believe the new formulation will be the future of the Ganaxalone franchise. The goal of this initiative is to deliver a Ganaxalone formulation with an improved pharmacokinetic profile, including better bioavailability and more predictable and durable drug exposure. We've started a phase one study of the initial second generation formulation candidate and look forward to announcing top-line data by the middle of this year. Following evaluation of this phase one data, we expect to initiate a Phase II study in Lennox-Gastaut syndrome in the second half of the year using reformulated Ganaxolone. Lennox-Gastaut syndrome is a rare epileptic encephalopathy that can result from many structural or genetic causes. It's highly treatment refractory, and we believe a new oral formulation will provide more consistent and predictable exposure to Ganaxolone. which should allow physicians to individualize dosing to achieve an optimal response for each patient. In parallel to initiation of the clinical program in Lennox-Gastaut syndrome, our CMC team is developing a modified release formulation to potentially allow twice or even once daily dosing. This will permit Kinaxalone to be utilized in a broader range of conditions with greater convenience and adherence to treatment. Additionally, a second candidate formulation has been identified, which may have a PK profile to allow for reduced dosing frequency and improved efficacy and tolerability without additional modification of its profile. Phase 1 studies with this formulation candidate are planned to begin early next year. Finally, we've identified two pro-drug candidates that we anticipate advancing into IND enabling studies in the second half of the year. Now, I'd like to turn the call over to Steve for updates on our commercial launch plans for Zetalny and a review of our financial results for the first quarter of 2022.
spk01: Thanks, Joe, and good afternoon to everyone. Before diving into our financial results for the first quarter of 2022, I would like to begin with an update on our commercial preparations for the U.S. launch of Zetalme. As Scott mentioned, we are on track for a July commercial launch of Zetalme in the U.S. following scheduling as a controlled substance by the U.S. Drug Enforcement Administration, which is expected in mid-June. Zetalme will be available through a designated specialty pharmacy and specialty distribution partner. Our commercial launch leadership is in place with 16 field representatives on board and beginning to engage with customers. The team comprises diverse backgrounds with deep promotional and rare epilepsy experience from over 10 organizations. With an average of 23 years of sales experience, all with either epilepsy or rare disease expertise, and with multiple product launches under their belts, we are confident in the team's ability to hit the ground running. To support the launch, we are pleased that results from the Pivotal Phase III Marigold Trial for Zutomi were recently published in the Lancet Neurology and will be available for use by our sales team. A now-approved marketing campaign with fully integrated marketing materials featuring authentic patient stories is on track for our planned July launch. The Zotomi.com website is also now active with designated sections to inform and educate patients and caregivers as well as healthcare providers on Zotomi. Preparations continue to advance for a simultaneous launch of the Zotomi One program. a comprehensive patient services program to provide assistance to healthcare providers, patients, and caregivers with product access and ongoing product support and offers programs for eligible patients who need financial support for their Zytomi prescription. We are working closely with advocacy organizations to increase awareness and provide information about access to Zytomi. We are committed to patients and their families and plan to continue our work with patient advocacy groups throughout our drug development and commercialization efforts. Our market access team has been deeply engaged with both commercial and government payers with a focus on genetically confirmed CDD rare disease patient populations and positioning of Zotomi. The CDD ICD-10 code, which was established in November 2020, is being implemented into practice by physicians and continues to increase month by month. We believe this consistent and high usage of the code will help ensure access alignment with payers and validate our commercial launch planning and preparedness strategies. We will initiate the conversion of patients on the expanded access program and open label extension to reimburse therapy upon commercial product availability in July while supporting a smooth transition. Most commercial and state Medicaid programs are expected to provide access and coverage over a period of six to eight months, driven by both patient need and physician demand through medical necessity requests. However, we can support patient access prior to established coverage criteria through the SOTAMI-1 program. As we evolve to a commercial stage