Q2 2021 Marinus Pharmaceuticals Inc Earnings Call
Greetings and welcome to the Marinus Pharmaceuticals second quarter, 2021 business update call.
Operator: Greetings and welcome to the Marinus Pharmaceuticals second quarter 2021 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.
At this time, all participants on a listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During the session you will need to press star 1 on your telephone if you require any further assistance. Please press star zero and now it is my pleasure to introduce your host Sasha Simoni.
Operator: To ask a question during this session, you will need to press star 1 on your telephone. If you require any further assistance, please
Operator: And now it is my pleasure to introduce your host, Sasha DeMoney Ellis, Vice President of Corporate Affairs and Investor Relations. You may begin, Ms. DeMoney Ellis.
Les Vice President Corporate Affairs, and Investor Relations you may begin missed him on the Alice.
Thank you with me from Meredith, Our Doctor, Scott Braunstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, Steve Fence Hill, Chief Financial Officer, and Kimberly Mccormack Senior Vice President of regulatory Affairs also on the call as Christie Schaefer Chief commercial officer.
Sasha Damouni Ellis: Thank you. With me from Marinus are Dr. Scott Braunstein, Chief Executive Officer, Dr. Joe Hulihan, Chief Medical Officer, Steve Pfanstiel, Chief Financial Officer, and Kimberly McCormick, Senior Vice President of Regulatory Affairs. Also on the call is Christy Shafer, Chief Commercial Officer, who will be available during Q&A. Before we begin, I would like to remind everyone that some of the statements made 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.
And he will be available during Q&A.
Before we begin I would like to remind everyone that some of the statements made 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 and 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.
Sasha Damouni Ellis: These risks and uncertainties and risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Form 10-K, 10-Q, and 8-K. I will now turn the call over to our CEO, Scott Braunstein. Scott?
Company's reports filed with the Securities and Exchange Commission, including form 10-K, 10-Q and 8-K.
I will now turn the call over to our CEO Scott Braunstein Scott.
Thank you Sasha and welcome to our second quarter, 'twenty, 'twenty, 1 business and financial update building.
Scott Braunstein: Thank you, Sasha, and welcome to our second quarter 2021 business and financial update. Building on our busy first quarter, we've continued to make significant progress across our oral and IV clinical programs. And just last week, we made two important announcements.
Building on our busy first quarter, we've continued to make significant progress across our oral and IV clinical programs. Just last week, we made 2 important announcements for.
Scott Braunstein: First, we entered into an exclusive collaboration with Orion Corporation for the European commercialization of Ganaxalone and CDKL5 deficiency disorder, tuberous sclerosis complex, and refractory status epileptic. We believe that the Orion team will be an excellent strategic partner for the Ganaxalone franchise. We also announce that we have submitted a new drug application to the FDA for Gonaxalone for the treatment of seizures associated with CDD. Within 60 days of submission, we expect to receive a filing notification letter from the FDA. That communication should occur prior to the end of the third quarter.
First we entered into and exclusive collaboration with Orion Corporation for European commercialization of <unk> alone and C. D. Calpine deficiency disorder, tuberous sclerosis complex and refractory status epilepticus, we believe that the Orion team will be and excellent strategic partner for the Max alone for.
<unk>, we also announced that we have submitted a new drug application to the FDA for Gyn acts alone for the treatment of seizures associated with T. D. D. Within 60 days of the submission we expect to receive a filing notification letter from the FDA that.
Communication should occur prior to the ended the third quarter.
Scott Braunstein: Not only are these two events meaningful accomplishments, but they represent important milestones in the evolution of our business. The European collaboration provides significant capital to continue advancing the development of Ganaxalone across Europe, and the FDA acceptance of the NDA for filing provides an opportunity to draw on the Oak Tree Credit Facility, extending our cash runway and allowing us to continue to expand our pre-commercial activities. In addition, the organization is executing on a number of regulatory milestones. During Q2, we submitted our Phase 3 TSC trial design to the FDA, and the agency indicated that it was in overall alignment with our clinical development plan. I will leave the details to Kim.
Not only are these 2 events meaningful accomplishments, but they represent important milestones and the evolution of our business and the European collaboration provide significant capital to continue advancing the development of <unk> alone across Europe, and the FDA acceptance of the NDA for filing provides an opportunity.
And to draw on the Oaktree credit facility.
And our cash runway and allowing us to continue to expand our pre commercial activities.
In addition, the organization is executing on a number of regulatory milestones. During Q2, we submitted our phase 3 T. S. He trial designed to the F. D E and the agency indicated that they were and overall alignment with our clinical development plan and I will leave the details to Kim we can.
Scott Braunstein: We continue to prepare for the TSE Phase III trial that we have named TRUST-TSE, with an expected first patient enrolled in the fourth quarter of this year. I would like to thank the TSC Alliance, whose support has been instrumental in driving this program forward. Now, I will move to an important update for the IV franchise.
To prepare for the PSC phase III trial that we have named trusts T. S. C with an expected first patient enrolled in the fourth quarter of this year.
I'd like to thank the T. S. C Alliance, whose support has been instrumental in driving this program forward.
Let me move to an important update for the IV franchise, we received a notice of allowance for the patent application for the RNC IV dosing and method of treatment from the U S patent and trademark office, we anticipate the pattern to be formally granted later in the third quarter.
Scott Braunstein: We received a notice of allowance for the patent application for the RSC IV dosing and method of treatment from the U.S. Patent and Trademark Office. We anticipate the patent to be formally granted later in the third quarter. When granted, we expect the patent to run through 2040.
And granted we expect the pattern to run through 2040, and the patent application highlights the dosing regimen and method of treatment for RSV and aligns with the phase 3 trial. We believe this pattern has the potential to create meaningful shareholder value. Following the completion of our phase III U S. Registrational.
Scott Braunstein: The patent application highlights the dosing regimen and method of treatment for RFC and aligns with the Phase III trial. We believe this patent has the potential to create meaningful shareholder value following the completion of our Phase 3 U.S. Registrational Study, the RAISE trial. The organization is continuing its work on other key initiatives.
The rays trial the.
The organization is continuing their work on other key initiatives planned for the C. D. D launch are progressing we look towards and FDA action date on the day Max alone NDA by the end of the first quarter of 2020.2 as a reminder, FDA approval would result in a 3 month period for DEA scheduling.
Scott Braunstein: Plans for the CDD launch are progressing; we look towards an FDA action date on the Ganaxalone NDA by the end of the first quarter of 2022. As a reminder, FDA approval would result in a three-month period for DEA scheduling, followed by a mid-2022 law. As mentioned, we have signed a European collaboration agreement with Finland-based Orion Corporation. After a diligent and competitive process, we believe that Orion checked all the boxes that we were looking for.
Followed by a mid 'twenty 2 launch.
As mentioned, we have signed a European collaboration agreement with Finland based Orion Corporation. After a diligent and competitive process. We believe that Orion checked all the boxes that we were looking for a strong presence across western Europe, and rare neurological disorders, a desire to be a leader and orphan diseases.
Scott Braunstein: A strong presence across Western Europe in rare neurological disorders, a desire to be a leader in orphan diseases and epilepsy, significant expertise in hospitals and the ICU, as well as an extensive European commercial infrastructure. Importantly, Orion offers a strong cultural fit to our organization, and we look forward to working together towards future milestones. Orion has been granted exclusive rights to commercialize the oral and IV formulations of Ganaxalone in the European Economic Area, the UK, and Switzerland, where they will be responsible for all reimbursement and pricing approvals.
And epilepsy significant expertise and the hospital and the ICU as well as and extensive European commercial infrastructure Importantly, Orion offers a strong cultural fit to our organization and we look forward to working together towards future milestones.
Orion has been granted exclusive rights to commercialize the oral and IV formulations of <unk> alone and the European economic area, the U K, and Switzerland, where they will be responsible for all reimbursement and pricing approvals. We've received approximately $30 million as an upfront payment and are eligible to it.
Scott Braunstein: We've received approximately $30 million as an upfront payment and are eligible to achieve up to approximately $115 million in R&D reimbursement, development, and commercialization payments, as well as tiered royalties on future net sales that could reach the high teens for the oral programs and the low 20s for the IV programs. We believe that this deal structure strikes the right balance between upfront payments and royalties, allowing Marinus and our shareholders to benefit from the long-term success of the Ganaxalone franchise.
Keep up to approximately 115 million and R&D reimbursement development and commercialization payments as well as tiered royalties on future net sales that could reach the high teens for the oral programs and low twenties for the IV program. We believe that this deal structure strikes the right balance on upfront payments.
Royalties, allowing marinus and our shareholders to benefit from the long term success of they've been excellent franchise.
Scott Braunstein: Importantly, this agreement supports a mid-22 European launch of oral gonapsolone for CDD and underscores our commitment to the CDD patient community. We are on track to file a European Marketing Authorization application for Ganaxalone in CDD by the end of Q3 2021. In the near term, we see this collaboration having the potential to provide an important new alternative for patients and families living with CDD throughout Europe. Both organizations are committed to improving the availability of Ganaxolone for refractory CDD patients, including the desire to support an expanded access program.
Importantly, this agreement supports a mid 'twenty 2 European launch of Oregon, Exelon for C. D D and underscores our commitment to the CDB patient community.
We are on track to file the European marketing authorization application for <unk> loans in TDD by the end of Q3.2021in the near term we see this collaboration having the potential to provide an important new alternative for patients and families living with TD D throughout Europe.
Organizations are committed to improving the availability of the next womb to refractory T D D patients, including the desire to support a geographically broader expanded access program.
And keeping with our commitment to the see the patient community. We plan to support our collaborative observational study and C. D. D sponsored by the Lulu Foundation, a nonprofit organization dedicated to advancing research to better the understanding and development of Therapeutics for C. D D.
Scott Braunstein: In keeping with our commitment to the CDD patient community, we plan to support a collaborative observational study in CDD sponsored by the Lulu Foundation, a non-profit organization dedicated to advancing research to better the understanding and development of therapeutics for CDD. This observational study is designed to provide a high-quality natural history database on a variety of clinical outcomes to better describe disease severity, unmet need, and inform future trials. We are excited to be a part of this research consortium and are committed to contributing critically necessary resources to the CDD community.
This observational study is designed to provide a high quality and natural history database on a variety of clinical outcomes to better describe the disease severity unmet need and inform future trials. We are excited to be a part of this research consortium and are committed to contributing critically necessary resources.
2 the C D D community.
Moving to our T. S. C program, we remain on track to announce top line data from the open label Phase 2 trial and the third quarter as I noted earlier, we believe that we have reached overall alignment with the F. D E on and appropriate regulatory path. We are also expecting to obtain scientific advice from the EMA.
Scott Braunstein: Moving to our TSC program, we remain on track to announce top-line data from the Open Label Phase 2 trial in the third quarter. As I noted earlier, we believe that we have reached overall alignment with the FDA on an appropriate regulatory path. We are also expecting to obtain scientific advice from the EMA and now expect that meeting to occur in the first quarter of 2022. We continue planning for Phase III site initiations to begin in the third quarter, with the first patient expected to be enrolled in the fourth quarter of 2021. We are currently targeting initial sites in the U.S. and will add EU sites following our regulatory interaction with the EMA.
