Q1 2022 Marinus Pharmaceuticals Inc Earnings Call

[music].

Operator: Greetings and welcome to the Marinus Pharmaceuticals first quarter 2022 financial results and business update call.

Greetings and welcome to the Marinus Pharmaceuticals first quarter 2022 financial results and business update call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session. If you would like to ask a question. Please press star one on your telephone.

Operator: At this time all participants are in a listen only mode.

Operator: After the speaker's presentation, there will be a question and answer session.

Operator: If you would like to ask a question, please press star 1 on your telephone keypad.

Operator: If you would like to remove yourself, please press star 1 again.

Pat did you would like to remove yourself. Please press star one again.

Operator: And now it is my pleasure to introduce your host, Sasha Damouni-Ellis, Vice President of Corporate Affairs and Investor Relations.

And now it is my pleasure to introduce your host Sasha.

Ellis Vice President of corporate Affairs, and Investor Relations you may begin.

Okay.

Sasha Damouni-Ellis: You may begin.

Thank you and good afternoon, everyone.

With me from Meredith are Dr. Scott Braunstein, Chief Executive Officer, Dr. Joe Houlihan, Chief Medical Officer, and Defense Hill, Chief Financial Officer.

Before we begin I would like to remind everyone that some of the statements. We're making today are forward looking statements under the securities laws.

These forward looking statements involve substantial risks and uncertainties that could cause our clinical development programs future results performance or achievements to differ significantly from those expressed or implied by such forward looking statements.

Yes.

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.

Sasha Damouni-Ellis: Thank you and good afternoon, everyone.

Thank you Sasha and welcome to our call. This.

This has been an exceptional year for the company marked by the Fda's approval of the tall need for the treatment of seizures associated with C. D. K L five deficiency disorder.

We've been diligently preparing to bring our first product to market and are on track to launch the Ptolemy commercially in the U S in July which Steve will speak to in greater detail.

Sasha Damouni-Ellis: With me from Marinus are Dr. Scott Braunstein, Chief Executive Officer, Dr. Joe Hulihan, Chief Medical Officer, and Steve Pfanstiel, Chief Financial Officer.

It has also been a busy year another front, specifically advancing our pipeline.

We were pleased to announce earlier this month that our phase three double blind placebo controlled trial in status epilepticus. The raise trial re initiated screening and recruitment our teams have been working diligently behind the scenes to ensure that sites would be ready to begin screening immediately after we shipped new clinical.

Sasha Damouni-Ellis: Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws.

I cannot be more proud of the efforts by the entire Americas team and the cooperation and dedication of our clinical sites.

Moving to our Oregon ex loan program I'm thrilled to share that we are actively recruiting at U S sites for the phase three trusts PSC trial in tuberous sclerosis complex and expect to expand globally over the summer and fall.

Site Activations continue to advance we are now planning to expand the trial to include 65 to 75 sites compared to the 60 sites. We were initially targeting in an effort to maximize recruitment and move up the study timelines we.

We are currently planning to focus on sites in the U S Western Europe , Canada, and Israel and expect top line data in the first quarter of 2024.

Now I would like to give a quick update on our second generation product development efforts before handing it over to Joe for a deeper dive on our clinical activities. The goal of our second generation program is to achieve better bioavailability and extend the therapeutic value of can ask alone. We have started phase one dosing.

Sasha Damouni-Ellis: These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development program, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements.

Of the first next generation, Oregon, excellent formulation and to remain on track to announce top line data by the middle of this year.

Following the evaluation of the phase one data with the specific goal of achieving more consistent and higher blood concentrations up good acts alone. We expect to utilize this novel formulation and a phase two study of Lennox <unk> syndrome in the second half of this year. We are excited to follow the progress of the <unk>.

First new formulation of <unk> alone and over 15 years I'll leave the details to Joe Let me conclude my remarks by discussing how we plan on bringing the tall need to patients and families around the globe. We are targeting submitting responses to the Ema's day 120 list of questions with the CTD marketing.