company, we look forward to continuing to update you on our launch progress and the opportunity to make a difference in the lives of patients suffering with CDD. The approval of Zotami provided us with the potential for significant non-dilutive funding in the near term to execute on our business strategy and invest in our future programs. As previously disclosed, we received an additional $30 million in funding under our existing credit agreement with Oaktree Capital, which became available upon the approval of Zotami. In addition, we were awarded a rare pediatric disease priority review voucher by the FDA. We remain committed to monetizing this PRV, and we have seen recent voucher sales continue to exceed 100 million. I'll now move to our financial results. For the first quarter of 2022, we recognized 14.2 million in revenues for the period ending March 31, 2022, as compared to 1.8 million in the same period in the prior year. The increase in revenue was driven by a one-time revenue recognition of $12.7 million related to the previously received Orion Collaboration upfront payment, which is no longer subject to a callback provision as a result of successful completion of required M2 metabolite testing. Excluding the Orion Collaboration revenue, we recognized $1.5 million in BARDA federal contract revenue for the three months ended March 31, 2022, as compared to $1.8 million for the three months ended March 31, 2021. Research and development expenses decreased slightly to $18 million for the three months ended March 31, 2022, as compared to $18.6 million for the same period in the prior year. The change versus the prior year was due primarily to reduce CDD development and safety study activities in 2022, partially offset by increased headcount costs and TSC clinical development costs. General and administrative expenses increased to $11.7 million for the three months ended March 31, 2022, compared to $10.4 million for the same period in the prior year. The primary drivers of the change over the prior year were increased support for scale-up of the company's operations, as well as preparation for commercialization. During the quarter, a one-time cost of IP license fee of $1.2 million was recognized as expense associated with the recently signed agreement with Avid Therapeutics to license patents and patent applications for the use of Ganax Loan in the treatment of CDKL5 deficiency disorder. The company reported a net loss of $19.4 million for the three months ended March 31, 2022, compared to $27.1 million in the same period a year ago. These totals include non-cash stock-based compensation of $3.4 million and $5 million in Q1 2022 and 2021, respectively. The first quarter of 2021 included $2.1 million of stock-based compensation related to a severance agreement with our prior CFO. Cash use and operating activities increased to $27.1 million for the three months ended March 31, 2022, compared to $16.2 million for the same period a year ago. As of March 31, 2022, we had cash and cash equivalents of $126.3 million. We believe this balance is sufficient to fund our operations and maintain the minimum cash balance required under our debt facility into the first quarter of 2023. Now I'll turn the call back to Scott, who will provide concluding remarks.
spk12: Thanks, Steve. This is an extremely exciting time for our company, and we are hard at work preparing for our first commercial launch while remaining diligently focused on driving forward our clinical programs. Operator, can you now open the call for questions?
spk07: Thank you. At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. We'll pause just a moment to compile the Q&A roster. And we'll take our first question from Joseph Tone at Callen.
spk12: Joe, we can't hear you.
spk02: And it looks like... Still can't hear you, Joe.
spk07: Looks like he may have disconnected himself. Let's move next to Mark Goodman at SVB.
spk10: Yes. Can you talk about any learnings from Zorgenics' launch with Pentapolar or GW's launch with Epidiolex that you can apply, you know, to Tommy? And then secondly... Talk about just raise for one second and just enrollment trends. I heard you mention that a lot of these sites that previously had issues with COVID are now back up and coming back to you. Can you just give us some anecdotal information of what's going on out there with respect to actual enrollment and how many patients per site or are happening relative to how you're thinking about it. Thanks.
spk12: Joe, do you want to take raise? And then we'll turn over the commercial piece. And Mark, I think the only comment I'll make before I turn over to Joe is we are still actively opening our sights. We're very comfortable with where we are. And right now, we are very comfortable with our guidance. but I think we'll, and so we're not going to talk specifically about sites and per enrollment per site, but certainly our estimates include our expectation on a certain patient per site number, which is still about 20, 25% of what we saw in the phase two. But Joe, why don't I turn it over to you?