And now expect that meeting to occur in the first quarter of 2020.2.
We continue planning for phase III site initiations to begin in the third quarter with the first patient expected to be enrolled and the fourth quarter of 2021.
We are currently targeting initial sites and the U S and will add EU sites. Following a regulatory interaction with the EMA and we plan on providing enrollment timelines for trust T. S. C trial later this year.
Scott Braunstein: We plan on providing enrollment timelines for a TrustTSC trial later this year. Turning to our IV programs, due to COVID-19 priorities and several major academic medical centers participating in the RAISE trial, we've experienced site initiation and enrollment delay. We believe these delays are primarily caused by staff turnover due to COVID-19 fatigue and the need for clinical sites to devote significant resources to patients with COVID-19. These challenges most acutely impacted second quarter site enrollment.
Turning to our IV programs due to COVID-19 priorities and several major academic medical centers participating in the range trial, we've experienced site initiation and enrollment delays. We believe these delays are primarily caused by staff turnover due to COVID-19, fatigue and the need for clinical sites to devote.
<unk> resources to patients with COVID-19.
These challenges most acutely impacted second quarter site enrollment.
Fortunately our clinical operations team believes that the majority of these issues are now behind Us Carter.
Scott Braunstein: Unfortunately, our clinical operations team believes that the majority of these issues are now behind us. Consequently, we expect to have the vast majority of our sites open by the end of the third quarter 2021, with our top line raised trial data readout in the second half of 2022. We've already seen July site initiation numbers improving, giving us confidence in this timeline.
Consequently, we expect to have the vast majority of our sites open by the end of third quarter, 2020, 1 with our topline raised trial data readout and the second half of 2022, we've already seen July site initiation numbers, improving giving us confidence and this timeline, we are actively engaged with our Si.
Scott Braunstein: We are actively engaged with our sites and will provide additional updates during our October R&D day. As a reminder, planning continues for the RAISE-2 trial to support European registration of IV gonaxalone in RSE. This trial is on track to launch in the first half of 2022.
And we will provide additional updates during our October R&D day.
As a reminder, planning continues for the raised 2 trial to support European registration of IV, you can ask alone and RSC. This trial is on track to launch and the first half of 2020.2 the phase 2 reset trial of the junk took and acts alone and established that a simple up to guess or ESC is.
Scott Braunstein: The Phase 2 Reset Trial of Adjunctive Gonaxalone in Established Status Epilepticus, or ESE, is planned to begin U.S. enrollment in the first half of next year. Before turning the call over to Kim, I wanted to share our thinking on Lennox-Gastaut syndrome, or LGS. Of note, six CDD patients with an LGS phenotype were treated in the Marigold study.
Planned to begin U S enrollment and the first half of next year.
Before turning the call over to Kim I wanted to share our thinking on Lennox <unk> syndrome, or lgs of note 6 DDD patients with and Lgs phenotype were treated and the Marable study we have submitted that data for presentation at the annual American Epilepsy Society meeting.
Scott Braunstein: We have submitted that data for presentation at the annual American Epilepsy Society meeting. We have also reviewed the company's prior Phase II LGS study and noted that the majority of patients did not achieve an adequate serum blood concentration of Ganaxin. We believe that our current PID dosing regimen, including an appropriate titration schedule should lead to higher blood concentrations that were seen in that earlier study, similar to those observed in the marigolds.
We have also reviewed the company's prior phase 2 lgs study and noted that the majority of patients did not achieve and adequate serum blood concentration of can ask alone.
We believe that our current tid dosing regimen, including and appropriate titration schedule and should lead to higher blood concentrations that were seen in that earlier study similar to those observed and the Marigold study.
Scott Braunstein: That said, the LGS development landscape is highly competitive, and patients and families suffering from LGS are looking for the best possible anti-epileptic therapy. Our team is committed to the right investment in LGS and believes that our clinical work should be closely tied to Marinus' Next Generation Oral Program. We believe that these Next Generation Formulations, or novel pro-drugs, will deliver a solid drug candidate with improved bioavailability, more reliable steady-state plasma concentrations, and create the potential for incremental dose titration and higher efficacy.
That said the lgs development landscape is highly competitive and patients and families suffering from Lps are looking for the best possible anti epileptic therapy. Our team is committed to the right investment and lgs and that our clinical work should be closely tied to Meredith is next generation oral program, we believe that.
These next generation formulations or novel Pro drugs will deliver a solid drug candidate with improved bioavailability more reliable steady state plasma concentrations and create the potential for incremental dose titration and higher efficacy.
Scott Braunstein: Further on the new formulation front, we continue to evaluate several platform technologies for oral and IV Ganax. We plan to evaluate these new formulations in Phase 1 studies in 2022 and ultimately in additional refractory epilepsy indications. We expect to advance at least one of these formulations into the clinic next year and currently have reason to believe that it is more likely that we will advance two formulations in 2021. We are enthusiastic that our investments are the first step to a second-generation platform.
Further on the new formulation front, we continued to evaluate several platform technologies for oral and IV you can ask alone we plan to evaluate these new formulations and phase 1 studies in 2020, 2 and ultimately and additional refractory epilepsy indications.
We expect to advance at least 1 of these formulations into the clinic next year and currently have reason to believe that is more likely that we will advance 2 formulations in 2020.2.
We are enthusiastic that our investments are the first step to a second generation platform more to come on our re formulations during Marin and since R&D day.
Scott Braunstein: More to come on our reformulations during Marinus' R&D day. I also want to welcome Dr. Santiago Arroyo to the Board of Directors. Dr. Arroyo brings a distinguished career in academic neurology and clinical research and development, including his leadership in the neurology department at the John Hopkins Hospital. In addition, he has extensive experience in epilepsy drug development, contributing to numerous new therapeutic alternatives. With that, I would now turn the call over to Senior Vice President of Regulatory Affairs, Kim McCormick, for an update on our regulatory interactions. Kim?
I also want to welcome Dr. Santiago Arroyo to the board of directors, Dr. Arroyo bring a distinguished career and academic neurology and clinical research and development, including his leadership and the Neurology Department at the John Hopkins Hospital.
In addition, he has extensive experience and epilepsy drug development and contributing to numerous new therapeutic alternatives.
With that I would like to now turn the call over to senior Vice President of regulatory Affairs, Kim Mccormick for an update on our regulatory interactions Kim.
Kimberly A. McCormick: Thank you, Scott. We are pleased to have recently announced the submission of an NDA to the FDA for Ganaxone for the treatment of seizures associated with CDD. Within 60 days of the submission, the FDA will notify Marinus whether the NDA is accepted for filing and is expected to notify us if prior review designation is granted during that 60-day period. The NDA also includes a request for a Rare Pediatric Disease Priority Review Voucher, or PRV.
And so Scott we are pleased to have recently announced the submission of an NDA to the FDA for economics for them for the treatment of seizures associated with C. D. Within 60 days of the submission the FDA will notify Meredith whether the NDA was accepted for filing and is expected to notify if private review designation is granted during that 60 day.
Period the.
And they also create a request for a rare pediatric disease priority review voucher or P. R V.
Kimberly A. McCormick: If a PRV is granted, it may be used to obtain priority review for a subsequent human drug or biologic application, or we could sell or transfer the PRV to a third party. The team is actively preparing for a potential advisory committee meeting.
And if a PR because granted and may be used to obtain priority review for subsequent and human drag for biologic application or we could sell a transfer of a purely for a third party.
And the team is actively preparing for a potential advisory Committee meeting.
Kimberly A. McCormick: FDA has indicated they may let Marinus know if they plan to hold an advisory committee meeting as early as at the end of the 60-day filing period. If priority review is granted, the PDUFA action date would be targeted for March 2022. If FDA approves the Ganaxone NDA, DEA scheduling would then be expected within 90 days of the approval. Consistent with our data set, our recommendation in the NDA, as well as other benchmarks, we anticipate a Schedule 4 designation. We look forward to working with the FDA in its review process and remain focused on preparing for an anticipated launch. We've had several questions related to our MGMA Tablet, if you'd like.
As indicated they may let Meredith now if they plan to hold an advisory committee meeting as early as at the end of a 60 day filing period.
If priority review was granted and put it.
<unk> action date would be targeted for March 'twenty, and 'twenty 2 and F.
And it proves that the and act on NDA.
And scheduling and would then be expected within 90 days of the approval.
The system with our dataset, a recommendation and the NDA as well as other benchmark, we anticipated schedule for designation and we look forward to working with the FDA and review process and remain focused on preparing for anticipated launch.
We've had several questions related to our MTO metabolite and excellent.
Kimberly A. McCormick: As a reminder, Marinus identified the MQ metabolite in 2019, and we have had discussions with the FDA on how best to characterize it. As part of the pre-NDA interactions with FDA, agreement was reached on what was required in the NDA submission with respect to the metabolites. We recently completed an activity assay for the M2 metabolite and have included the results in the NDA submission as agreed with the FDA. We are planning to conduct an in vivo micronuclear test with common analysis and anticipate that this testing will be complete in the first quarter of 2022.
Reminder, merits identify the MTO metabolite and 2019, and we have had discussions with the FDA on how best to characterize it.
As part of the pre NDA interactions with FDA agreement was reached on what was required and the NDA submission with respect for the metabolite.
And we recently completed and activity assay for the MTA My top right and have included the results and the NDA submission as agreed with the FDA.
We are planning to conduct an in vivo micronucleus tests with common analysis anticipates that this testing will be complete and the first quarter of 2020.2.
We expect that any additional studies required such day for toxicology package on the MTO metabolite. They can be conducted poster critical.
As Scott mentioned, we are dedicated to advancing and axon for CBD and markets outside the U S and remain on track to file a marketing authorization application with the European Medicines agency by the end of the third quarter. We are pleased to share it and we expect the EMA granted accelerated assessment and asking for the treatment of seizures, especially.
Kimberly A. McCormick: We expect that if any additional studies are required, such as a full toxicology package on the M2 metabolite, they can be conducted post-approval. As Scott mentioned, we are dedicated to advancing Genoxone for CVD in markets outside the U.S. and remain on track to file a marketing authorization application with the European Medicines Agency by the end of the third quarter. We are pleased to share that we expect the EMA to grant an accelerated assessment of Genoxone for the treatment of seizures associated with CVD.
And with D D D.
If granted accelerated assessment will reduce the target review time for 150 days from the standard to turn.
This could mean, we could receive a C. H M. P recommendation by the second quarter of 2022.
Applications are eligible for accelerated assessment at the theater and Pete determined that the product is of major interest for public health, particularly from the point of view of therapeutic innovation.
Kimberly A. McCormick: If granted, the accelerated assessment will reduce the target review time to 150 days from the standard 210 days. This could mean we could receive a CHMP recommendation by the second quarter of 2022. Applications are eligible for accelerated assessment if the CHMP determines that the product is of major interest for public health, particularly from the point of view of therapeutic innovation. With regard to TSC, the update indicated overall alignment on our TSC clinical development plan as part of the written responses to our request for a Type B meeting to review our proposed Phase 3 trial.
With regard to T. S T. The FDA indicated overall alignment on our T O T clinical development plan as part of their written responses to our request for a type B meeting to review our proposed phase III trial.
