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spk02: Ladies and gentlemen, thank you for standing by, and welcome to Marinus Pharmaceuticals' fourth quarter 2020 financial results. At this time, all participant lines are in a listen-only mode. If you require any further assistance at any time, please press zero on your telephone. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star and then number one on your telephone keypad. To withdraw your question, press the pound key. I would now like to turn the call over to Sasha Damouni, Vice President of Investor Relations and Corporate Communications Please go ahead.
spk11: Thank you, and good morning, everyone. With me from Marinus are Dr. Scott Bronstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, Dr. Alex Ahmadi, Vice President of Scientific Affairs, Ed Smith, Chief Financial Officer. Also on the call to participate in the Q&A is Christy Schaefer, our Chief Commercial Officer, and Kimberly McCormick, Vice President of Regulatory Affairs. Before we begin, I would like to remind everyone that some of the statements made today could be termed as forward-looking under the securities laws. These forward-looking statements are subject to certain risks and uncertainties that are associated with our business and covered in part in the company's Form 10-K and 10-Q, as filed with the Securities and Exchange Commission. I will now turn the call over to Scott.
spk05: Thank you, Sasha. Good morning, everyone, and welcome to our fourth quarter and fiscal year-end 2020 business and financial update. The fourth quarter was another period of tremendous progress, providing strong momentum for what is shaping up to be a very exciting 2021 for Marinus. Before I touch on this year, let me share with you some of the highlights from the fourth quarter, which included compelling clinical trial and research presentations, at the American Epilepsy Society annual meeting focused on the use of Ganaxalone in treating both CDD and supra-refractory status epilepticus, raising $70 million in a December equity offering and enhancing our investor base, as well as launching an expanded access program in the United States for patients suffering from CDD who did not participate in our Phase III clinical trial. If we look at 2021, this year has already been incredibly exciting as we have announced several important milestones. Firstly, we are enthusiastic to share promising top-line data from the Phase 2 Violet Trial in PCDH 19-related epilepsy, which Alex will review following my opening remarks. Next, we are happy to report that enrollment will complete this week in the ongoing Phase II trial, evaluating efficacy and safety of adjunctive Ganaxalone treatment in patients with tuberous sclerosis complex, or TSC. The top-line study results are on track and expected in Q3 of this year. Importantly, after analyzing an interim evaluation of the COM study, the open-label Phase II trial in TSC. We are confident that the data supports moving to a global, randomized, double-blind, placebo-controlled Phase III registration trial. Joe will review this in more detail, but our hope is to meet with the FDA to discuss the Phase III trial design by the middle of Q2. In conjunction with this news, we are happy to report that the NDA for the use of Ganaxalone in CBD-related epilepsy is on track for submission by mid-2021. We also reported having enrolled our first patient in the Phase III clinical trial of intravenous Ganaxalone, the RAISE trial, for the treatment of refractory status epilepticus. We continue to screen and enroll additional patients in the trial and look to have the vast majority of sites fully activated by the middle of this year. Despite the challenges that have been created by the COVID pandemic, we continue to believe that we are on track for top-line data from the RAISE study in the first half of 2022. Before expanding on our 21 plans, I would like to turn the call over to Dr. Alex Zimetti, Head of Scientific Affairs, to discuss our results from the VIOLA trial, our proof-of-concept study in patients with PCDH-19-related epilepsy. Alex?
spk03: Thank you, Scott. I'm very excited to share with you the top-line clinical data from our Phase II placebo-controlled study in PCDH-19-related epilepsy. As a reminder, in May of 2020, we announced the truncation of the study as a strategic business decision. As a result of this decision, the study was not adequately powered to demonstrate statistical significance between treatment arms. Nonetheless, we believe the results are very encouraging as they were generated from a well-controlled study and are directionally consistent with the results observed in CDD, further validating the effects of three times a day Ganaxalone dosing. First, I wanted to remind you of the study design. The study included an 8 to 12-week baseline period in which patients tracked their baseline seizure frequency. Patients were then randomized to receive dexamethasone or placebo added to standard of care anti-seizure medications. Seizure frequency was then tracked for the 17-week treatment period. The primary efficacy endpoint was the percent change in primary endpoint seizure frequency during the treatment period relative to the baseline period in all patients randomized. Twenty-one patients were randomized with 10 patients in the Ganaxalone arm and 11 patients in the placebo arm. Patients in the Ganaxalone arm experienced a median 61.5% reduction in primary endpoint seizure frequency compared to a 24.0% reduction in the placebo arm. This directional improvement resulted in a p-value of 0.17. The study was originally designed to further evaluate the hypothesis that baseline endogenous allopregnanolone sulfate levels may predict Ganaxalone's response. Contrary to the hypothesis, the Ganaxalone response observed in this study was independent of allopregnanolone sulfate levels, providing preliminary evidence that Ganaxalone's effects may be observed across the broader PCVH-19 patient population. This finding was consistent with our observation in CDD and provides further confidence that Ganaxalone may have anti-seizure effects across broad treatment refractory epilepsies. Lastly, Ganaxalone was generally well tolerated, with only one Ganaxalone patient discontinuing the study due to an adverse event. All in all, we are very encouraged with these data, despite the study's small sample size. With that, I'll turn the call back to Scott to round out his remarks.