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.

Authorization application or MAA by mid year.

With a mid year submission, we would expect to see HMP opinion by the end of the year, we have been collaborating extensively with Orion our European strategic partner as they prepare for commercial launch of Kodak's alone should it receive approval by the MAA.

In addition, we believe that there is a broader global opportunity and are exploring additional ex U S strategic partnerships to expand good excellence commercial footprint.

Our goal is to achieve another strategic partnership by the end of the year. Our organization is committed to expanding global access of the <unk> franchise and helping to improve the lives of more patients suffering from Cte D. T. A C in status epilepticus.

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

I'll now hand, the call over to Joe for more on our clinical development activities.

Scott Braunstein: Thank you, Sasha, and welcome to our call.

Thank you Scott low everyone I'd like to begin by discussing our IV development programs we.

We currently have two trials and refractory status epilepticus or RSC raise in rates too.

Both phase III trials are designed to demonstrate rapid onset of action and durable.

Station.

In the rave study, which is ongoing durability will be measured by prevention of progression to IV anesthesia, which is associated with high rates of morbidity and mortality.

And the race to study for European registration, which is planned to begin in the first half of 2023.

Your ability to effect will be assessed by prevention of any escalation of treatment IV anesthesia otherwise.

Which can also prolong hospital stays and intensive medical care and.

In addition to the demonstration of efficacy. Both studies are designed to allow us to assess the health economic impact and excellent treatment and its potential benefit on healthcare utilization and cost.

As mentioned, we announced earlier this month, the screening and recruitment of resumed in the res trial.

We paused after routine stability monitoring showed visible particulate so aluminum phosphate in the IV solutions.

The chair of the independent data monitoring committee for the trial reviewed the clinical safety data and reported that there were no concerning safety events identified.

The study is now utilizing new batches of the current IV formulation.

Current clinical trial supply has a shelf life of 12 months.

And we are working towards developing a commercial supply with at least two years of shelf life.

There are several ongoing strategies to achieve this goal, including modification of the buffer variety you can ask long weed.

We don't believe the changing the buffer will require bridging studies and we anticipate using this improved formulation and our global registration studies.

We plan on putting these new batches on stability in the third quarter of this year.

With the data from the stability batches included in the NDA filing for status epilepticus.

With the resumption of the raise study screening recruitment and U S site Activations.

To advance with over 50 sites now open.

We expect to have over 60 sites activated by the end of the third quarter.

Extensive discussions with advisers and studies that.

Provided insights to inform site specific approaches to enrollment.

Study sites were eager for the trial to resume and they expressed enthusiasm for continuing to identify and enroll patients to address the considerable unmet need and provide the first high quality evidenced guide the treatment of refractory status epilepticus. Additionally, a number of sites previously experiencing resource.

Strange due to COVID-19.

Come back to us expressing their interest in participating in the study.

To support recruitment and enrollment we're expanding the study to include sites in Canada, Israel and Australia.

And we continue to expect top line data in the second half of 2023.

Yes.

Our second ongoing status epilepticus trial, the phase III reset study is focused on established status symbol of the guests in earlier stage in the status continue.

While the annual incidence of refractory status Epilepticus is approximately 35000, the number of patients presenting with established status epilepticus in the U S.

Those failing initial treatment with benzodiazepines is approximately 75000 per year.

By investigators can ask alone and establish status epilepticus, we have the potential to broaden that utilization in the status.

I would note that this broadening to establish status is not expected to reduce the eligible population for treatment of RSC with can excellent.

First the reset study is evaluating <unk> ballston status epilepticus, whereas most patients with RSC had nonconvulsive status. Additionally, the reset study will be focused on emergency department treatment, whereas the raise trial will predominantly enroll patients from the ICU.

The recent study will investigate can ask alone as an adjuvant to the standard therapies for established status to determine whether it can shorten the time to onset of effect as well as improve the overall proportion of patients having complete cessation of status.