And that'll be a Mad River view, a single pivotal phase 3 study could be sufficient to support the approval of can axa and this indication following and approval of the C D D and yet.
We believe this paradigm of a single pivotal trial would be applicable for other rare and orphan indications that was a per se with oil can ask for them.
In addition, and scientific advice meeting with EMA and on the TST program is targeted for the first quarter of 'twenty 'twenty 2.
And you know enrollment and a phase II trial is likely to begin following that meeting.
As a reminder, we have estimated orphan drug designation request to FDA and EMA and we are expecting to receive responses by the end of the third quarter.
Kimberly A. McCormick: Although it will be a matter of review, a single Pivotal Phase III study could be sufficient to support the approval of Gonaxone in this indication following an approval of the CDD and DA. We believe this paradigm of a single pivotal trial would be applicable for other rare orphaned indications that we would pursue with oral ganoxin. In addition, a scientific advice meeting with EMA on the TSC program is targeted for the first quarter of 2022.
Turning to our trial and establish status epilepticus or E. S. E. I'm pleased to share that we've just overall alignment with the FDA on the design for E. S. C. Reset trial. Additionally, we have recently received notification and our R&D to support the reset trial may per seat and we continue to expect to begin enrollment and the first.
Half of 2020.2 and.
And there'll be further to tell from Joe on this now I would like to turn the call over to our Chief Medical Officer, Dr. Joe Houlihan Joe.
Thank you Kim and good morning, everyone.
Kimberly A. McCormick: Your moment in a phase 3 trial is likely to begin following that moment. As a reminder, we have submitted orphan drug designation requests to FDA and EMA. We are expecting to receive responses by the end of the third quarter. Turning to our Trial and Established Status Epilepticus, or ESE, I am pleased to share that we have reached overall alignment with the FDA on the design for our ESE reset trial. Additionally, we have recently received notification that our IND to support the reset trial may proceed, and we continue to expect to begin U.S. enrollment in the first half of 2022. There will be further detail from Joe on this. Now, I would like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan.
As you've heard the first half of this year has been extremely productive putting us on course for a busy next 12 months and beyond.
I'd like to start by highlighting progress on our I V franchise and the raised trial as Scott mentioned, we expect to have the vast majority of sites opened by the end of the third quarter. Although topline data is now expected a little later than originally planned rates of screening and study sites are high with only those patients appropriate for the study being enrolled.
That is those who meet protocol requirements. We believe we have the right study design and a carefully considered response rates and the control arm and as I D.
Detailed last quarter, our clinical team is driving outreach to study centers and has expressed confidence and the outlook for site initiations and patient enrollment over the next few months, our clinical operations and medical teams continue to have strong interactions with our sites, including regularly scheduled training case studies and interactive.
<unk> sessions.
And the RSC pivotal trial for European registration and raised 2 remains on target for launch and the first half of 2020.2.
Joseph Hulihan: Thank you, Kim, and good morning, everyone. As you know, the first half of this year has been extremely productive, putting us on course for a busy next 12 months and beyond. I'd like to start by highlighting progress on our IV franchise. In the RAISE trial, as Scott mentioned, we expect to have the vast majority of sites open by the end of the third quarter, although top-line data is now expected a little later than originally planned.
And I discussed on the call last quarter. The raised 2 trial differs from the raise trial and the U S and that most notably can exelon can be initiated earlier in the course of RSC and raise too.
If successful this study will provide complementary data to the raise trial and the U S.
Such that raised 2 could not really serve as a pivotal registration trial in Europe, but it also may have and important clinical implications for the global market.
1 of our goals is establishing leadership and the treatment of status Epilepticus. We were pleased to hear that our approach to studying RSC could potentially influence. The next version of EMEA epilepsy treatment guidelines.
Joseph Hulihan: Rates of screening at study sites are high, with only those patients appropriate for the study being enrolled, that is, those who meet protocol requirements. We believe we have the right study design and have carefully considered response rates in the control arm, as I detailed last quarter. Our clinical team is driving outreach to study centers and has expressed confidence in the outlook for site initiations and patient enrollment over the next few months. Our clinical operations and medical teams continue to have strong interactions with our sites, including regularly scheduled training, case studies, and interactive educational services.
Kim mentioned, we gained alignment from the FDA and plan to initiate a phase II trial of adjunct and can ask loans and establish status epilepticus.
The reset trial, which stands for researching establish status epilepticus treatment.
And is expected to begin U S enrollment and the first quarter of 2022. After we've completed the process of exception from informed consent.
Yes, he is earlier than RSC and kantar.
Can you walk status epilepticus and it's defined as status continues for first line treatment with benzodiazepines fails.
Joseph Hulihan: The RSC Pivotal Trial for European Registration, RACE-2, remains on target for launch in the first half of 2022. As I discussed on the call last quarter, the RAISE II trial differs from the RAISE trial in the U.S. in that, most notably, Ganaxalone can be initiated earlier in the course of RSE in Rays 2. If successful, this study will provide complementary data to the RAISE trial in the U.S., such that RAISE II could not only serve as a pivotal registration trial in Europe, but it also may have an important clinical impact for the global market.
The reset trial will examine a shorter dosing regimen and we.
Which can actual will be initiated in conjunction with the initial second line <unk>.
And he will specifically target patients with convulsive, rather than Nonconvulsive status epilepticus and.
<unk> from emergency departments.
Because patients who qualify for the reset trial have a type of status distinct from those who would enter the raised trial. We can consider the same sites for our established status trial without compromising enrollment and the raised trial.
And the reset trial can actually is intended to act as an adjuvant to the initial second line standard of care AEP and the established status epilepticus treatment trial known as he said.
Joseph Hulihan: Since one of our goals is establishing leadership in the treatment of status epilepticus, we were pleased to hear that our approach to studying RSE could potentially influence the next version of the EMA Epilepsy Treatment Guide. As Kim mentioned, we gained alignment from the FDA and plan to initiate a phase two trial of adjunctive Ganaxilone in established status epilepticus. The Reset Trial, which stands for Researching Established Status Epilepticus Treatment, is expected to begin U.S. enrollment in the first quarter of 2022 after we've completed the process of exception from informed consent. ESE is earlier than RSE in the continuum of status epilepsy.
And that response rates to standard of care, aedes or less and 50% within the first hour.
We believe the connect slow and has the potential to increase response rates, including reducing the time to response and increasing the durability of effect compared with standard of care a diesel loans.
Our goal and this study is to find and effective safe and well tolerated dosing regimen for can act on and ESC.
The trial utilizes our novel sequential designed to assess the safety and effectiveness of several doses and infusion durations of can actually with.
With the optimal dose regimen and progressing to a double blind phase III study versus placebo.
In addition, we continue to field requests from investigators for IV can actual on for patients with Super refractory status epilepticus under emergency investigational new drug applications.
Joseph Hulihan: And it's defined as status continues if first-line treatment with benzodiazepines fails. The reset trial will examine a shorter dosing regimen in which Ganaxalone will be initiated in conjunction with the initial second line AED. The study will specifically target patients with convulsive rather than non-convulsive status epilepsy. Enrolled from the Emergency Department.
We're optimistic and an additional case reports will be presented at an upcoming medical meeting.
Now I'd like to provide more color on our oral programs.
Scott and Tim discussed, we recently submitted an NDA for C D D.
Diligently focused on advancing can actual and clinical development for patients suffering from CBD and this submission is a very important milestone and those efforts.
The NDA and supported by data from the Phase III <unk> trial.
Joseph Hulihan: Because patients who qualify for the RESET trial have a type of status distinct from those who would enter the RAISE trial, we can consider the same sites for our established status trial without compromising enrollment in the RAISE trial. In the RESET trial, Ganaxalone is intended to act as an adjuvant to the initial second-line standard of care AED. The established status epilepticus treatment trial, known as ESET, showed that response rates to standard of care AEDs were less than 50% within the first hour. We believe ConnexLoan has the potential to increase response rates, including reducing the time to response and increasing the durability of effect compared with standard of care AEDs alone.
Double blind placebo controlled trial and enrolled 101 patient.
Those treated with can actually showed a 37% median reduction and 28 day major motor seizures frequency.
Compared to a 6.9% reduction for those receiving placebo.
Achieving the trials primary endpoint with a P value of 0.0036.
We plan to submit a series of abstracts for the December Aes meeting <unk>.
Moving the 1 year open label extension data from the Marigold study.
So far with preliminary data on 48 patients who reached 1 year of open label treatment. We're seeing a median percent reduction from baseline of 49, 6%.
We continue to work with several centers across the U S who have shown interest and the CVD expanded access program and we're committed to making can actual available patients prior to a potential U S approval through this program.
Joseph Hulihan: Our goal in the study is to find an effective, safe, and well-tolerated dosing regimen for canaxilone in ESG. The trial utilizes a novel sequential design to assess the safety and effectiveness of several doses and infusion durations of Ganaxin, with the optimal dose regimen progressing to a double-blind phase 2 study versus placebo. In addition, we continue to field requests from investigators for iVeganAxalone for patients with supra-refractory status epilepsy under an emergency investigational new drug application. We're optimistic that an additional case report will be presented at an upcoming medical meeting. Now I'd like to provide more color on our oral program.
We're also committed to identifying opportunities throughout the rest of the world to help improve the lives of more patients, including through additional collaborations and compassionate use programs.
With regard to the TSV.
We're expecting to present, the topline data from the patients who participated in our phase 2 open label trial, the calm study and the third quarter.
This trial is evaluating the effectiveness and safety and Tolerability of adjunct took and actual treatment and patients with PSC.
It consists of a 4 week baseline period, followed by a 12 week treatment period, and a 24 week extension.
We're expecting them to initiate a global phase 3 double blind placebo controlled trial and T. S. C. Later this year.
Joseph Hulihan: As Scott and Tim discussed, we recently submitted an NDA for CDD. We are diligently focused on advancing Gynaxolone's clinical development for patients suffering from CDD, and this submission is a very important milestone in those efforts. The NDA is supported by data from the Phase 3 Marigold trial, a Double Blind Placebo Controlled Trial that enrolled 101 patients. Those treated with Ganaxalone showed a 30.7% median reduction in 28-day major motor seizure frequency, compared to a 6.9% reduction for those receiving placebo.
Each will enroll approximately 160 patients who have had inadequate seizure control and have been treated with at least 2 prior aedes.
We expect that 50% of our patients will have been treated with the most recently approved day E D for PSC at the dialogues.
Unlike the other dialects GSE study our trial will allow enrollment of patients taking a full range of concomitant medications, we expect to enroll the first patient during the fourth quarter of 2021.
We're also reviewing our clinical development options for Lennox <unk> syndrome, which we believe will complement our work and other pediatric epilepsies as we've had several patients and our CVD and TLC studies with carried the diagnosis of lgs.
Joseph Hulihan: Achieving the trial's primary endpoint with a p-value of 0.0036. We plan to submit a series of abstracts for the December AES meeting, including the one-year open-label extension data from the Marigold study. So far, with preliminary data on 48 patients who reached one year of open-label treatment, we're seeing a median percent reduction from baseline of 49.6%. We continue to work with several centers across the U.S. who have shown interest in the CDD Expanded Access Program, and we're committed to making Ginaxulin available to patients prior to a potential U.S. approval through this program. We are also committed to identifying opportunities throughout the rest of the world to help improve the lives of more patients, including through additional collaborations and compassionate use programs, with regard to TSC.