spk05: Thank you, Alex. We are very pleased with the results of the VIOLET study. The data are highly consistent with our expectations and support our belief in Ganaxalone as an anti-epileptic compound with broad applicability. I would like to thank the Marinus team, our physician investigators, patients suffering from PCDH19, and their families for supporting us through this journey. With the help of Alex and his team, we would expect to present data at a scientific meeting later this year, as well as seek a medical journal for publication. As a reminder, This is the first double-blind placebo-controlled trial in patients suffering from PCDH-19-related epilepsy. I would like to turn back to the other important events for Marinus as we look forward to the rest of 2021 and beyond. We remain guided by our basic principles that the organization's work should be both scientifically sound and fill a meaningful unmet medical need. We believe that our NDA submission for the use of Ganaxalone in the treatment of CDD-related epilepsy is the next step in developing a sustainable oral franchise to address the meaningful opportunities that we envision over the long term. While we intend to intensify our commercialization planning efforts in front of a potential mid-year 2022 CDD launch, we continue to progress our oral reformulation and pro-drug endeavors, maintain a focus on our intravenous RSC Phase III registrational trial, and evaluate other opportunities for Ganaxalone in additional orphan epilepsy indications. Based on our progress to date, we believe that Ganaxalone's success in CDD, PCDH19, and our early interim analysis in TSC may pave the path for additional future indications. Our investment decisions will be driven by the scientific rationale of using Ganaxalone in other rare epilepsies, the commercial opportunities, our growing clinical data set focused on TID dosing, and a thorough evaluation of previous Marinus studies, examining trial design, PK data, as well as patient dosing paradigms. We believe that Ganaxalone has the potential to become an important drug in a range of rare seizure disorders. To support these efforts, we continue to build the team and strengthen the organization. We've bolstered our commercial, clinical, legal, regulatory, and other operations personnel. During the quarter, we added several members to the leadership team. including Ian Hunt as Vice President, Market Access and Channel Strategy. Ian will be reporting to Christy Schaefer, who has been building out her commercial team, conducting market research, and developing a reimbursement strategy for both franchises. Dr. Ian Miller has officially joined the organization as Vice President of Clinical Development, reporting to Dr. Joe Houlihan. Ian brings several decades of treating patients with rare epilepsies, has been considered a top-ranked key opinion leader in the field, and has worked with several advocacy organizations in the rare epilepsy space. We are equally pleased to announce that Fred Halperin has joined the organization as Vice President, Marinus Technology. Behind the scenes, we've continued to build out our MSL presence and have been focusing on strengthening our patient advocacy relationships our messaging, and identifying the key centers that are critical to our future success. Finally, a shout-out to Sasha, our commercial and strategic leadership, and the creative team for coming up with a fantastic new Marinus logo and helping align our company mission, which encompasses commitment, innovation, and community. I want to stop for a moment and quickly give kudos to the entire Marinus team. They have battled tirelessly to overcome the many obstacles presented by COVID-19. Their efforts have resulted in extremely positive feedback on the quality and thoughtfulness of our clinical trials, specifically the Phase 3 RAISE trial. As we see signs of hope that the pandemic has begun to subside, We are now fielding several inbound calls from sites interested and ready to be involved in our own ongoing clinical trials. We believe that both our IV and oral programs will yield important therapeutics in major markets around the world. So let me quickly provide the highlights of our IV and oral trials before turning over the call to Joe for a more detailed discussion. Looking first at our oral programs, I am pleased to announce that interim data from the Phase II open-label trial to evaluate the safety and tolerability of adjunctive Gnaxilone treatment in patients with TSC met our safety and efficacy criteria to proceed to a Phase III trial with the first patient expected to be enrolled in the fourth quarter. Once the trial is initiated, We will confirm our expectations for the timing of the top line data. Our goal is to significantly shorten the window between our potential CDD and TSC launches. We also plan to submit an orphan drug designation request for the use of Ganaxalone in TSC later this year. In January, we received a positive response from the FDA indicating that the efficacy and safety data from our Phase III Marigold study in CDD appear sufficient to support the filing of a new drug application. And as a reminder, the sufficiency of the data to support approval will be determined during the FDA review of the application. We'll shortly have our one-year stability data for the oral suspension, as well as a formal update through February of this year from the ongoing Open Label Marigold Trial. We are expecting to complete our NDA package by the end of Q2 and make the NDA submission by the middle of this year. This will be followed by a planned Q3 EU submission. We look forward to Ganastalone as the first potential FDA and EMEA approved medication specifically indicated for the treatment of seizures as a result of CDKL5 deficiency disorder. Keep in mind that if approved, we expect to receive a rare pediatric disease voucher from the FDA. We believe this voucher could be used to significantly strengthen our balance sheet in 2022. We are also enthusiastic that we can drive a strategic partnership outside the U.S. for both the oral and IV franchises, and we are targeting to have a specific European partner in place over the summer. This will be critical for a European launch if Ganaxalone is approved in the second half of 2022. Our IV program for the treatment of refractory status epilepticus, the RAISE trial, as mentioned, continues to make good progress. With the gradual reduction in COVID-19 restrictions, we are opening high quality sites, screening patients, and seeing encouraging trends in the early enrollment. We now expect the vast majority of sites to either be enrolling or to be opened by the second quarter. As a result, we believe that we are on track to report top line data in the first half of 2022. Planning continues for a separate RSE trial to be conducted in Europe to support an EU registration. The trial is planned to commence in the first half of 2022. In addition, we continue to receive requests from physicians to use Ganaxalone in the treatment of super refractory status epilepticus, the most advanced stage of status where patients have failed to respond to IV anesthetics. We firmly believe that canaxolone can provide a rapid onset of action and a durable effect in patients with SE, and that it can potentially play an important role in preventing the devastating consequences of the most severe forms of uncontrolled seizures. Before turning the call over to Joe for more detailed clinical discussion, I want to thank our CFO, Ed Smith, who is leading Marinus to pursue other career opportunities. We have made meaningful progress since Ed joined the company, and he has been a valuable part of our continued development. I speak for the management team in thanking Ed for his contribution to our success and wishing him well in his future business pursuits. We are happy to announce that Steve Fanstiel will be joining the organization as our new Chief Financial Officer. Steve has had a diverse career in finance and strategy, with the majority of his professional experience at Johnson & Johnson, and more recently in leadership roles at Opti-Nose and LifeScan. We look forward to having him join the organization in the mid-April timeframe. With that, I would now like to turn the call over to our Chief Medical Officer, Joe Houlihan. Joe?