spk13: Yeah, no, Mark, we have had a lot of interest from sites. They're very excited to be getting going again. Some of the sites that initially had declined are coming back to us to participate. Sites are screening and they're very active in getting up and running quickly. As I mentioned, we have over 50 sites that are ready to go or active now and expect to have probably 60 or more by the third quarter. Um, and, uh, you know, we spent the time, uh, during the pause really getting to understand what's going on at the site level. We have some new staff and particularly someone who came from, um, the MGH, uh, hospital pharmacy with no ICU experience. And she's been reaching out to sites and has been great. You know, pharmacists turn out to be probably a key contact at the site level. which is an insight we gained along the way. So very optimistic about, you know, hitting the targets for enrollment and keeping this thing going.
spk12: Yeah, and let me just add, Mark, I think, you know, we were really disappointed that we had a positive trial in February. But at the same time, you know, we're now in the middle of May. COVID numbers from a hospitalization point are as low as they've been in two years. ICUs are less burdened than they've been in two years. Now, we are still facing real personnel challenges, physicians leaving their posts, nurse coordinators leaving. I think we all read that in the New York Times and the Wall Street Journal every day. But now with what we think are our key sites, the hospital systems not overrun, everyone ready to go, I really feel like these next several months are a very fair way to judge what we're expecting in terms of enrollment and what we should see going forward through the conclusion of the study. So we'll make sure to keep you very up to date on that over the coming months, but I will say I feel like this has been now the best opportunity we have to really achieve given where hospitalizations are today and where we are in terms of the numbers. I'm excited about the next few months. It's been a slow start. It's been a terrible pandemic and much worse than we would have ever thought from an ICU perspective. And so we really think this is our best chance to move this study along actively. Christy, you want to jump on the commercial question?
spk07: Sure. Hi there, Mark. Good afternoon. You know, we've done a lot of work to really try and best understand what our key launch priorities should be, and we certainly used the comparator launches from Zogenix and GW to have some key learnings. But, you know, not unlike traditional rare disease launches, really early engagement with both the KOL community as well as with the advocacy groups and, of course, the payers has been very, very insightful to help guide a lot of the assumptions that we had and to inform any near decisions that we had. In addition to that, really understanding what the patients, their caregivers, and the advocacy organizations were going to be looking for from a patient support model. We learned and really felt that an exclusive specialty agreement in this patient population to ensure seamless access was going to be pivotal to our success. And then, obviously, for us, we're going to really need to ensure and we have to really get the Marinus name out there. Similarly, with GW and the Zogenics launches, you know, not big pharma names, we had to create some trust in the community with a new name on the market. And again, that early outreach and early engagement has really helped support that.
spk02: We'll go next to Joseph Tome at Cowen.
spk12: Hi there. Good afternoon. Can you hear me? We can, Joe. Good to have you back.
spk08: All right. Sorry about that. Good afternoon. Congrats on the progress and thanks for taking my questions. Maybe just as we're thinking about the follow-on candidates, we have the modified release and then the two pro-drugs and then the two kind of secondary candidates here. How should we think about advancing those? If they all show intriguing data, would you move them all forward for different indications? Would you try and prioritize one over the other? Kind of how do we think about that?
spk12: And then I'll have a follow-on question too. Yeah, why don't I start, and then I'll turn it over to Jojo. So what we want to see in a proof-of-concept study is there is a correlation with clinical efficacy and blood levels. And we believe that's a very strong correlation from Marigold, and we would expect to see that in whatever formulation we test, but hopefully that will be our first formulation that's moved into the clinic. That's our goal. Then I think where we decide to ultimately go in the epilepsy space is really going to be dependent on which of the three platforms. I would say certainly we have good tolerability issues, which will be, I would presume, some form of a blunted C-max, a good half-life, which will get us to twice a day or better dosing, And certainly we want this to be a pediatric-friendly formulation. So whether it's suspension, whether it's a sprinkle or a solution, we want it to be friendly for the pediatric community. And certainly we're building a strong IP platform around all of those. If we are fortunate to see those things with more than one candidate, And I think that would really give us the luxury about, as an example, using one of our new Ganaxalone formulations in epilepsy, in pediatric epilepsy, and then potentially using a pro-drug as an example, which right now our early data also has a blunted C-max and what looks to be a very prolonged half-life. in other disease states. So that would be the perfect outcome here. I think that we'd have more than one candidate with the potential of more than one indication. They will be very closely monitoring what we see in the depression space as an example today. But certainly our key focus is in epilepsy. Joe, any, Joe Houlihan, any other, any thoughts that I didn't hit that you'd like to add?