Rather than representing a clinical phenotype to a single genetic mutation L.
<unk> is a clinical syndrome that can have several underlying etiologies.
And it's lgs seizure types for much like those occurring and C. D. D. We expect that can actually loans would be a good candidate for development and lgs, regardless of the TD allergy.
Our plans are to pursue and lgs trial with 1 of our new formulations to provide a greater and more consistent exposure took and excellent.
As always and closing.
I would like to thank the patients families and medical professionals and advocacy groups, who have been so supportive of our efforts.
Now I would like to turn the call over to our CFO, Steve and steel for a financial update.
Thank you Joe I am pleased to be able to share our financial results for the first half of the year.
For the second quarter of 2021, we recognized $1.9 million and $3.7 million and federal BARDA contract revenues for the 3 and 6 months ended June 32021, respectively.
Joseph Hulihan: We're expecting to present the top-line data from the patients who participated in our Phase 2 open-label trial, the CALM study, in the third quarter. This trial is evaluating the effectiveness, safety, and tolerability of adjunctive connectional treatment in patients with TSC and consists of a four-week baseline period followed by a 12-week treatment period and a 24-week extension.
The BARDA contract was signed in September 2020, there are no revenues associated with this and the corresponding periods from the prior year.
Research and development expenses increased to $18.6 million and $37.2 million for the 3 and 6 months ended June 32021, respectively, as compared to $11.8 million and $26.8 million for the same period and the prior year.
Joseph Hulihan: We're expecting to initiate a global phase three double-blind placebo-controlled trial in TSC later this year, which will enroll approximately 160 patients who have had inadequate seizure control and have been treated with at least two prior AEDs. We expect that 50% of our patients will have been treated with the most recently approved AED for TSC, Epidiolex. Unlike the Epidiolex TSC study, our trial will allow enrollment of patients taking a full range of concomitant medications.
The change was due primarily to startup of the RSV phase III trial regulatory activities associated with the C. D D submission and increased R&D head count.
General and administrative expenses increased to $6.8 million and $17.2 million for the 3 and 6 months ended June 30th 2021, respectively, as compared to $4.1 million and $8 million for the same period and the prior year.
Primary drivers of the change were increased support for scale up on the Companys operations as well as preparation for commercialization.
The company reported net losses of $23.8 million and $51 million for the 3 and 6 months ended June 30th 2021, respectively as compared to net losses of $15.7 million and $34.3 million for the same period and the prior year.
Joseph Hulihan: We expect to enroll the first patient during the fourth quarter of 2021. We're also reviewing our clinical development options for Lennox-Gastaut syndrome, which we believe would complement our work in other pediatric epilepsy, as we've had several patients in our CDD and TSC studies who carried the diagnosis of LGS, rather than representing a clinical phenotype due to a single genetic mutation. LGS is a clinical syndrome that can have several underlying etiologies. Since LGS seizure types are much like those occurring in CDD, we expect that Gonaxalone would be a good candidate for development in LGS, regardless of the tediology. Our plans are to pursue an LGS trial with one of our new formulations to provide a greater and more consistent exposure to Ganax. As always, in close.
These totals include noncash stock based compensation expense of $3 million and $8 million for the 3 and 6 months ended June 30th 2020, 1 respectively as compared to $1.8 million and $3.7 million for the same periods and the prior year.
Cash used in operating activities increased to $23 million and $39.1 million for the 3 and 6 months ended June 30th 2021, respectively as compared to cash used in operating activities of $16 million and $30 million for the same periods and the prior year.
As of June 30th 'twenty, 'twenty, 1 we had cash and cash equivalents of $112.5 million.
We believe this balance combined with the net upfront proceeds of the recently signed European collaboration with Orion is sufficient to fund our operations for at least 12 months, while maintaining the minimum cash balance required under the debt facility.
Steven E. Pfanstiel: I would like to thank the patients, families, medical professionals, and advocacy groups who've been so supportive of our efforts. Now, I would like to turn the call over to our CFO, Steve Pfanstiel, for a financial update. Thank you, Joe.
Additionally, as Scott mentioned upon FDA acceptance for filing of the NDA, we have the opportunity to draw on additional $30 million of financing under our <unk> facility.
Steven E. Pfanstiel: I am pleased to be able to share our financial results for the first half of the year. For the second quarter of 2021, we recognized $1.9 million and $3.7 million in federal BARDA contract revenues for the three- and six-month-ended June 30, 2021, respectively. As the BARDA contract was signed in September 2020, there are no revenues associated with this in the corresponding periods from the prior year. Research and development expenses increased to $18.6 million and $37.2 million for the three and six months ended June 30, 2021, respectively, as compared to $11.8 million and $26.8 million for the same period in the prior year.
We have further opportunities to significantly strengthen our balance sheet upon and FDA approval, including a second 30 million tranche of funding from Oaktree as well as the opportunity to monetize the P. R V. If awarded.
For the fiscal year 2021, our GAAP operating expense estimate remains unchanged and the range of $113 million for $118 million, which includes approximately $16 million of noncash stock based compensation.
Separately for the fiscal year 2021, we are adjusting our guidance for BARDA revenues to be and a range of 7 million to $10 million compared to our prior guidance of $9 million to $12 million, which reflects updated timing of the contract activities.
Total expected value of the BARDA contract revenue remains unchanged at 21 million net.
Steven E. Pfanstiel: The change was due primarily to the startup of the RSE phase 3 trial, regulatory activities associated with the CDD submission, and increased R&D headcount. General and administrative expenses increased to $6.8 million and $17.2 million for the three and six months ended June 30, 2021, respectively.
Now I'll turn the call back to Scott, who will provide concluding remarks.
Steve It has been a highly productive first half of 2021 and none of this would have been possible without the hard work of our dedicated Mariners employees and the support of our advocacy partners. We look forward to the exciting developments over the coming months and we want to thank our shareholders for their support and encouragement operator.
And you now open the call to questions.
Yes, ladies and gentlemen at this time, if you would like to ask and audio question Press Star then the number 1 once again that it started any number 1 on your audio keypad and watch and I think a question, we'll pause for just a moment to compile the Q&A roster.
Steven E. Pfanstiel: As compared to 4.1 million...
Steven E. Pfanstiel: $1,000,000 and $8,000,000 for the same period in the prior year.
Steven E. Pfanstiel: The primary drivers of the change were increased support for scale-up of the company's operations as well as preparation for commercialization. The company reported net losses of $23.8 million and $51 million for the three.
Our first question comes from the line of Joseph <unk> with Cowen and company.
Hi, there and good morning, Thank you for taking my questions and congratulations on the progress.
Maybe just a first 1 on on the new formulations.
Steven E. Pfanstiel: The 3 and 6 months ended June 30, 2021, respectively.
And because the CTD indication may potentially be approved with sort of the first generation and you ought to be in the clinic with TFC. How are you thinking about it is it possible to bridge I guess, the new formulation and back to some of these initial indications or will the new formulations and should just be for for kind of the next wave of Oh.
Steven E. Pfanstiel: Compared to net losses of $15.7 million and $34.3 million for the same periods in the prior year. These totals include non-cash, stock-based compensation expense of $3 million and $8 million for the three and six months ended June 30, 2021, respectively, as compared to $1.8 million and $3.7 million for the same periods in the prior year. Cash used in operating activities increased to $23 million and $39.1 million for the three and six months ended June 30, 2021, respectively, as compared to cash used in operating activities of $16 million and $30 million for the same periods in the previous year.
Lipstick indications and then second maybe just a point of clarification.
On the in vivo nuclease activity assay that was mentioned in prepared remarks.
And of course, Florida share is this necessary ahead of a decision on on the <unk> NDA.
And.
Thanks, Joe and good morning, and let me just jump and take the second question. We are we've had good interactions with the agency over the plan on the M too and we will very likely provide them the in vivo micronucleus tests, but not necessary for.
At the time of filing so.
And we'll get that year, and and we'll be happy to supplement and should the FDA require it.
And we don't see that as a major amendment, we've had that discussion.
Steven E. Pfanstiel: As of June 30, 2021, we had cash and cash equivalents of $112.5 million.
It'll be a relatively.
And a brief report.
On the new formulation work.
Steven E. Pfanstiel: We believe this balance, combined with the Net Upfront Process,
It's a step by step process I think first and foremost we're really excited where we are today. We've we've seen some early preclinical data from from at least 2 formulations that are showing substantially.
Steven E. Pfanstiel: of the recently signed European collaboration with Orion is sufficient to fund our operations for at least 12 months while maintaining the minimum cash balance required under the debt facility. Additionally, as Scott mentioned,
Substantially higher bioavailability.
Steven E. Pfanstiel: As mentioned, upon FDA acceptance for filing of the NDA, we have the opportunity to draw an additional $30 million of financing under our Oak Tree facility. We further have opportunities to significantly strengthen our balance sheet upon FDA approval, including a second $30 million tranche of funding from Oaktree, as well as the opportunity to monetize the PRV if awarded.
And then can ask alone and.
And we understand that we're gonna start in humans with these new formulations, we're gonna and think about how to really maximize both peaks and troughs.
And to achieve steady state concentrations and certainly right now our thinking is to bring this formulation first into a new indication.
And in and how we're thinking about prior indications like CBD I would say TBA me My general feeling Joe is that if we know that 10 or 20 per cent of patients don't respond to and Exelon and CBD. There is and all these the opportunity to go back and re study and new Formula.
Steven E. Pfanstiel: For the fiscal year 2021, our GAAP operating expense estimate remains unchanged in the range of $113 million to $118 million, which includes approximately $16 million of non-cash stock-based compensation. Additionally, for the fiscal year 2021, we are adjusting our guidance for BARDA revenues to be in a range of $7 million to $10 million, compared to our prior guidance of $9 million to $12 million, which reflects updated timing of the contract activity. The total expected value of the BARDA contract revenue remains unchanged at $21 million.
And in those patients.
And that we really believe that blood levels are tied to the lack of success and those patients and that a new formulation with bioavailability would certainly increase the odds of success I think there are some real practical challenges with that Joe.
Will will can we enrolled patients and a second CTD study. So so I would say on the C D and your front TBA.
We certainly are thinking about the opportunity and new indications first and foremost.
Scott Braunstein: Now I'll turn the call back to Scott, who will provide concluding remarks.
And and were given a lot of thought to TLC as well at this time.
Scott Braunstein: Thanks, Steve. It has been a highly productive first half of 2021. None of this would have been possible without the hard work of our dedicated Marinus employees and the support of our advocacy partners. We look forward to the exciting developments over the coming months, and we want to thank our shareholders for their support and encouragement. Operator, can you now open the call to questions? Yes.
Most importantly is as I mentioned I'm really excited about where we are and and the opportunity to have several shots on goal next year and.
And I think we have a very good understanding from the marigold data on exactly what we'd like to achieve with the new formulation.
So I'll stop there. Thanks for the question, Joe and operator, why don't we go to the next question.