spk01: Thank you, Scott, and good morning, everyone. Marinus is focused on a well-defined and strategically targeted program in the treatment of rare epilepsies, where there's high unmet need and where we believe Ganaxalone has true potential to significantly improve patient outcomes. This year, we expect several key data readouts and regulatory meetings and filings, including submission of an NDA for CDKL5 deficiency disorder, or CDD. These activities will further advance Ganaxalone formulations in the treatment of rare and often devastating epilepsies. Turning first to our oral Ganaxalone franchise. In tuberous sclerosis complex, or TSC, we are conducting a phase two open label study called the CALM study, where we had targeted enrollment of at least 25 patients at eight sites. I am pleased to report that we expect to reach our enrollment goal within the next few days. Based on current enrollment, we've conducted an interim analysis that showed that the study has achieved our efficacy and safety targets for proceeding to Phase III. In addition to overall safety and efficacy, the interim analysis provided support for efficacy of Ganaxalone across seizure types, as well as when used as adjunctive treatment with currently available medications, including newer AEDs such as Afinitor and Epidiolex. Top-line data from the study is on track to be available in Q3 2021. Based on the interim results, we are planning an end-of-Phase II meeting with the FDA in the second quarter and a meeting with EMA in the third quarter of this year, and plan to have the first patient enrolled in a Phase III trial in the fourth quarter. We are proposing to the FDA that the study will be a double-blind, placebo-controlled, multicenter trial with a planned enrollment of 160 patients from 1 to 65 years of age with genetically confirmed tuberous sclerosis complex. After obtaining baseline data on seizure frequency, study participants will be randomized to Ganaxilone or placebo and enter a 16-week double-blind phase. After a titration period lasting four to six weeks, they will receive Ganaxalone at a dose of up to 1,800 milligrams per day in three divided doses or matching placebo. Then enter a maintenance period lasting for the remainder of the double-blind phase. Following this, they will have the opportunity to enter an open-label extension in which all participants will receive Ganaxalone. Our positive data in CDD The encouraging interim Phase II data in TSC and the PCDH-19 data that Alex presented are all supportive of what we believe to be Ganaxolone's broad-spectrum efficacy across different seizure types, both focal and generalized. Returning to CDD, I'm pleased to report that we've had fruitful and encouraging discussions with the FDA in advance of our NDA filing. We appreciated the concern of the FDA that the robustly positive results of the Marigold study in CDD follow older studies that failed to demonstrate efficacy. In particular, a phase three study of focal seizures in adults that was discontinued in 2016. A key insight from our review of the data from that and other studies was the importance of three times a day dosing as we used in the Marigold study. versus the twice daily dosing in the focal onset seizure trial. We believe that this information and the consistent results of the Marigold study satisfied the agency that the data from a single study in CDD could support the NDA filing. We plan to follow filing of the NDA very quickly with our EU submission. The open label extension of the Marigold study is ongoing. And we're planning analysis of long-term data to evaluate the durability of effect of Ganaxolone and CDD, a disorder that's characterized by a loss of effect of AED treatment over time. The data from the open label extension will be included in our NDA submission. The Marigold study demonstrated the efficacy of the Ganaxolone three times a day regimen and CDD. Analysis of the PK-PD profile from this and other studies gives us great confidence in the ability of Ganaxolone to demonstrate anticonvulsant efficacy in other refractory epilepsies. In our IV franchise, we announced that we have enrolled our first patient in the RAISE trial in refractory status epilepticus, and we continue to screen and enroll additional patients. In the early phase of study startup, The COVID-19 pandemic diverted hospital resources and slowed site activation. However, the pace of hospitals coming back online for study enrollment has accelerated, and we expect to have most sites activated by the end of the second quarter. We're getting positive feedback that investigators are excited about the study and eager to begin enrolling patients. We clearly see momentum building. Based on this and the early signals about the pace of enrollment, we remain on track for a top-line data readout in the first half of 2022. As we mentioned last quarter, we're initiating a trial evaluating Ganaxalone earlier in the treatment continuum of status epilepticus, in the stage known as established status epilepticus, or ESE, where patients have failed the first line of treatment with benzodiazepines It's estimated there are approximately 50,000 to 75,000 cases of ESE per year in the U.S. The trial is