spk13: No, just maybe a little bit more about the PK we're looking for. And there are a lot of branch points in the decisions for the clinical programs when we see the profiles of these reformulations. And I think the one, as Scott mentioned, the one that gives us the best exposure in terms of area under the curve and the least kind of variability to speak in trough On the peak side, presumably lowering the CMAX on improved tolerability and increasing the trough will give us more even efficacy. And that's really what we're looking for. I think that'll be the choice to move into either phase 2B or phase 3 with one of those, you know, the more favorable looking peak A troughs.
spk08: Perfect. And then maybe one, just to follow on a little bit on the commercial side, maybe, I don't know if Chris would be the best one for this, but I know in the prepared remarks, there was some mention of payer kind of adoption and populations coming online. But maybe you could just go into a little bit more detail on how that's going to play out with the launch. progress toward any sort of codes that would help ease access and maybe kind of the key inflection points that we should be looking for in the first kind of six or 12 months. Thank you very much.
spk07: Absolutely. Good afternoon, Joe, and thanks for the question. As I spoke earlier, we've been engaging quite significantly already. with the payer community, not only just the large conferences that have most recently come up, like PCMA, AMCP, and most recently, Assembio, I believe, just last week, but really also deeply engaged directly with the largest PDMs and commercial payers, and of course, the state Medicaid plans. Those engagements are focused on ensuring coverage criteria, and making sure that that criteria is consistent with our label. And therefore, we expect pretty rapid adoption of the TAMI as the first and only treatment procedure associated with CDD. You know, the ICD-10 code was established in November of 2020. So, we've gotten some most recent data collections that our operations team is pulling together. even prior to our approval, the ICD-10 code is being utilized. And quarter over quarter, we're finding that that utilization is growing, which is extraordinarily encouraging to us. There will, of course, be another inflection point once the sales team is live and the ICD-10 code is being educated on specifically from a promotional standpoint. That ICD-10 code is going to be key. That diagnosis code along with, you know, the failure of two potential ASMs is going to be the two hurdles that quite frankly for us don't seem like big hurdles right now to get to access for patients. Does that answer your question?
spk12: Yep. Thank you all very much. Christy, maybe a little timing on what you expect from Medicaid reimbursement across the board since it's going to be the biggest payer.
spk07: Absolutely. So just as a quick reminder, we believe that about 60% of the patients are going to be utilizing access through a state Medicaid plan. So with that, it's going to be really important for us, not only internally but with external partners um between you know at the at our july launch till the end of the year we think we'll have access to between 40 and 50 of those payers and then the majority of them about 90 in q1 of 2023 we are targeting 22 major states and those states will be the most populous states um as well as those states that overlap with our centers of excellence so by next year we'll have pretty much full coverage from our Medicaid standpoint.
spk08: Excellent. Thank you so much.
spk07: Thanks. We'll take our next question from Andrew Tai at Jefferies.
spk06: Hey, thank you. Good afternoon. Thanks for taking my questions. My question is actually on TSC or RSC, your phase three programs. I noticed in the CDD publication, there were two interims built in at 50% or 75% of enrollment. So are there similar interim analyses built in for TSC and RSE? And if not, would you consider doing an interim pilot program? Thanks.