Our next question comes from the line of Joon Lee with true Securities.
Operator: Yes, ladies and gentlemen, at this time, if you would like to ask an audio question, press star, then the number one. Once again, that is star, then the number one on your audio keypad in order to ask a question. We'll pause for just a moment to compile the Q&A roster.
I think there's no question for.
On the RSV trial, where are you now on enrollment and what gives you the confidence that you can complete enrollment by year end and.
For the start of recent trial and.
And ESB would be contingent on waste trial enrollment completion and I have a follow.
Operator: Our first question comes from the line of Joseph Tomei with Cohen and Company.
Yeah.
Thanks June our all of our timelines on the RSC trial and had to raise trial are based on.
Scott Braunstein: Thank you for taking our questions and congratulations on the progress. Maybe just a first one on the new formulations. Because the CDD indication may potentially be approved with sort of the first generation, and you'll already be in the clinic with TSC, how are you thinking about it? Is it possible to bridge, I guess, the new formulation back to some of these initial indications, or will the new formulation essentially just be for kind of the next wave of epilepsy indications?
Our expected per patient per site on a monthly basis initiations and we're expecting we've been very transparent about this we expect that R. R.
Our active sites will enroll somewhere between 3 to 6 patients per year.
We have seen that early on and the trial the sites that we expect it to be high enrollment sites have had really.
Scott Braunstein: And then second, maybe just a point of clarification, the in vivo nuclease activity assay that was mentioned in the prepared remark that was completed in the first quarter of next year, is this necessary ahead of a decision on the CDD NDA? Thanks. Thanks, Joe. Good morning.
On there thus far on their enrollment curves have been in line with our per site enrollment expectations, where we've really hit a snag, particularly in Q2 getting some of our key new sites up and enrolling.
As I mentioned and we already feel much better about July and.
Scott Braunstein: And let me just jump to the second question. We've had good interactions with the agency over the plan for the M2, and we will very likely provide them with the in vivo micronuclease test, but it is not necessary at the time of filing. So we'll get that by year-end, and we'll be happy to supplement it should the FDA require it. And we don't see that as a major amendment.
Talk to the clinical team last night, and we Inc, and it.
Continue to be very enthusiastic Louisiana pick that new sites getting opened in August and September and then by the end of Q3, we expect to have the majority of our sites open and then of course with the majority of those sites open those key sites to enroll somewhere between 3.
Scott Braunstein: We've had that discussion. It'll be a relatively brief report. On the new formulation work, It's a step by step process. I think, first and foremost, we're really excited where we are today. We've seen some early preclinical data from at least two formulations that are showing substantially higher bioavailability than Ganaxalone, and we understand that we're going to start in humans with these new formulations. We're going to think about how to really maximize both peak and trough concentrations and achieve steady-state concentrations.
2 to 4 patients per year and that is really how we align on our timing of second half 'twenty..2 so the change is really driven by the site initiations, which had really started very nicely and a 'twenty 1 early 'twenty 2 through COVID-19, but as both Joe and I mentioned on the call.
Paul.
Really took a turn for the worse in Q2 as personnel changes, we lost several site investigators and more than double digit site coordinators and I think people change their life. They changed your lifestyle. It caught us off guard, but those major academic centers are now really.
Scott Braunstein: And certainly right now, our thinking is to bring this formulation first into a new indication. And how we're thinking about prior indications like CDD, I would say TBA. I mean, my general feeling, Joe, is that if we know that 10 or 20% of patients don't respond to Canaxone and CDD, there's an obvious opportunity to go back and restudy a new formulation in those patients, given that we really believe that blood levels are tied to the lack of success in those patients and that a new formulation with bioavailability would certainly increase the odds of success.
Playing catch up and before we go to your second question, Joe anything you want to add there.
No Scott I think you've covered it.
And then.
A quick follow up because and want to make sure we get the other questions.
Yes.
So the price on what actually include a day when the startup recent trial would be contingent upon feeding and enrollment rate, yes, yes, sorry about that.
Raise too, which we've now got alignment with the European regulatory authorities.
<unk> is the study that we're certainly going to talk to our partner Orion about.
Scott Braunstein: I think there are some real practical challenges with that, Joe. Can we enroll patients in a second CDD study? So I would say on the CDD front, TBA. We certainly are thinking about the opportunity and new indications first and foremost, and we're giving a lot of thought to TSE as well at this time. Most importantly, as I mentioned, I'm really excited about where we are and the opportunity to have several shots on goal next year. And I think we have a very good understanding from the Marigold data of exactly what we'd like to achieve with the new format.
And we see them as an important strategic partner.
We have good alignment with the EMA on that study design that being said, we'd love the opportunity to speak with Orion about the sites that were using C arose sites that they've had experience and and we've already.
And requested through our alliance group to have those discussions progress and so my expectation is by the end of this quarter. We will have very strong alignment with Orion and have every intention of moving raised 2 for word of raised 2 will certainly storage in some key European.
Operator: So I'll stop there. Thanks for the question, Joe and operator. Why don't we go to the next one? When your next question comes...
And sites will likely add a potentially U S sites and 22, but we're expecting rates to be largely driven by European sites, we don't see that as a conflict at all remember raise is in the U S for the ESG study, which as we've talked about will really and issue beginning in 'twenty 2.
Operator: Your next question comes from the line of Joon Lee with True Securities.
Scott Braunstein: Thank you for your questions. For the RSC trial, where are you now on enrollment, and what gives you the confidence that you can complete enrollment by year end? And will the start of the RISA trial in ESC be contingent on RAISE trial enrollment completion? And I have a follow-up.
And 2 we certainly feel by the time that study is up and running from a U S perspective, our U S. Res trial will have ours sites initiated and enrollment curves are where they should be and as Joe mentioned.
Scott Braunstein: Thanks, Joon. All of our timelines for the RSE trial and the RAISE trial are based on our expected number of patients per site on a monthly basis. And we're expecting, and we've been very transparent about this, we expect that our active sites will enroll somewhere between three to six patients per year. We have seen that early on in the trial, the sites that we expected to be high enrollment sites have really, thus far, their enrollment curves have been in line with our per site enrollment expectations, where we've really hit a snag, particularly in Q2, getting some of our key new sites up and enroll As I mentioned, we already feel much better about July.
We will have some overlap just a handful of sites and the ESC study and the reset trial, but remember those patients are coming in through the emergency room, and we see them as very different patient populations. So there maybe a chance of some overlap and by by Q2 of 'twenty, 2 but we certainly don't think debt.
And will impact Reis timelines at all and certainly there are you know they were going to be 1 or 2 sites that are just very active and the status epilepticus space and we feel fortunate that we may have the opportunity to work with them with more than 1 trial I would not expect any sites from the raise trial to be.
Scott Braunstein: I talked to the clinical team last night, and we continue to be very enthusiastic about new sites getting open in August and September. And then, by the end of Q3, we expect to have the majority of our sites open. And then, of course, with the majority of those sites open, those key sites will enroll somewhere between three to four patients per year.
Active and rollers and raise too that would create a potential overlap in terms of patients. So that's something we certainly would avoid.
Between res and raise too.
Scott Braunstein: And that is really how we align on our timing of second half of 22. So the change is really driven by the site initiations, which really started very nicely end of 21, early 22 through COVID. But, as both Joe and I mentioned on the call, things really took a turn for the worse in Q2 with personnel changes, several site investigators, and more than double digit site coordinators. And I think people changed their lives. They changed their lifestyle. It caught us off guard. But those major academic centers are now really playing catch up.
Is that clear true yes, yes. Thank you very much that's exactly true I wanted to understand thank you.
Absolutely.
Operator next question, Yes. Your next question comes from Douglas Tsao with H C. Wainwright.
Hi, good morning, Thanks for taking the questions just maybe since that Christy on the line and provide an update on the pre commercialization activities for the company and what you've been able to accomplish so far and as you gear up ahead of the potential launch. Thank you.
Yeah.
Christy why don't you jump for them.
Yes.
Christie do you want to jump right and did you hear that question.
I had thought she and I think we're having some technical issues Doug so.
Joseph Hulihan: Before we go to your second question, Joe, anything you want to add there? No, Scott, I think you covered it. Thank you. Thank you, sir. A quick follow-up question because I want to make sure we get to other questions.
Would you do you want and need to.
[laughter], let's see and you can take it.
Sure Chris He has hired a great team, we now have leadership across sales across marketing.
A great commercial obsolete or and.
Scott Braunstein: Yes, so the question was actually included: will the start of Lisa's trial be contingent upon completing the moment?
And 1 of our first hires was on the reimbursement side.
I'll add to that I don't want to forget anyone.
Our clinical supply chain. So we have all the key leadership positions in place we're actually now recruiting for our sales leadership for our 2 territories. Those leaders will be responsible for high on our sales reps our plan would be to make those offers early into 2022.
Scott Braunstein: Yeah, sorry about that. RAISE2, which we've now got alignment with the European Regulatory Authorities, is a study that we're certainly going to talk to our partner Orion about. We see them as an important strategic partner, and we have good alignment with the EMA on that study design. That being said, we'd love the opportunity to speak with Orion about the sites that we're using, CROs, sites that they've had experience with, and we've already requested through our alliance group to have those discussions progress.
Contingent on approval.
And and from a from a sales team perspective, we're in great shape, just on the flipside on the medical science liaison side we.
Scott Braunstein: And so my expectation is that by the end of this quarter, we will have very strong alignment with Orion and have every intention of moving RAISE2 forward. RAISE2 will certainly start in some key European sites. We'll likely add potentially U.S. sites in 22, but we're expecting RAISE2 to be largely driven by European sites. We don't see that as a conflict at all.
We're almost complete with our and myself across our our 5 territories. The R and the cells are now interacting with Kols. We're building those relationships and really understanding who art key treaters are and wants to have and interesting. Doug is we continue to do a little bit of market research on the side and.
We are finding many physicians, who have significant numbers for TD patients and their practice much more than I would have expected. So the commercial team is is really working hard we feel like we're in great shape will have solid identification of the CVD patient base to a large degree.
Scott Braunstein: Remember, RAISE is in the U.S. For the ESE study, which, as we've talked about, will really begin in 22; we certainly feel by the time that study is up and running from a U.S. perspective, our U.S. RAISE trial will have our sites initiated, enrollment curves where they should be, and as Joe mentioned, we will have some overlap, just a handful of sites in the ESE study in But remember, those patients are coming in through the emergency room, and we see them as very different patient populations.
And we're really looking forward to the launch we were certainly going to have a very busy a S. R. Our MSL team is working on a on a major program and Aes will have abstracts.
And we'll see it for lives and in fact, I talked to the team yesterday about.
Preparing for a live meeting I'm, a little bit more suspicious come just come December we're gonna be inside and Chicago, given what's going on with Delta virus, but we will certainly be ready for all forms of communication.
Scott Braunstein: So there may be a chance of some overlap by Q2 of 22, but we certainly don't think that will impact RAISE timelines at all. And certainly, there are going to be one or two sites that are just very active in the status epilepticus space, and we feel fortunate that we may have the opportunity to work with them on more than one trial. I would not expect any sites from the RAISE trial to be active enrollers in RAISE2. That would create a potential overlap in terms of patients. So that's something we certainly would avoid between RAISE and RAISE2. Is that clear to you? Yes, yes. Thank you very much. That's exactly right.