targeting patients presenting to the emergency room with convulsive status epilepticus, with a study design and patient population that parallel those of the ESET trial published last year in the New England Journal of Medicine. We believe one of the keys to a successful trial in ESE is engagement of centers with experience in obtaining community consent and in conducting studies involving the urgent care of patients with status epilepticus. That's why we're enlisting many of the same centers that participated in the ESET study. We anticipate that patients seen in emergency departments in this earlier stage of status and who have convulsive rather than nonconvulsive status may be more treatment responsive compared to patients enrolling in the RAISE study who will have refractory, primarily nonconvulsive seizures. This means that the dose of Ganaxolone necessary for status control will likely be lower than that in the RAISE study. So we are thinking carefully about dosing and the duration of therapy that will be required. The study design we plan to propose to the FDA involves the initiation of IV Ganaxolone at the same time as the first AED following benzodiazepine failure. The trial utilizes a novel sequential design to assess the safety and efficacy of several doses and infusion durations of Ganaxolone, with the optimal dose progressing to a double-blind Phase II study versus placebo. We plan to initiate the ESE study in early 2022 after we've completed the process of exception from informed consent. It's important to note that patients who qualify for this trial have a condition distinct from those with refractory status epilepticus who would enter the RAISE trial. So we can consider the same sites for our established status trial without compromising enrollment in the RAISE study. Quickly following up on Scott's comments about the emergency use of Ganaxalone in super refractory status epilepticus, we continue to supply medication in response to emergency IND requests. Though this condition is not on the immediate horizon for a formal trial, we're learning a lot about the dosing paradigm for Ganaxalone in this very serious condition, which is informing our knowledge about its dosing, potential efficacy throughout the treatment continuum of status epilepticus. Once again, I'd like to thank the patients and their families who participate in these trials. Through your support, we're making significant progress in our efforts to improve the lives of all patients and families suffering from these often debilitating neurologic disorders. With that, I'll turn the call over to Dr. Alex Amedy. Alex?
spk03: Thank you, Joe. I share Scott and Joe's excitement about the progress that we have achieved across our entire clinical development pipeline, as well as the promise for what lies ahead. So let me provide some additional insight into each of those respects. First, in December, we presented additional clinical data from the Marigold Study in CDD at the annual American Epilepsy Society meeting. There we communicated data indicating a consistent efficacy signal for Ganaxalone across multiple patient subgroups, demonstrating the potential for Ganaxalone across the broad CDD population. In addition, we provided evidence suggestive of Ganaxalone's anti-seizure durability in a preliminary analysis of the open-label data, which demonstrated that patients experienced a median 52.7% reduction in major motor seizure frequency when on Ganaxalone for approximately one year. We believe this supports a durable effect of Ganaxalone, and as we have said before, durability of anti-seizure medication is of enormous need to the CDD community and see this as a potential key differentiator from existing therapies. We look forward to sharing additional open-label data demonstrating the longer-term effects of Ganaxalone at upcoming medical meetings. And lastly, we presented data suggesting higher average Ganaxalone plasma concentrations correlated with improved seizure frequency reductions in CDD patients. These data provided additional evidence of Ganaxalone's drug effect and further support three times a day dosing. And as a reminder, the Marigold study was the first phase three study of Ganaxalone that evaluated three times a day dosing, which aims to improve trough concentrations to levels that we believe are important to show a meaningful anti-seizure effect compared to two times a day dosing. Consequently, we feel confident that these findings demonstrate the broad anti-seizure effects of Ganaxalone when dosed appropriately and can be extended to other chronic epilepsy patient populations, including TSC, as well as other future rare epilepsy indications with high unmet need where three times a day dosing would be appropriate. In addition, these findings support our ongoing efforts to develop improved oral Ganaxalone formulations aimed to deliver higher, more consistent Ganaxalone levels, which could expand the opportunities to broader patient populations in need. Again, I'm very excited about our recent pipeline progress and the future scientific and clinical direction that Marinus is headed. With that, let me turn the call over to our CFO, Ed Smith, for a review of our financials.