spk13: Yeah. Thanks for the question. We do have an interim built in to the RSE study. And that would be at approximately two-thirds of the way through. We looked at statistical modeling for at what point we would expect to be able to stop the trial for efficacy if we showed a signal and also show statistical significance on some of the secondary endpoints, health economic endpoints and so on. That's what we're doing for RSE. Now, if it's enrolling very quickly, you know, the enrollment curves typically, you know, start more slowly and pick up speed. And there's the potential we wouldn't be able to get an interim done two-thirds of the way through before the trial is fully enrolled. And it's a short study. It's an inpatient study. It's only a few days. And so, you know, we did leave open the option to cancel the interim analysis if things are going too quickly. In terms of TSC, I think we're not really considering an interim for TSC, but I think that's something we could reconsider. I think you pay a bit of a price on statistical power with these interim analyses. And we actually ended up not doing the interim for CDD, the second interim analysis, because of what I mentioned earlier. By the time it would have been done, the trial would be finished. So we ended up actually canceling the second one. Right.
spk06: Thanks. And the second question is, you know, given the volatility in the market today, you know, I can argue the cost of capital has gone up. So I guess the next question is maybe talk about your confidence in your ability to get your PRV voucher sold and possibly even striking a synthetic royalty deal. Just curious what the landscape is out there for you guys. Thank you.
spk01: Yeah. Hi, Andrew. This is Steve. We're actively engaged in a process to monetize the PRV. We're working with a financial advisor on the process. We've seen these numbers stay above $100 million, with the last couple being sold at $110 million. So we're pretty confident that we'll be able to execute an agreement here in the near term on that. In terms of royalty monetization, that is available to us under the Oak Tree Agreement. That allows us to monetize up to 5% revenue stream from our business in the U.S. That's something we're actively looking at as well. I think that's how we structure that deal to be able to have that additional flexibility. I think there is a good opportunity to get something done on that in fairly short order as well. And I should add, you know, if we're able to execute both those, you know, I would anticipate that gives us potentially a minimum of another year's worth of cash runway, if not more.
spk06: Okay. So, right, these two potential cash inflows can boost your cash towards 2024 timeframe, basically.
spk02: Yeah, absolutely. Okay, very good. Thank you.
spk07: Hi, good afternoon.
spk04: Thanks for taking the questions. Just to confirm, on the first new formulation, the one that would be advanced into for LGS, it sounds like that focus is going to be on the bioavailability, and that would still be three times dosing and that it's in the second round of next generation formulations that we would potentially look at the reduction in dose and frequency?
spk13: That's right. The first formulation actually won't be intended to have the smoother PK curve. It's really going to move into a proof of concept for some initial safety and PK information. and it would be the modified release of that formulation or the second formulation that would move into full clinical development.
spk04: And when we think about the next generation formulation, do you have any thoughts in how, because obviously it would in some ways be preferable to the original Zotami formulation, and I would think patients or CD patients would be interested in it. How do you approach that, or have you given that much thought from a regulatory standpoint? And I've got one more quick question.
spk12: Let me kick it off, and then I'll turn it over to Joe and maybe Chrissy. But, you know, first and foremost, Doug, I'm really happy with the IP estate that we've been building around the the Ptolemy franchise, and I think that will give us a lot of flexibility down the road. My hope with our lead indication in LGS is that we'll see a meaningful improvement in efficacy. So where we are very comfortable with our 30% delta in CDD, we'd look for a 35% or 40% delta as the goal we're really striving for in LGS. When you look at the subset of patients in the CDD study who had blood levels close to 150 to 175 nanograms, those efficacy results were well north of 40% in terms of seizure reduction. So I think first and foremost, we have to see a delta in efficacy that we would hope to see. To Joe's earlier comment, we have to smooth the PK so that tolerability is not an issue. I think that's an easy one for us to manage. And I think if we hit those parameters, it's going to be a really interesting discussion for us about what's the right approach in TSC and CDD. I mean, my general thought is our TSC studies in a highly refractive population, we continue to hear the unmet need in earlier lines of therapy in TSC. And I certainly think that's a real possibility there. I think in CDD, we're always going to be looking at a highly refractory population by the nature of the beast. But I think that we're already thinking about strategies in smaller ways that we can continue to build on the strength of the franchise. So I'll stop there. I think we've got some time. We've got some economic decisions. Joe or Chrissy, anything that you guys want to add on top of that?