And if online education.
Is necessary in that regard so I couldnt be happier with where the commercial team is today Christy is doing a great job I'm not gonna.
Give her a lot of grief because their audio is down today and Chris you are you still out for the count.
And I'm not I I am now back on.
Well I I did my best rambling on Christy I'm, sorry about that anything you want to add to that please do.
And so Doug I'm sure that Scott hit on everything I think some of the high level things that we're really excited about where we're really excited about the filing obviously, but and anticipation of a priority review and we're looking at a mid 'twenty 2 launch and 1 on the largest pieces and parts that we fully finally.
Operator: Thank you very much. That's exactly what I wanted to understand.
Operator: Operator, next question.
Operator: Yes, your next question comes from Douglas Tsao with HC Wainwright.
Operator: Hi, good morning. Thanks for taking the questions.
<unk> is the integrated product launch strategy for all 5 functional departments.
Scott Braunstein: Maybe, since we have Christy on the line, you could provide an update on the pre-commercialization activities for the company and what you've been able to accomplish so far and as you gear up ahead of the potential launch. Thank you.
And then on the heels and that we've now executed on enterprise wide launch readiness and blueprint that will support and all functional areas with and Marinus as an organization to be on board with how this launch it should look to the community and.
Scott Braunstein: Christy, you want to jump right in? Did you hear that question? I think we're having some technical problems, Doug.
And from a marketing perspective, we have our new marketing agency on board, we would like to have a very balanced approach with our caregiver and our physician strategy and I think I heard Scott talk just a little bit about the market research that we're doing and and it continues to inform how we will launch into.
Scott Braunstein: So, would you like me to take it? You can take it. Sure. Christy's hired a great team. We now have leadership across sales, across marketing, a great commercial operations leader, and one of our first hires was on the reimbursement side. I'll add to that, I don't want to forget anyone, our clinical supply chain. So we have all the key leadership positions in place. We're actually now recruiting for our sales leadership for our two territories. Those leaders will be responsible for hiring our sales reps. Our plan would be to make those offers early in 2022, contingent on approval.
And C D K all 5 but we continue to be really encouraged with the communication that we're getting back from our Kols that will help support at that from a 1 on 1 strategy from a marketing and sales perspective, as we get out there and really have these interactions and.
And with that our first line leaders are being chosen for both access and sales and these access leads will be really important to get the insights from our payers early on so that we can continue with that strategy. So I hope that wasn't duplicate and on on what Scott gave you, but where we're thrilled where we are where were incurred.
Scott Braunstein: And from a sales team perspective, we're in great shape. But on the flip side, on the medical science liaison side, we're almost complete with our MSLs across our five territories. Our MSLs are now interacting with KOLs. We're building those relationships and really understanding who our key prescribers are. And what's been interesting, Doug, is we continue to do a little bit of market research on the side, and we are finding many physicians who have significant numbers of CDD patients in their practice, much more than I would have expected. So the commercial team is really working hard. We feel like we're in great shape.
Range with having this filing and and we are on track for next year.
Okay, great. Thank you so much.
And a great day.
Yes.
Your net operating and comes from the line. Yes. Your next question comes from the line of Andrew Tsai with Jefferies.
Great. Good morning, and thanks for having me I have another question on C. D D. It's more like a housekeeping question on you.
And you mentioned in your prepared remarks, how I guess your base case expectation is a schedule for by the D. And general can you kind of talk about why schedule for would be a non issue as it relates to uptake and I guess at what point does a stricter schedule I guess start to become an issue and then for context.
Scott Braunstein: We'll have solid identification of the CDD patient base to a large degree, and we're really looking forward to the launch. We're certainly going to have a very busy AES. Our MSL team is working on a major program at AES. We'll have abstracts.
Scott Braunstein: We'll see if we're live. In fact, I talked to the team yesterday about preparing for a live meeting. I'm a little bit more suspicious come December. We're going to be inside in Chicago, given what's going on with the Delta virus. But we will certainly be ready for all forms of communication. If online education is necessary in that regard, so I couldn't be happier with where the commercial team is today.
Can you talk about what kinds of scheduling the other epilepsy drugs have received from past, including some of the gathers out there. Thanks.
Well Andrew Thanks for the question, Ken Why don't you talk a little bit first about where and why you think will be scheduled for and then we'll turn it over to Christi for the commercial side.
Sure Scott day, so in regards to the schedule and I think as required we had cash and non clinical and clinical abuse liability study.
Scott Braunstein: Christy's doing a great job. I'm not gonna, you know, give her a lot of grief because her audio is down today. Christy, are you still out for the count?
And you just mentioned and based on that data.
And based on the fact, we are.
Christy Shafer: I am not. I am now back on.
Terrible and saw similar effects and.
Christy Shafer: Okay. Well, I did my best rambling, Christy. I'm sorry about that. Anything you want to add to that, please do.
Volume.
And that support it and.
Part of our.
Our recommendations and benchmarks such as price gallons I stand on haven't scheduled for.
Christy Shafer: So Doug, I'm sure that Scott hit on everything. I think some of the high-level things that we're really excited about first. We're really excited about the filing, obviously, but in anticipation of a priority review, we're looking at a mid-22 launch, and one of the largest pieces of work that we fully finalized is the integrated product launch strategy for all five functional departments. And on the heels of that, we've now executed a full enterprise-wide launch readiness blueprint that will support all functional areas within Marinus as an organization to be on board with how this launch should look to the community. From a marketing perspective, we have our new marketing agency on board. We would like to have a very balanced approach with our caregivers and our physician strategy.
And by channel because of the mechanism action similarity with and.
And I found that in addition to Rfps fidelity stuff and data and some data and we talk from our clinical study we conducted over the past several years that why that's true, making a recommendation and as part of for NDA submission and.
And to protect the schedule for that.
And that kind of on and how we land on that recommendation and now.
For a further endorsement.
And Chris do you want to talk about the commercial thinking about that.
Sure to Kim's point, where there's several analogs to help support the schedule for us.
And we've anticipated debt with our conversations with specialty pharmacy to understand what needs to be done from that perspective that when we put dragon into the channel and.
Christy Shafer: I think I heard Scott talk just a little bit about the market research that we're doing, and it continues to inform how we will launch into CDKL5, but we continue to be really encouraged by the communication that we're getting back from our KOLs that will help support us from a one-on-one strategy from a marketing and sales perspective as we get out there and really have these interactions. And with that, our first-line leaders are chosen for both access and sales.
And they're very well burst and schedule for our products and we don't anticipate any large hurdles and.
To get to hear from the specialty prospect and the only and slight thing that we need to remember is that during that scheduling period. We do have 90 days from approval to when we actually can officially market drug which means put dragged into the channel however, and during that time, we're able.
To fully promote and have good communication with our physician understanding where the patients are identification of the patients. So and really we had that 90 day period on where we'll pause and wait for that schedule and chicken farm that it will be a schedule for which 1 and then well update RPI and all necessary materials that are set for.
Christy Shafer: These access leads will be really important to get insights from our payers early on so that we can continue with that strategy. So I hope that wasn't duplicative of what Scott gave you, but we're thrilled where we are. We're encouraged by having this filing in, and we are on track for next year. Okay, great. Thank you so much.
Operator: Operator? Yes, your next question comes from the line of Andrew Tsai with Jefferies.
Operator: Great. Good morning, and thanks for having me. I have another question on CDD. It's more like a housekeeping question.
And it.
Great and thanks for that.
I wanted to just yeah, do you want to remind folks about epidiorite and their scheduling.
Operator: You mentioned in your prepared remarks how, I guess, your base case expectation is a Schedule 4 by the DEA. In general, can you kind of talk about why Schedule 4 would be a non-issue as it relates to uptake? And, I guess, at what point does a stricter schedule start to become an issue? And then, for context...
Just as a comparator.
Is that can make that.
And so on episodic initially was schedule and Oh 5. However, subsequently these kathleen was removed from average outlet. So it is currently now scheduled dry but I don't believe that day scheduled for I think we're fairly consistent with other anti epileptic drugs and I don't anticipate you'll be barrier on I know, Chris you can achieve it.
Operator: What kinds of scheduling the other epilepsy drugs have received in the past, including some of the GABAs out there? Thanks.
As mentioned and I guess.
A barrier to our commercialization or uptake.
Makes sense. Thanks.
The next question comes from the line of Marc Goodman with SBB Leerink.
Scott Braunstein: Well, Andrew, thanks for the question. Kim, why don't you talk a little bit first about why you think we'll be scheduled for, and then we'll turn it over to Christy for the commercial.
Yeah.
As you've gotten into the research and really touching all of the sites and everything and get and getting ready for this launch for <unk> can you just give us a sense of the patients who started to I think it was Scott you mentioned that as you guys have done more work you sound more patients give us a sense of the number of patients and the U S debt.
Kimberly A. McCormick: Sure, Scott, thanks. So in regards to the scheduling, I think, as required, we had to conduct some non-clinical and clinical abuse viability studies to support the NDA's submission. And based on that data, and based on the fact that we were, comparable and similar effects as to volume, that supported part of our recommendations to the FDA, as well as benchmarks, such as Brixanil, and Brixanil has a Schedule 4 similar to, and because of the mechanism of action similarity with Ganaxilone, that in addition to our abuse liability assessment data, and some data we saw from our clinical studies that we conducted over the And now it'll go to the DEA for further endorsements.
And that you thought you had out there you know a year ago and how many are thinking there are there now and how many you know where they are and you know just.
And just how much visibility we have on that and then second of all just on the range and just remind us.
Some of the products that Orion has done a really good job with and impressed you.
To make them a partner have they done epilepsy before or is it really just you know kind of orphan. Thanks.
Thanks, Mark let me take the second part on Orion and then I'll flip it and I'll give a little bit of background on patients and and I'll flip it over to Christie.
Uh Huh, Brian the really nice thing about the Orion team.
Is that they have both neurology expertise so 1 of their key products and the area of Parkinson's disease.
Christy Shafer: And Chris, do you want to talk about the commercial thinking about that?
Christy Shafer: Sure. To Kim's point, where there are several analogs to help support Schedule 4, we've anticipated this with our conversations with specialty pharmacy to understand what needs to be done from that perspective. And when we put the drugs into the channel, they're very well versed in Schedule 4 products. However, during that time, we're able to fully promote and have good communication with our physicians, understanding where the patients are, and identification of the patients. So, really, we have that 90-day period where we'll pause and wait for the scheduling to confirm that it will be a Schedule 4, which will then update our PI and all necessary materials that are associated.
And second is there in the ICU and they have precedents. It in Europe. They are have recently branched into <unk>.
Warfarin.
Orphan products and in fact, they have a leader on the commercial team who has tremendous experience with with with other companies with global pharmaceutical and biotech companies on the rare orphan disease side of the commercial business. So they really had all 3 parts of the puzzle from our standpoint.
And as a result, they've been really great to work with we've had strong alignment in terms of how we think about approaching European market. Both from an access reimbursement and data collection standpoint. So so I think they brought a lot of value to the table and.