spk06: Thank you, Alex, and good morning, everyone. Our results for fiscal 2020 reflect results from operations and capital initiatives in support of Ganaxalone development and commercial preparedness activities. As a result of the BARDA contract, we recognized $1.5 million and $1.7 million in federal contract revenue for the three and 12 months ended December 31st, 2020, respectively. There were no like revenue a year ago, As a reminder, our base BARDA contract initially provides $21 million of non-dilutive funding over the approximately next 24 months, most of which will be directed towards our Phase III program in refractory status epilepticus. With options based on success milestones, their funding may increase to $51 million. Research and development expenses increased to $13 million and $51.1 million for the three and 12 months ended December 31, 2020, respectively, as compared to $12.5 million and $43 million for the same periods in the prior year. The increase over the year-to-year period was due primarily to costs associated with enrollment in our CDD trial. Expenses in the current year also reflect increased drug development activity, including preclinical studies and manufacturing activities in preparation for a potential NDA filing for CDD, as well as the recently initiated Phase III clinical trial in RSC. General and administrative expenses increased to $6 million and $18.6 million for the three and 12 months ended December 31, 2020, respectively, compared to $3 million and $11.5 million for the same periods in the prior year. The primary drivers of the increase over fiscal 2019 were increased legal and consulting fees of 2.7 million. Personnel costs also rose by 1.5 million from a year ago as we increased headcount to support the scaling up of the company's operations and prepare for potential commercialization. Compared to a year ago, non-cash stock-based compensation was up 1.6 million. The company reported net losses of $17.5 million and $67.5 million for the three and 12 months ended December 31, 2020, respectively, compared to $15.4 million and $54.1 million in the same period a year ago. Cash used in operating activities increased to $60.9 million for the year ended December 31, 2020, compared to $48.6 million for the same period a year ago. At December 31, 2020, we had cash, cash equivalents, and investments of $140 million, which will enable us to fund the company's current scale of operating expenses and capital expenditures into the second quarter of 2022. We project spend in the range of $18 to $20 million per quarter, offset by approximately $2 to $3 million per quarter in revenue from BARDA, this spend could tick up in the third quarter with the initiation of the TSC trial and ongoing expenses associated with the RSE trial. Keep in mind, these projections do not include potential resources that could be realized through the monetization of the priority review voucher or through European partnership. Before handing the call back to Scott for some closing remarks, as Scott mentioned, I will be leaving Marinus. I would like to thank our investors for their continued support and confidence in our programs. While I've enjoyed and will miss working with many friends and colleagues at Marinus, I am excited for Marinus' future, and I am proud of the finance organization that I now turn over to Steve, who will lead the next leg of what promises to be an exciting journey. I expect a smooth transition and will be from the sidelines as a Marinus shareholder, rooting for Scott and the rest of the Marinus team in what promises to be a bright future. I will now turn this call back to Sasha Damouni to highlight some of the efforts in advocacy and branding. Sasha?
spk11: Thanks, Ed. We recognize the value of meaningful partnerships and collaborations with patient organizations who serve communities that we are striving to bring beneficial change to. Recently, we've made considerable efforts to strengthen existing and build new relationships with key organizations within the CBD, tuberous sclerosis, PCDH-19, status epilepticus, and broader epilepsy communities. We aim to work alongside these groups to help increase disease awareness and education in an effort to improve the overall quality of care. We thank the organizations for their partnership and believe we can more efficiently progress the field by working together. As mentioned earlier, we have rolled out our expanded access program, providing access to Ganaxalone for patients who did not participate in the Marigold study, and we are working closely with the advocacy groups for awareness throughout the patient community. I'd also like to mention that Marinus has launched a new branding campaign and logo to highlight our guiding principles of commitment, innovation, and community. We believe we are at an inflection point in our company's history with the potential launch of our first treatment and believe that we should communicate broadly these principles to our important stakeholders, including patients, their families, the epilepsy community, the medical community, and our investors. With that, I would like to turn the call back to Scott before we enter the Q&A portion of the call. Scott?
spk05: Thank you, Sasha. Once again, on behalf of everyone here at Marinus, I want to wish Ed the best of success in his future endeavors. Before opening the call to questions, just let me conclude with a few final thoughts. Importantly, we are dedicating resources for future oral formulation development in the hopes of achieving improved PK properties that ultimately could lead to incremental clinical efficacy. We have recently filed a series of patents that support two of these ongoing research efforts. Our current goal is to have at least one second generation formulation in the clinic in 2022. Additionally, we continue to expand and strengthen our organization. We have added recent high-quality hires throughout the team, including clinical operations, regulatory, human resources, and legal, to name just a few. We are thrilled to have Steve Sansil, our incoming CFO, join the team next month. We expect to have head of both sales and marketing hired by the middle of this year as Christy Schaffer continues to round out her senior leadership team for the commercial organization. And finally, let me echo the sentiments of everyone here at Marinus when I say how grateful we are for the continued commitment and dedication of the study site personnel, our investigators, our patients, and their families. as well as everyone who has been supportive of the company's efforts through these trying times. I also want to thank the Marinus team that has worked tirelessly through what feels like thousands of Teams and Zoom calls and have not been deterred by the headwinds created by the ongoing pandemic. And with that, we will now open the call for questions. Operator?
spk02: Thank you. If anybody would like to ask a question at this time, please press star 1 on your telephone keypad. Again, that would be star 1 on your telephone keypad. Your first question comes from Joseph Thome from Cowan & Company. Your line is open.
spk00: Hi there. Thank you for taking my questions, and congratulations to Ed and the rest of the team on some great progress. First question for me is just on TSC. You indicated the interim analysis met the efficacy and safety targets that you had laid out. If you could just give us a little bit more detail on maybe what that efficacy target was that gave you the confidence to move into Phase III. And then second, as you are approaching CDD and have some positive TSC data here, maybe how are you thinking about initial pricing decisions and kind of what information has gone into that? Thank you.