spk13: Just real quickly, I mean, I think Scott said we've been thinking quite a bit about that, looking at the options for patients who want to convert. But as Scott also mentioned, we have a bit of luxury of time to do that and can get some more data in There are a number of options to evaluate kind of the regulatory feasibility of some of those to do that in the most efficient way. So it's still on the table, but we have time to look at that.
spk04: Oh, go ahead. Just one quick question. Christy noted that the ICD-10 code is being used more. I'm just curious.
spk07: why that might be um and what is that necessarily what's your take on that to the market you know it's a great question one that we don't have an answer to and we'll most likely be able to read back once we um once we're out in the field more deeply and gaining some insights but um you know current hypothesis is that this is a super refractory patient population um there are certain pockets of the country that a lot of these patients are centralized in and these kols are are driving this code i'd like to think that the fact that the tommy was approved and on the horizon that there was a lot of disease awareness and education already going on from the kols to the caregivers um so i do think that we've created a bit of noise out in the community already just with the development program and now with the approval so We're hopeful that our sales team will just even, you know, grow that from there.
spk12: And Doug, I'm just going to add, yeah, I feel really fortunate that we have great alliance partners here. And, you know, the Lulu Foundation really drove the ICD-10 becoming a standard code. The first few months, it was quite slow. It really started to pick up, not surprisingly. But, you know, they've done a lot of the heavy lifting, so we have a lot to be thankful for in that regard. Similarly, as IFCR really collects families and an understanding of patients out there. So different than other disease launches, we have a lot of terrific partners that are helping us prepare. And I think the ICD-10 code is just one of those tools. So we have a lot to be thankful for, particularly from the Lulu Foundation in that regard. I think, Doug, I don't know if that's your background. I don't think that's mine. Oh, it was mine.
spk04: Sorry, I was just opening my desk drawer.
spk12: Well, that's okay because Sasha was beating me up. She thought I was doing terrible things on the line. So I'm glad that you passed up to it. No, thanks for the question.
spk07: And next we'll move to Brian Scorny with Baird.
spk05: Hey, good afternoon, everyone. Thanks for taking the question. My question is probably for Joe. On the RESET study, just looking at the study design of the five-patient cohorts, getting dosed and evaluated before selecting the dose for the next five patients, just wondering if you'd help us understand how you sort of think about optimizing here, looking at safety and efficacy for the bolus, then during the infusion, and then durability. I guess, based on your experience so far with iDigenX alone, is there sort of an order of prioritization for those three? Like, do you figure out on sort of a stable IV that you're comfortable with, and then once you maximize that, then you look to optimize the IV side of things, and are you committed to doing all 40 patients, or might you get three cohorts in and feel like it's fully optimized and then move into the double-blind phase? Thanks.
spk13: Yeah, that's a great question, Brian. Thanks. Yeah, so we'll be evaluating. This is actually called a Bayesian optimal interval design. And I got the idea looking at a trial of hypothernia for treatment of infants with hypoxia. And they needed to look at efficacy and safety at the same time and make decisions based on that. And so we have an algorithm. It looks concurrently at the bolus the infusion dose and the infusion duration. So, for example, if the patient gets the bolus and then they start on the infusion and the seizures recur during the infusion, we go up on the infusion dose for the next cohort. If they get the bolus and it's overly sedating at that dose and the status stops, we go down on the bolus dose. And then look at seizure recurrence, whether there's seizure recurrence at each stage, and look at tolerability at each stage. And then we can come up, again, from a predetermined algorithm, what the dose and the duration of infusion would be for the next cohort. And, oh, to answer the second part of your question, no, if we have a good handle on the dose, we'll stop for 40 patients.
spk02: Got it. Thanks. That's helpful. We'll move next to Jun Li at Truist Securities.
spk03: Hi, thanks for taking our question. In the prior comment to a question, you said you may consider doing an interim for tuberous sclerosis study. What would determine that? And for the ongoing trust TSE, you know, what do you and the KOLs view as a hurdle for commercial success in terms of percent seizure reduction or responder rate? Thank you.