Christy Shafer: Do you want to remind folks about Epidiolex and their schedules? Just as a comparator. Thank you.
Christy Shafer: So, Epidiolic initially was scheduled at Schedule 5, however, subsequently, the scheduling was removed from Epidiolic, so it's currently not a scheduled drug, but I don't believe that Schedule 4, I think, was fairly consistent with other anti-epileptic drugs, and I don't anticipate it will be a barrier, and I know Christy can, as she just mentioned, I don't anticipate it being a barrier to our commercialization The next question comes from the line of Marc Goodman with SBB Lear, Inc.
And our thinking already and that's led to some discussions from members of Christie's team with some specific countries within Europe, and how they're thinking about.
Market access and reimbursement so we already felt like we've had a nice jump in that regard and we're very fortunate on the Iranian side that they're bringing a lot of skill sets for the tables table on on the U S side of CBD and by the way, we're already seeing that changing landscape and a good way in Europe around CBD.
Operator: Yeah, as you've gotten into the research and really touched all the sites and everything and are getting ready for this launch for CDD, can you just give us a sense of the patients you started to see? I think Scott mentioned that as you guys have done more work, you found more patients. Give us a sense of the number of patients in the US that you thought you had out there, you know, a year ago and how many you think are there now and how many, you know, you know, just how much visibility we have on that.
We just talked to a UK center that became a recent center of excellence and and they've gone from having to patients and our phase III CTD trial to now 20 identified CDK, all 5 patients and and they believe that number is going to grow so almost everything we talk about it I think and the U S. We're seeing that changing dynamic and Europe is.
Well on the U S side quick and Dirty We believe about 100 kids are born in the U S. Every year with TD Cal 5 almost all of them given the severity of their illness are going to be diagnosed within the first year of age are recommended for genetic testing. So there's a very high likelihood that that incidence number.
Operator: And then, second of all, just on Orion, just remind us some of the products that Orion has done a really good job with that impressed you enough to make them a partner. Have they done epilepsy before? Is it really just, you know, kind of orphaned?
We're capturing many of those patients and as a reminder, our phase 3 dataset and the largest your largest global C. D. D day that said the average age of a patient and 6 years old aligning with what's being done and the genetic testing world.
Scott Braunstein: Thanks. Thanks, Marc. Let me take the second part on Orion, and then I'll flip it, and I'll give a little bit of background on patients, and then I'll flip it over to Christy. Orion, the really nice thing about the Orion team is that they have both neurology expertise and ICU experience, so one of their key products is in the area of Parkinson's disease, and second, they're in the ICU, and they have Pre
And so we feel very confident particularly that younger population being identified as being referred to centers of excellence and maybe I'll just stop there Christine and kind of turn the rest over for you to you.
Scott Braunstein: They have recently branched into orphan products, and in fact, they have a leader on the commercial team who has tremendous experience with other companies, with global pharmaceutical and biotech companies on the rare orphan disease side of the commercial business. So they really had all three parts of the puzzle from our standpoint, and as a result, they've been really great to work with.
Sure. So just as a quick reminder, there are 8 C. D day centers of excellence across the United States and and 40 total really key epilepsy centers.
And we've continued to really really focus on market research just to test our assumptions and you know and it's.
And it's fun when I get to call Scott and say, it's better than we thought right. So we continue to have really deep K O L involvement that has.
Scott Braunstein: We've had strong alignment in terms of how we think about approaching the European market, both from an access and reimbursement data collection standpoint. So, I think they bring a lot of value to the table in our thinking already, and that's led to some discussions from members of Christy's team with some specific countries within Europe and how they think about market access and reimbursement. So, we already feel like we've had a nice jump in that regard, and we're very fortunate on the Orion side that they're bringing a lot of skill sets to the table.
A significant number of patients.
Gives me and.
But what they're doing and what we're finding is they're they're working very closely with their key local pediatric neurologists and Apple App colleges to really best treat these patients I think that Covid will give us an interesting perspectives on how patients are being treated and the virtual environment, which is supportive of us we will have that.
Our sales teams and so in order for us to get to these 8 C. D D centers and 40 ever on large epilepsy centers it will be much much easier and how physicians are engaging with that so again. These patients are really concentrated and meet large centers potentially treated and.
Scott Braunstein: On the U.S. side of CDD, and by the way, we're already seeing a changing landscape in a good way in Europe around CDD. We just talked to a U.K. center that has become a recent center of excellence, and they've gone from having two patients in our phase three CDD trial to now 20 identified CDKL5 patients, and they believe that number is going to grow. So, almost everything we talk about, I think, in the U.S., we're seeing that changing dynamic in Europe as well.
Locally at some level as well, but we're getting really great feedback and we're all up and our.
Okay.
So in total and the U S. Do you think there how many patients right now.
You know, it's really hard to say I'll remind you that on the ICD 10 code is only about 6 to 10 months old gosh. The time is I think it was a light at the end of last summer and so we are.
Scott Braunstein: On the U.S. side, quick and dirty, we believe about 100 kids are born in the U.S. every year with CDKL5. Almost all of them, given the severity of their illness, are going to be diagnosed within the first year of age or recommended for genetic testing. So there's a very high likelihood that that incidence number, we're capturing many of those patients. And as a reminder, in our phase three data set and the largest global CDD data set, the average age of a patient is six years old, aligning with what's being done in the genetic test. And so, we feel very confident, particularly that younger populations are being identified and referred to centers of excellence. And maybe I'll just stop there, Christy, and kind of turn the rest over for you.
Not 100% sure and but we do believe it's and about 1 and 40000 and I'll remind you that we're just looking at the pediatric population right now they're really looking you know between 2 and 4000 pediatric patients right now because we will not be looking at those adult probably on diagnosed patients or for that time being.
Thank you.
Your next question comes from the lined up for Lithia Young Cantor Fitzgerald.
Hi, Good morning, and this is neena on for leap year.
Thanks for taking our questions.
We are wondering if you could just share more on the PSC phase 3 proposed to design and also for the top line update and the third quarter can you. Please share any details on what will be disclosed and.
Christy Shafer: Sure. So just as a quick reminder, there are eight CDD Centers of Excellence across the United States and 40 total really key epilepsy centers. We've continued to really, really focus on market research just to test our assumptions. And, you know, it's fun when I get to call Scott and say it's better than we thought, right? So we continue to have really deep KOL involvement that has, you know, a significant number of patients. Excuse me, but what they're doing, and what we're finding is they're working very closely with their key local pediatric neurologists and epileptologists to really best treat these patients. So, again, these patients are really concentrated in these large centers, potentially treated locally at some level as well, but we're getting really great feedback on where all of them are.
How we should think about expectations. Thank you.
Good morning, Joe why don't I turn the call turn the question over to you.
Sure.
Yeah, the phase III <unk> study, it's a fairly standard design very much like the CTD study.
Patients have and this case they'll have a 4 week baseline and.
And then be treated for 16 weeks on on.
And actually the placebo same titration schedule for week titration 12 weeks of maintenance and.
The endpoint is going to be the same endpoint as per cent reduction in major seizures, the seizure types for a little bit different.
The.
Seizure types in TSB most of the seizures of focal which is not the case.
With and.
CBD.
So that's 1 thing we'll be interested and looking at in the.
Christy Shafer: So in total, in the U.S., you think there are how many patients right now?
Phase II data when we see it.
<unk> and <unk>.
Christy Shafer: You know, it's really hard to say. I'll remind you that the ICD-10 code is only about, you know, six to 10 months old. Gosh, the time is, I think it was the last, at the end of last summer.
Again, it's a.
'twenty 3 'twenty 2 'twenty 3 patients.
A single arm open label.
And so I think they're going to be a number of things we'll look at we'll look at non.
Christy Shafer: So we're not 100% sure, but we do believe it's in about one in 40,000. I'll remind you that we're just looking at the pediatric population right now. So really looking, you know, between two and 4,000 pediatric patients right now because we will not be looking at those adult, probably undiagnosed patients for the time being.
And not just the magnitude of effect really was that number of patients there could be pretty wide.
And the confidence intervals around.
The effect, we've seen a lot of variability so as long as moving that variability we see a good.
Chance for a response and then response by seizure type.
But the initial top line results will be the first set of data.
But we'll continue to explore the data on it and see if it has implications for the design of the phase III.
Operator: Thank you. Your next question comes from the line of Lizia Young with Canterfields General. Hi, good morning. This is Nina on behalf of Aletheia.
Right.
Yes, so does that answer your question Neal.
Yeah. It does thank you.
Operator: Your next question comes from the line of Lizia Young with Cantor Fitzgerald.
Okay. Let me let me just add on to Joe. We certainly are going to be very very keen on looking at response rates and in young patients who are on a finished tour as well as the entire patient cohort that previously on Epidiorite. So we're thinking about this phase III is a a refractory study effectively a third line.
Joseph Hulihan: Good morning, Joe. Why don't I turn the call over to you? Sure. Yeah, the Phase III TSC study is a fairly standard design, very much like the CDD study. Patients have, in this case, they'll have a four-week baseline and then be treated for 16 weeks on an axonal placebo, same titration schedule, four-week titration, and 12 weeks of maintenance. And the end point is going to be the same end point as the percent reduction in major seizures. The seizure types are a little bit different. In TSC, most of the seizures are focal, which is not the case with CDD.
And we want to make sure that there were seeing reasonable and real responses and those patients on that.
That'd be the only thing I'd add to Joe's commentary and.
I'll add I'm really very happy we've done this phase 2 we've learned a lot. We recently had and S. A b board we've gotten a lot of insights. If you go back and look at the 2 trial designs for both Novartis for these tended towards study and the GW study there are some differences and that and that study design and I think we're trying to be extremely thoughtful about.
Joseph Hulihan: So that's one thing we'll be interested in looking at in the... phase two data when we see it. And again, it's 23, 22, 23 patients, single arm, open label. And so I think there's going to be a number of things we'll look at; not just the magnitude of the effect, really; with that number of patients, there could be pretty wide confidence intervals around the effect. We've seen a lot of variability.
On appropriate design and.
Thrilled to have Dr. Joe or our house uplift colleges Doctor Arroyo, who just joined our board with great epilepsy background and so we'll be we'll be quite thoughtful if we need to make any tweaks to the to the study design, but certainly very happy that we're aligned with the agency and and feel like we have a really nice paradigm.
Joseph Hulihan: So as long as within that variability, we see a good chance for response, and then response by seizure type. But the initial top-line results will be, you know, the first set of data. But we'll continue to explore the data and see if it has implications for the design of phase three. [inaudible] Yeah, so does that answer your question, Nino? Yeah, it does.
Going forward as well right I think it's really important to say if the agency and if we're if.
If we move forward with TD and the agency granted this approval. We now have a paradigm of a single study as a potential registration strategy.
Joseph Hulihan: Thank you. Okay, let me just add to Joe, we certainly are going to be very, very keen on looking at response rates in young patients who are on Affinitor, as well as the entire patient cohort that was previously on Epidiolex. So, you know, phase three is a refractory study, effectively a third line study, and we want to make sure that there we're seeing reasonable and real responses in those. That would be the only thing I'd add to Joe's commentary.