spk05: Good morning, Joe. Thanks for the question. This is Scott. Let me handle the TSC question. So as Joe mentioned in his prepared remarks, We looked at several criteria for the phase three go, no-go decision. We looked at overall efficacy, and we were looking for a consistent signal, similar to what we've seen now in CDD and PCDH-19. That is a meaningful number of patients overall having what we view as an important clinical response. Secondly, Joe spent a lot of time looking at seizure types. And we wanted to see a differentiation in improvement in different seizure types. And I'll let Joe expand on that. Third, I think it was critically important from a commercial standpoint that we see efficacy in patients who were refractory to all standards of care, including epidiolex. And we've had several patients in the Phase II study who who were either on Epidiolex who had failed Epidiolex, and that was an important go decision for us. And I think, finally, we were looking for what we typically would think about as, you know, a responder analysis where patients are having 40% or 50% response rates and looking at the percent of patients who are having meaningful clinical responses. So all of those factors played in our decision. We're not going to give any more specifics on that. Before I turn it over to Christy to talk a little bit more about pricing, Joe, anything else you want to add on that topic? on our TSC decision?
spk01: Yeah. Well, hi, Joe. Scott mentioned seizure types, and we know from CDD the drug has efficacy across what we call major motor seizures, drop attacks, and convulsions. Those are generalized seizures. In TSC, the patients predominantly have focal seizures because they have lesions often in the brain. uh so the seizures start in one location vocally and i just wanted to make sure that we showed the same trend in efficacy in the focal seizures as we do in the generalized seizures and we saw a good signal there so that was part of the decision to proceed christy you want to jump in and talk a little bit about pricing
spk12: Yeah, absolutely. Thanks, Scott. It's a pleasure to meet you, Joe. Thanks for the question. As you can imagine, we're dedicating a significant amount of time to our pricing and value construct for both the oral suspension and our IV franchises. So specific to CDD, to establish our value, we've done quite a bit of work that's been dedicated to understanding our patient journey, their treatment landscape, and any access hurdles there are for our patients. So understanding that for CDD will be the first and only indicated brings a lot of optionality. However, we're designing our thoughts around both indications So both CDD and TSC fall into a traditionally defined orphan disease model. And we have prior launches, both in and out of the space, to look to as reference points. So nonetheless, we have confidence in Ganaxlan's ability to address the significant unmet need and the fact that it's highly differentiated. So where we ultimately land on price will reflect that.
spk00: Great. Thank you so much.
spk02: And your next question will come from Douglas Tasso from HC Wainwright. Your line is open.
spk10: Hi. Good morning. Thanks for taking the questions. Just, Joe, as a follow-up to that last comment, obviously with the TSC data, we've now gotten some evidence of effect in both general as well as focal onset seizures. I'm just curious, you know, for you, Joe, as well as Scott, you know, what does that potentially mean In terms of the future development, how does that affect your thinking about development across epilepsy?
spk01: Yeah, that's a good question. I think it gives us confidence about the drug being a broad-spectrum agent. As I mentioned in the remarks, one of the older studies in focal seizures, a Phase III study, failed to show efficacy. in phase three, although it did in phase two. The larger study, it did not. So now this gives us confidence about the seizure types and then also further reinforces the PK aspect of it with three times a day dosing. With this formulation, it's important to have adequate levels throughout the day. So I think it tells us something about that as well.
spk10: And You know, Scott, you've also spoken a lot about sort of new formulations. How quickly do you think those could be sort of advanced into the clinic? And obviously, how do you sort of weigh that balance between advancing with the current formulation, which seems to be having quite a good effect, versus, you know, perhaps slowing down, but advancing with the formulations that could have, you know, better commercial potential or just sort of clinical effect? Thank you.
spk05: Yeah, thanks for the question, Doug. I think at least what we've shared with you in the CDD trial, certainly in the PCDH-19 trial, and our early look at the TSC data, we're seeing a consistent signal of somewhere between 7 and 8 out of 10 patients having a meaningful clinical response, and we think that meaningful clinical response is clearly tied to to drug PK, bioavailability, absorption, and serum concentrations. So we know from our market research that if we have a meaningful effect that's durable in these patients, that's a very important drug. And to your comments, Doug, we feel very good and the best certainly I've ever felt about our current oral suspension three times a day dosing. That being said, I think we can make this drug incrementally better. I would like to see all patients have good absorption. I'd love to give physicians the opportunity to dose titrate. If patients, let's say, are absorbing and having blood levels somewhere between 50 and 75 nanograms per mL, and still having seizures that physicians could titrate to 100 to 150 nanograms per ml, we are quite convinced that that would have a meaningful effect on the number of seizures patients are having. So we're really targeting two parameters in our second-generation programs, and we certainly believe it will incrementally improve the efficacy of the drug. We've talked about it a lot, Doug, that we have a few different formulation plans in place. They're not expensive. We've made a tremendous amount of progress. As I commented on the call, we've now filed a series of patents in at least two different novel formulations. We're excited about that. And we think we can move pretty quickly, and our hope is to have one of these compounds in the clinic in 22, possibly two in 22. And again, we'd be looking to incrementally drive the efficacy of the drug. And I think it never would hurt to smooth the peaks and troughs of a drug that you're looking for steady-state doses. So let me stop there, and Operator, thanks, Doug. Let's move on to the next question because we're a little tight on time today.
spk02: Okay. Your next question will come from Althea Young from Cantor. Your line is open.