spk13: So for the TSC study, one of the things we're going to do is, in terms of medical monitoring, stay in close touch with the physicians about tolerability. I don't have a predetermined sense of an interim. It's a blinded study, so we won't have an idea about efficacy. The one thing we'll know is tolerability, and we're going to need to manage that closely and look at the data and see if there's any relationship potentially between tolerability and efficacy that may make us want to do an interim. And so there are, you know, we don't have set criteria about an interim, but we'll be looking at an ongoing basis, again, mainly at tolerability. And I'm sorry, could you repeat the second part of the question? I didn't catch it.
spk03: Yeah, so for what's the, you know, what do you or the KOLs view as a hurdle for commercial success? of Ganaxalone and Tuberculosis. How do you think, what do you think you need to show in the trial in terms of efficacy or safety or tolerability that was set up for success commercially?
spk13: Yeah, well, I could start and then I could turn it over to Christy. But, I mean, as Scott mentioned, the effect size. We want to see good separation between Ganaxalone and placebo. And, you know, in the CBD study, The main side effect was somnolence, but patients didn't drop out. There were very few dropouts in the study, and I hope we see the same in the TSC study. I don't know, Christy, if you have any comments about this.
spk12: And, Joe, just to remind you, in the powering, the 160-patient study powered for the 90% power, I believe it's a 20% delta, 20, 25% delta, I think. 20, 20% Delta, if I recall.
spk13: It's 20%. It's powered on 20%, I believe.
spk12: Yeah. But, Chris, maybe you want to talk a little bit commercially what you're hoping to see?
spk07: Sure. So, you know, when speaking to physicians first, we know that there's still a very large population in the TSC community that is refractory to current medicine. So we do know that there's a large need. Our 30%, reduction in cdd has been you know really received nicely um and scott's point earlier about lgs the goal will be you know even more once we get to a new formulation but if we find 30 35 in an ultra refractory patient population in tsd i think that that will be received very nicely
spk12: Yeah, June, the only thing, I'd add one or two things just to be crystal clear. Given our enrollment curves and really site activations, with so many global sites coming on in the fall, summer, fall, I think we'll be in the middle of very robust enrollment, kind of third, fourth quarter. And so I'm struggling to see the real possibility of us doing an interim kind of when our all, you know, 70 plus sites are up and running. It's a possibility, but I think it's much lesser so. Whereas with RSC, that's an easier decision given the incidence population and the monthly enrollment numbers being more similar than different, right? Where in a TSC study, where you're really dealing with a prevalence population as we get our sites up, the numbers should increase pretty nicely. So that's at least the way I'm thinking about enrollment. So I do think that you really, it's unlikely that we would do an interim unless there was a specific reason or a signal that we were looking for. And I think the last piece on the commercial side is, I think you know better than anyone, the Epidiolex 25% deltas kind of the bar in TSC, but I think, you know, we'll continue to show really strong durability data in the CDD population. That's clearly very important. We've actually had very nice durability in the open-label phase two of TSC, so those patients responding are still staying on drug. We've seen that in our open-label extension of PCDH-19 as well. So we've got multiple data points on the durability of Ganaxalone, and I think we have no reason to believe that's going to differ tremendously in TSC, and I think that's also going to factor into the equation. So just one or two other thoughts. Yeah.
spk03: Is there any mechanistic rationale why targeting GABA would have more durable effect than epidiolex or other mechanisms?
spk13: Yes. Well, I think, if anything, we wonder whether it's the extrasynaptic activity, activity at the extrasynaptic GABA-A receptor that differentiates that from the benzodiazepines. Yeah, and so, yeah, in the open-label CDD, it looks like we're seeing good maintenance of effect, so especially in that, we're very happy to see that. Great.
spk02: Thank you. Thanks, Jim. We'll go next to Jay Olson at Oppenheimer.