This study uses a novel sequential cohort designed to identify the optimal dose of <unk> alone in terms of both efficacy and tolerability.

The response of each patient cohort.

Form the dosing for the next and the design will provide solid evidence for an optimal dose and duration of infusion to utilize in a double blind placebo controlled study.

We're currently working through the community consent process known as exception from informed consent or ethic, a pathway for clinical research and patients requiring urgent treatment.

We're on track to begin U S enrolment in the second half of this year and expect top line data from the first dosing cohorts by year end 2023.

Patient enrollment in our phase III <unk> trial for European registration raise too.

It is expected to begin in the first half of 2023.

This trial is designed to serve as a critical piece of the European approval strategy and we believe it has the potential to further broaden the use of IV you can ask alone in the U S.

Moving to our Oregon excellent programs since Scott provided an update on our trustees C trial in tuberous sclerosis complex.

To spend some more time on our second generation formulations.

We believe the new formulation will be the future of the excellent franchise.

The goal of this initiative is to deliver an excellent formulation with an improved pharmacokinetic profile.

Including better bioavailability, and more predictable and durable drug exposure.

We've started a phase one study of the initial second generation formulation candidates and look forward to announcing top line data by the middle of this year.

Following evaluation of this phase one data, we expect to initiate a phase two study in Lennox <unk> syndrome in the second half of the year using reformulated Maxwell.

Lennox <unk> syndrome is a rare epileptic encephalopathy.

Result for many structural or genetic causes it's highly treatment refractory.

We believe our new oral formulation will provide more consistent and predictable exposure to make an actual which should allow physicians to individualized dosing to achieve an optimal response for each patient.

In parallel to initiation of the clinical program in Lennox <unk> syndrome or <unk>.

CMC team is developing a modified release formulation to potentially allow twice or even once daily dosing.

This will permit can ask alone to be utilized in a broader range of conditions with greater convenience and adherence to treatment.

Additionally, a second candidate formulations have been identified which may have a PK profile to allow for reduced dosing frequency and improved efficacy and tolerability without additional modification of its profile.

Phase one studies with this formulation candidate or plan to begin early next year.

Finally, we have identified two pro drug candidates that we anticipate advancing into IND, enabling studies in the second half of the year.

Scott Braunstein: This has been an exceptional year for the company, marked by the FDA's approval of Zitolami for the treatment of seizures associated with CDKL5 deficiency disorder. We have been diligently preparing to bring our first product to market and are on track to launch Zitolami commercially in the U.S. in July, which Steve will speak to in greater detail.

Now I'd like to turn the call over to Steve for updates on our commercial launch plans for <unk> and a review of our financial results for the first quarter of 2022.

Scott Braunstein: It has also been a busy year on other fronts, specifically advancing our pipeline.

Scott Braunstein: We were pleased to announce earlier this month that our Phase 3 double-blind placebo-controlled trial in Status Epilepticus, the RAISE trial, re-initiated screening and recruitment. Our teams have been working diligently behind the scenes to ensure that sites would be ready to begin screening immediately after we ship new clinical supplies. I could not be more proud of the efforts by the entire Marinus team and the cooperation and dedication of our clinical sites.

Scott Braunstein: Moving to our oral gonaxalone program, I'm thrilled to share that we are actively recruiting at U.S. sites for the Phase 3 TRUST-TSC trial in tuberous sclerosis complex and expect to expand globally over the summer and fall.

Scott Braunstein: Site activations continue to advance. We are now planning to expand the trial to include 65 to 75 sites compared to the 60 sites we were initially targeting in an effort to maximize recruitment and move up study timelines. We are currently planning to focus on sites in the U.S., Western Europe, Canada, and Israel and expect top-line data in the first quarter of 2024.

Thanks, Joe and good afternoon to everyone.

Scott Braunstein: Now, I would like to give a quick update on our second-generation product development, efforts before handing it over to Joe for a deeper dive on our clinical activities. The goal of our second-generation program is to achieve better bioavailability and expand, the therapeutic value of Ganaxalone.