spk09: Hey, guys. Thanks for taking my question. And, Ed, wishing you all the best and great working with you. So a couple. One, can you just talk a little bit about with RSE, you know, your decision to make a separate study in Europe? Is that potentially due to kind of different treatment protocols there for refractory status. And then just another question, can you just talk a little bit more about the safety event, the series A that was seen in the CCDH study that was attributed to the Naxalon? I mean, do you think there's anything to make there, you know, as it relates to the asset? I mean, I know it's well characterized and it's pretty low rate, but just wanted to get any color there, I think.
spk01: Yeah, Scott, I could take those. So in terms of the serious adverse event, I'll take that one first. It was what the investigator characterized as psychogenic seizures and attributed it to the drug. I won't say anything that minimizes the event. I think that the patient needed to be admitted for EEG monitoring. to characterize the event. And because it was a hospitalization, that means it's a serious adverse event. The severity was characterized as moderate. Psychogenic seizures are sometimes called more contemporary terms, non-epileptic seizures, meaning there's no electrical discharge in the brain. It's felt to be a behavioral symptom and not something we see much of. And in terms of the U.S. versus Europe, initially that was the rationale for having a separate study. The treatment is different in Europe. They're less inclined to progress patients to IV anesthesia for treatment of refractory status than in the U.S. and tend to use a number of different anti-epileptic drugs before taking that step, particularly for non-convulsive status. And so it evolved over time. It evolved into a different study based on our design considerations and regulatory feedback. I think we've got now a complementary study to the U.S. study. In the U.S., they have to have failed at least two IVAEDs. In the EU, it's going to be at least one. And there are other design differences that make it actually a study that complements rather than duplicates the U.S. study. So we're very pleased with how things are going there.
spk09: Great.
spk01: Thank you.
spk08: Yeah, sure.
spk02: And your next question comes from June Lee from Tourist Securities. Your line is open.
spk08: Hi. Thanks for taking our question. For the TSC program, are you able to disclose how many of the planned 25 total patients were part of the interim look? And is there any strategic reasons for meeting with the FDA in second quarter with interim data as opposed to meeting in third quarter with the full data? Have you done any statistical work that would suggest that no further changes in the full data set is expected? And lastly, did the TSC study also stratify based on aloes? And if so, did you also not see any sort of difference based on that baseline and just see broad effect across the board? Thank you.
spk05: So it's a great question, June. Kim, maybe you want to just talk about the regulatory strategy for TSC, and then if Joe has anything to add, and then we can have Alex jump in and talk about the ALA signal.
spk13: Sure. So we do plan to submit a request to discuss the Phase III study with the FDA once the term cut. We're not waiting until the completion of the entire study. There is time it takes to submit the briefing document and have the meeting. So that meeting is targeted by the end of second quarter and then subsequently in Europe shortly after that. So the plans are to take the interim look to the FDA to support our phase three, assuming that we feel that the data is robust enough to support the phase three program moving forward.
spk05: So, Kim, maybe a little bit more specifically, June was really asking why the interim cut rather than the final cut. So maybe you should talk a little bit about, you know, our goal in terms of safety and meeting with the agency.
spk13: Sure. I think the agency is very, what's most important to them is the safety of the data to support a phase three as well as the signal. And I think we feel strong based on the interim cut that we'll have strong enough safety support from the study supported by our CDB and our other large database to take to the agency. So I don't think it'd be required to have the full data set in order to speak to the agency and get collaboration and agreement on the phase three study design. Does that answer the question, Scott?
spk05: Yeah, I think that's good. In June, just to complete the thought, we looked at about half the study population who had received drug for at least four weeks. And as a reminder, when we looked at the Marigold study, the efficacy of Ganaxolone is really the same at the four-week period as it is at the 12-week period. So we were able to look at about half the study population and take at least a four-week look at the data set. Alex, you want to talk a little bit about the biomarker?
spk03: Sure. Thanks, Scott, and thanks for the question, June. So before I talk about the allopregnanolone sulfate in TSC, I just wanted to quickly comment on the use of it in TCDH19. As everyone's aware, that study was designed to appropriately test the hypothesis whether endogenous allopregnanolone sulfate levels could potentially have a predictive effect on Ganaxilin's response. And as a result of that proper clinical trial design, I can say today with a higher degree of confidence that that does not appear to be the case. And although we recognize that a predictive biomarker for epilepsy is of high value, again, I think these data that we've shown here, the positive effects seen now in the broad CDD population and the suggestive beneficial effects in the broad PCDH19 population with three times a day dosing is significant. probably not surprisingly, a better predictor of Ganaxolone response. Now, to your specific question, we are going to explore baseline allopregnanolone sulfate levels in TSC patients, but they are not stratified in that study, and the primary efficacy endpoint is in all patients enrolled.
spk08: Thank you.
spk02: And your next question will come from Mark Goodman from SVB. Lyrinc, your line is open. Okay.
spk04: Scott, can you just talk to us about European partnership and how you're thinking about it? What is the optimal kind of deal in economics? And, you know, just to give us some baseline of how you're thinking about that. And then just secondly, can you just remind us of what is going on behind the scenes with increasing testing, just so when your product hits the market, you know, will there be complete testing for CDD? Will there be testing for COVID? you know, TSC, just to make sure we understand that. Thank you.