spk09: Oh, hey, congrats on the progress, and thanks for taking the questions. As you prepare for those that saw me launch, can you talk about your plans for physician education and specifically any speaker programs or DME events that you might sponsor at medical meetings? And also, what are the key messages that you want to deliver to these physicians? And specifically, since you have a very broad label, And I guess most of the patients in the Marigold study failed multiple lines of therapies. What is the opportunity to move to Tommy up into earlier lines of treatment?
spk02: So, this is Christy.
spk07: Jay, thanks for the question. There's a lot in there, so you'll remind me if I miss anything. But first, just talking about the traditional outreach to physicians. Yes, we will have a full-blown speaker program and speaker's bureau, if you will. I do foresee that that's going to look a little bit different than the traditional nature. You know, with eight CBD centers of excellence, these KOLs tend to know each other quite well. We will be targeting key physicians and national epilepsy centers that are more out in the community. So there may not be that traditional, you know, 20 physicians at a dinner program versus where we will be focusing quite significantly or those one-on-one interactions when they're appropriate. In addition to that, moving into Q4 of this year into the beginning of 2023, we'll be doing something similar with caregivers and patients as well as organizations. There's a lot of word of mouth. specifically in the CDKL5 community, and we want to ensure that folks have the opportunity to speak to folks on a one-on-one basis where it's more appropriate. Really talking about what we're doing from a communication standpoint. So right now, we're really, really focused on awareness, right? the awareness that Zatomi has been approved, a little bit of disease education. However, these folks, again, in the larger centers typically have been teaching us rather than us teaching them about CDKL5. But really what we're doing with this molecule is we want to make sure that we're establishing Ganaxalone as central to comprehensive CDD management. These kids tend to have lots of different things that are going on with their disease. One of them, and, you know, the one that tends to be the most debilitating. So bringing the attention back to the seizure management is really core to what we're doing here. And then obviously the rapid access to be able to get to Zatomi is the next portion of that education that we need to do.
spk13: Okay, great. No, I'll just quickly add, we have the medical science liaison team out there. They're not only gathering a lot of information about current state of treatment, but also they're able to manage some of the more complex scientific discussions uh a lot of talk about uh you know this is the first drug approved in this class of compounds uh and they're talking about that management of side effects and so on and um the other thing i'll mention is that we've been very successful uh with the publication plan our head of scientific affairs alex ametti has done a tremendous job we had eight presentations at the american epilepsy society and preparing close to that number for this year We were glad to see the paper for the CDD study published in Lancet Neurology, and it got a very nice editorial with it, which we were also pleased to see. So publications are going to be another big piece of things.
spk09: Super helpful. Thank you for that. Maybe if I could just ask one follow-on. As patients move into the open label extension phase of Marigold, are there any observations you could share with us in terms of
spk13: long-term benefits or or safety observations yeah um so i i mentioned briefly i don't have the numbers off the top of my head but we've we've the retention for the open label has been good it's been in line i think with what you tend to see in uh similar populations um and the efficacy uh that we're seeing is good we've had um some patients become seizure free during the open label and real durability and improvement of effect in terms of the patients who remain on the drug. So we're very interested in seeing what happens in the open label. You know, I mentioned durability of effect. It's a particular issue in CVD and there's some experimental evidence that suggests that this extra synaptic activation has particular benefit in terms of chronic durability. So, yeah, I appreciate the question about the open label. So far, we're very pleased with the results.
spk09: Great. Sounds like excellent outcomes. Thank you for sharing that with us, and thanks for taking the question. Sure thing.
spk07: And next, we'll move to Charles Duncan at Cantor Fitzgerald.
spk11: Charles, you still there?
spk12: Sounds like Sounds like we lost Charles. Well, thank you, everyone. Really appreciate you joining the call today. And we will continue to put our heads down, work very hard on our clinical trials. I think Christy's got her team ready for an exciting launch. So we plan on having some exciting updates over the coming months and appreciate you making the time today. Thanks, everybody.
spk07: And that does conclude today's conference. Thank you for your participation. You may now disconnect.
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