Cross the board and some of these rare epilepsy. So that was very comforting and again you know a lot of people ask us about our interactions with the FDA and Kinston and awesome job, but we continue to have very constructive dialogue, we're transparent we're forward thinking with them and.
In general we've been really happy with their their interactions with us.
Operator, why don't we go to another question, we have time for 1 more.
Brian <unk> from Baird.
Hey, good morning, everyone and thanks for fitting me in I guess I was hoping to get a little more color on the second generation formulations.
Joseph Hulihan: I'll add I'm really very happy we've done this phase two. We've learned a lot. We recently had an SAB board. We've gotten a lot of insights. If you go back and look at the two trial designs for both Novartis for the Affinitor study and the GW study, there are some differences in that study design.
I think I heard you say the word pro drug and the prepared remarks on it. So I was just wondering are you looking at actual changes and.
Chemical structure to the API.
Or just.
Just sort of changes on accepting and set or more kind of a standard formulations.
Scott Braunstein: And I think we're trying to be extremely thoughtful about the appropriate design. We're thrilled to have Dr. Joe, our house epileptologist, Dr. Arroyo, who just joined our board with a great epilepsy background, and so we'll be quite thoughtful if we need to make any tweaks to the study design, but certainly very happy that we're aligned with the agency and feel like we have a really nice paradigm going I think it's really important to say that if the agency and if we move forward with CDD and the agency grants us approval, we now have a paradigm of a single study as a potential registration strategy across the board in some of these rare epilepsies, so that was very comforting.
You know maybe characterize that and and also how we kind of think about that project.
Hospital, new chemical entity and new patents on and also.
And if any sort of 5 O 5 b 2 pathway references and utilize and.
And the development of the novel formulations. Thanks.
Thanks, Brian and we will take 1 more question. After you I really appreciate the question. So we are pursuing both.
And novel formulations from an excipient standpoint, and pro drugs Theres been a little bit and work with pro drugs in the past.
We've made a much larger effort we've made some fantastic progress we've had.
And we're certainly building and intellectual portfolio.
Around that we would expect at least where we are today with the pro drug that it very well could take some additional preclinical work.
Scott Braunstein: Again, a lot of people ask us about our interactions with the FDA, and Kim's done an awesome job, but we continue to have very constructive dialogue. We're transparent. We're forward-thinking with them, and in general, we've been really happy with their interaction. Operator, why don't we go to another question? We have time for one more.
As we as we move to a final pro drug formulation and so I would actually say I'm thinking today is that our prodrug technology will likely be a third generation step and the process.
We're hopeful that we could have a pro drug and the clinic and 'twenty 2 but as of today.
Operator: Brian Skorney from Bayard.
The first program and and very likely the second that we feel confident about is an excipient based.
Operator: Hey, good morning, everyone. Thanks for putting me in. I guess I was hoping to get a little more color on the second-generation formulations. I think I heard you say the word prodrug in your prior remarks, so I was just wondering, are you looking at actual changes in chemical structure to the API or, you know, just sort of changes in excipients that are more kind of standard formulations or, you know, maybe characterize that and also how we kind of think about that projecting to possible new chemical Thanks.
Improved for all your ability a set of formulations and.
And quite honestly I think this is going to be.
We have the opportunity to on and step.
Step 1 and improve bioavailability.
Ability with tid dosing still being very much.
The first step and I think our second step where I'm really interested in and utilizing the pro drug would be and either be ideal ESR formulations that would really improve dosing a simplified dosing regimens for patients and and so we're going on we're going to work to that goal it may be with it.
Scott Braunstein: Yeah, thanks, Brian. And we'll take one more question after you. I really appreciate the question. So we're pursuing both novel formulations from an excipient standpoint and prodrugs. There's been a little bit of work with prodrugs in the past, but we've made a much larger effort. We've made some fantastic progress.
With the and.
And excipient based formulation I think we've already we I can I can also share with you.
We're building some early intellectual property around both of the formulation.
We're moving into the clinic and 'twenty 2 so I think all of the right now all 3 programs and we're working on a fourth program today, we'll have incrementally meaningful or has the potential for having incrementally meaning intellectual property.
Scott Braunstein: We've had, and we're certainly building an intellectual portfolio around that. We would expect, at least where we are today with the prodrug, that it could very well take some additional preclinical work as we move to a final prodrug formulation. So I would actually say today that our prodrug technology will likely be a third generation step in the process. We're hopeful that we could have a prodrug in the clinic within 22, but as of today... The first program, and very likely the second that we feel confident about, is an excipient-based, improve solubility set of formulations.
But to your point I think we're just planning that the prodrug could take a bit longer to do all of that necessarily all the necessary preclinical work.
And tax we're able to pursue.
And then <unk> pathway and and right now that's my hope and expectation.
There has been a lot of recent.
Changes to the way the FDA thinks about pro drugs, and we're very familiar with that those recent decisions and FDA guidelines and with that being said I'm still quite enthusiastic that theres, a potential path to and T for us with our with what we're doing and the pro drug space I Hope that was helped.
Scott Braunstein: And quite honestly, I think this is going to be we have the opportunity to, in step one, improve bioavailability, with TID dosing still being very much the first step. And I think our second step, where I'm really interested in utilizing the prodrug, would be in either BID or SR formulations that would really improve dosing and simplify dosing regimens for patients. And so we're going to work toward that goal. It may be with an excipient-based formulation.
Paul.
Your next question will come from the line of Jay Olson with Oppenheimer.
Oh, Hey, congrats on all the progress and thanks for taking our questions.
Can you maybe talk about the prevalence of lgs and the U S and Europe and what are some of the key unmet needs and that patient population and what maybe some of the efficacy end points might look like and your phase 2 trial.
Scott Braunstein: I think we've already, I can also share with you, we're building some early intellectual property around both of the formulations that we're moving into the clinic in 22. So I think right now, all three programs, and we're working on a fourth program today, will have incrementally meaningful or have the potential for having incrementally meaningful intellectual property. But to your point, I think we're just planning that the prodrug could take a bit longer to do all the necessary preclinical work if, in fact, we're able to pursue an NCE pathway.
And then separately it seems like Marinus would be eligible for rare pediatric disease priority review voucher assuming.
And you get approval a net.
Next year and CBD can you just talk about your plans for that voucher. Thank you.
And Joe why don't we have Steve talk a little bit about the voucher and then I'll flip it over to you for lgs Okay.
Yeah, Good morning, Jay.
Yes. So we are you know we would expect that as a part of the <unk> approval from the FDA, we would receive a rare pediatric voucher I think when we look at our pipeline and and kind of the value to us of that we would look at that more as something we would monetize and use to.
Scott Braunstein: And right now, that's my hope and expectation. There have been a lot of recent changes to the way the FDA thinks about pro drugs. We're very familiar with those recent decisions and FDA guidelines. And with that being said, I'm still quite enthusiastic that there is a potential path to NCE for us with what we're doing in the pro drug space. I hope that was helpful.
Further strengthen the balance sheet, so and.
And that's something we think we could turn pretty quickly.
So if we got approval early next year, we would try and probably quickly monetize that strengthen the balance sheet and use debt to fund continued development.
Operator: Your next question will come from the line of Jay Olson with Oppenheimer.
When we look at kind of the value there is a very good value out in the marketplace, that's held pretty steady.
Operator: Well, hey, congrats on all the progress and thanks for...
Operator: Can you maybe talk about the prevalence of LGS in the U.S. and Europe and what the
So that's that's our thinking on the use of the pediatric voucher at this point.
Yeah.
So and on the Lgs, yeah, yeah. So in terms of.
Operator: What are some of the key unmet needs?
Operator: [inaudible]
Operator: You get approval next year in CDD. Can you just talk about...
Frequency of Lgs, they're about 40, or 50000 children and adults and the U S with Lennox <unk> syndrome.
Operator: Can you just talk about your plans for that voucher? Thank you.
Steven E. Pfanstiel: Joe, why don't we have Steve talk a little bit about the voucher and then I'll flip it over to you for LGS. Yeah, good morning, Jay.
And the syndrome as you know.
Range of different seizure types.
Steven E. Pfanstiel: Yeah, so we, you know, we would expect that as a part of the CDD approval from the FDA, we would receive a rare pediatric voucher. I think when we look at our pipeline and kind of the value to us of that, we would look at that more as something we would monetize and use to, you know, further strengthen the balance sheet. So, and that's something we think we could turn pretty quickly.
Developmental disabilities and on a particular pattern on EG called flow Spike and wave.
They have the same needs as a lot of other.
And developmental and epileptic encephalopathy or <unk>.
And they require a lot of supportive care.
And sometimes institutional care there.
Easily.
Fairly significantly disabled and.
Steven E. Pfanstiel: So if we got approval early next year, we would probably quickly monetize that, strengthen the balance sheet, and use that to fund continued development. You know, when we look at kind of the value, there's a very good value out in the marketplace that's held pretty steady. So that's, that's our thinking on the use of the pediatric voucher. So, um, yeah, yeah.
And and like some of the other epileptic encephalopathy as they have drop seizures, which can cause injury.
Or a range for behavioral problems.
The unmet need in terms of seizure treatment.
Despite.
The recent availability and I mean, there are several drugs approved for 1 on <unk>.
Unfortunately, there is still considerable unmet need and and the majority of patients with Lennox cash, though still have uncontrolled seizures.
Joseph Hulihan: So, um, in terms of, uh, [inaudible] Developmental Epileptic Encephalopathies, they require a lot of supportive care, sometimes institutional care, and are usually, you know, fairly significantly disabled. And, like some of the other epileptic encephalopathies, they have drop seizures, which can cause injury. They have a range of behavioral problems, and there is an unmet need in terms of seizure treatment despite, you know, recent availability. I mean, there are several drugs approved for Linus guesto. Unfortunately, there's still a considerable unmet need, and the majority of patients with Linux guestos still have uncontrolled disease. So there's going to be a need there, and we think it could be a real complement to the other available therapies to have Ganaxone available for those children and adults.
And so there's going to be a need there and.
And we think it could be a real complement to the other available therapies to help get back slow and available for those children and adults.
Great. Thank you for taking the questions.
Well I think we're going to wrap operator on and thank everyone for for jumping on the calls for and I know its busy time and early C and earning season and thank you for all the questions and just want to finish.
How proud I am the work that the teams doing the regulatory team has had some great wins this quarter Christy as you mentioned building her team and our clinical operations team working through really difficult times out there. So I appreciate everyone's support and.
Operator: Great, thank you for taking the question. Mm-hmm.
Scott Braunstein: Well, I think we're going to wrap, Operator. I want to thank everyone for jumping on the calls for me. I know it's a busy time of the earnings season, and thank you for all the questions. I just want to say how proud I am of the work that the team is doing. The regulatory team had some great wins this quarter.
And look forward to following up lives have a good day everyone.
Ladies and gentlemen, thank you for participating in today's conference call you may now disconnect.
Okay.
Operator: Christy, as she mentioned, is building her team and our clinical operations team is working through really difficult times out there. So I appreciate everyone's support and look forward to following up live. Have a good day, everyone. Ladies and gentlemen, thank you for participating in today's conference call. You may now disconnect.
And then.
And the growth.
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Yes.
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