spk05: Thanks, Mark. And maybe I'll pass a little bit of the testing over to Christy as well, because we're getting a lot of feedback from our market research in terms of where some of the trigger points are in terms of early diagnosis. But specifically on the partnership, Mark, we've had some great discussions with several organizations. The vast majority are focused in Europe. Several have some reach outside of Europe. We have some folks who are primarily focused on the orphan disease business. They have more of a specialty of focus, and certainly that's intriguing to us. We have other strategic partners, interestingly, who have and interest in both orphan and the hospital space, and that certainly has a different level of strategic interest to us. Now that we have good confirmation on what's needed in Europe for the IV program, we certainly want to make sure that we take full advantage of thinking about pricing and the commercial opportunities sooner rather than later. We still have a really important strategic decision ahead of us, which I think there's rationale for partnering both programs to a single partner. There's rationale for just partnering the oral program, and we would continue development of the IV program ourselves. And I think either way, Mark, we're going to lead the research effort for both the global TSC program and the European IV program. In terms of the economics, we're really thinking about the long-term MPV of the business. We have a lot of confidence in the business. Our balance sheet is certainly much stronger than it was, but some upfront payments and reimbursement around research and development will certainly extend our runway. So a combination of upfront commercial and research reimbursements are important to us. But certainly, as you would expect, we are really interested in what the royalties are going to look like, particularly as the product grows. And, again, I think a key focus for us is reaching NPVs that are really equitable for both parties. So I think I covered your question, Mark. Was there another question that I missed? I apologize.
spk04: Just on the genetic testing.
spk05: Oh, genetic testing. Sorry. Chris, do you want to jump in and take that?
spk12: Sure. So for CDD specifically, over the past six to seven years, it has become widely, widely acceptable, and it used genetic testing for CDD. When these patients present early in life, typically within the first few months of life, it's widely acceptable to have a panel, and there are several that physicians look to do these genetic tests. So early diagnosis in CDD is something that we will rely on. As we all know, these patients tend to cycle through different anti-epileptics in their first few years of life. So by the time they get to us at the age of two, they will have, you know, 85% of these patients will be considered refractory. So we believe, again, early diagnosis and the high refractory rate will bring us a large part of the patient population.
spk05: Thanks. Thanks, Mark. Operator, we have time for one more question. Before we also wrap and take the last question, we just wanted to remind the investor community that we have posted a new set of slides on our website, and those slides do include a little bit more detailed analysis of the PCDH-19 trial as well as our Phase III TSC trial design. So just as an FYI for individuals, Operator, why don't we move to our last question?
spk02: Okay. So our final question today will come from Jay Olson from Oppenheimer. Your line is open.
spk07: Oh, hey. Congrats on all the progress, and thanks for taking the question. Can you share any anecdotal feedback you've gotten from physicians or patients who received compassionate use of Ganaxone for super refractory SCs? And I think you said that a clinical trial in SRSC is not on the table at this time. But would you consider one in the future? And what are some of the lessons learned from the SAGE study in SRSC that didn't work out that might influence your decision to do a study or not or how to design that study?
spk05: Thank you. Thanks, Jay. Let me take a little bit of that question, and I'll pass over to Joe for the clinical experience. Okay. Certainly, we are going to support the research community If drug is requested on an EIND basis for patients with super refractory status, we are certainly going to provide drug when we can. We're learning that these patients can be extremely difficult. We've already been dosing patients at higher doses than our Phase III dose, over 1,000 milligrams per day, where we're going up to 63 or physicians are going up to 63 grams of captozole. And so we know there are real differences in this population compared to the RSC population or the ESE population. So I think we want to continue to support the research and understand differences before we could even consider any type of trial design. But as we've said consistently since the beginning of our IV program, Dosing really matters in the acute setting, and we want to get that right, and we don't want to make the same mistake others have made. I feel very good about where we are with RSE. We're taking a different approach in ESE and certainly, ultimately, a different approach in super refractory status as well. And I will say we are now creating some new formulations which may unleash our ability to be linked to captazole down the road as well, but a few years of development ahead of us on that path. But, Joe, let me turn it over to you for the clinical gestalt on SRSE before we wrap the call.
spk01: Yeah, no, I agree with Scott. The main thing we're learning about is dosing there and using a higher dose. The importance of getting high levels in initially. I don't think we have enough experience yet. I think it's been seven or eight patients so far have been treated under emergency. I don't think we have enough experience to look at patient types, age. Some patients have done very well, responded very quickly. And so there may be a role of etiology. Some patients tougher to treat. And as Scott mentioned, you know, the blood level, I think that's probably the main lesson learned is PK from the SAGE study and the doses they were, you know, the dosing was constrained. And so it's important to get the high levels done. and uh you know and ganaxolone may differ a bit from allopregnanolone um so uh anyway we're continuing you know we'll continue to respond and continue to explore different ways of dosing the drug in super refractory status great thank you very much
spk05: Well, I'm going to wrap up the call, and I'd like to thank everyone for joining us today and your continued support and confidence, and we look forward to providing updates in the coming months. Operator, back to you.
spk02: Okay. Thank you, everyone, for joining us today. This will conclude today's conference call. You may now disconnect.
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