Scott Braunstein: We have started phase one dosing of the first next-generation oral Ganaxalone formulation, and remain on track to announce top-line data by the middle of this year.

Scott Braunstein: Following the evaluation of the phase one data with the specific goal of achieving more, consistent and higher blood concentrations of Ganaxalone, we expect to utilize this novel formulation in a phase two study of Lennox-Gastaut syndrome in the second half of the year.

Before diving into our financial results for the first quarter of 2022, I would like to begin with an update on our commercial preparations for the U S launch of the Tommy.

Scott Braunstein: We are excited to follow the progress of the first new formulation of Ganaxalone in over, 15 years.

Scott Braunstein: I'll leave the details to Joe.

Scott Braunstein: Let me conclude my remarks by discussing how we plan on bringing Zytomy to patients and, families around the globe.

As Scott mentioned, we are on track for a July commercial launch of the Tommy in the U S. Following scheduling as a controlled substance by the U S drug enforcement administration, which is expected in mid June .

Scott Braunstein: We are targeting submitting responses to the EMA's Day 120 list of questions for the CDD, Marketing Authorization Application, or MAA, by mid-year.

Scott Braunstein: With a mid-year submission, we would expect a CHMP opinion by the end of the year.

The Tommy will be available through a designated specialty pharmacy and specialty distribution partner.

Scott Braunstein: We have been collaborating extensively with Orion, our European strategic partner, as, they prepare for commercial launch of Ganaxalone should it receive approval by the EMA.

Our commercial launch leadership is in place with 16 field representatives onboard and beginning to engage with customers.

Scott Braunstein: In addition, we believe that there is a broader global opportunity and are exploring additional, ex-U.S. strategic partnerships to expand Ganaxalone's commercial footprint.

Scott Braunstein: Our goal is to achieve another strategic partnership by the end of the year.

Scott Braunstein: Our organization is committed to expanding global access of the Ganaxalone franchise, and helping to improve the lives of more patients suffering from CDD, TSC, and status epilepticus.

The team comprises diverse backgrounds with deep promotional and rare epilepsy experience from over 10 organizations.

Scott Braunstein: I'll now hand the call over to Joe for more on our clinical development activities.

With an average of 23 years of sales experience, all with either epilepsy or rare disease expertise and with multiple product launches under their belt. We are confident in the team's ability to hit the ground running.

To support the launch we are pleased that results from the pivotal phase III Marigold trial for its a Tommy were recently published in the lancet neurology and will be available for use by our sales team.

And now approved the marketing campaign with fully integrated marketing materials, featuring authentic patient stories is on track for our planned to July launch.

Visit Tommy Dotcom website is also no active with designated sections to inform and educate patients and caregivers as well as health care providers on the Tommy.

Preparations continue to advance for a simultaneous launch of this etame one program a comprehensive patient services program to provide assistance to health care providers patients and caregivers with product access and ongoing product support and offers programs for eligible patients who need financial support for Theres, a Tommy prescription.

We are working closely with advocacy organizations to increase awareness and provide information about access to the Tommy.

We are committed to patients and their families and plan to continue our work with patient advocacy groups throughout our drug development and commercialization efforts our market access team has been deeply engaged with both commercial and government payers with a focus on genetically confirmed C. D D rare disease patient populations and positioning of the Tommy.

C D D. ICD 10 code, which was established in November 2020 is being implemented into practice by physicians and continues to increase month by month. We believe this consistent and high usage of the code will help ensure access alignment with Payors and validate our commercial launch planning and preparedness strategies.

We will initiate the conversion of patients on the expanded access program and open label extension to reimbursed therapy upon commercial product availability in July while supporting a smooth transition.

Most commercial and state Medicaid programs are expected to provide access and coverage over a period of six to eight months driven by both patient need and physician demand through medical necessity requests.

However, we can support patient access prior to establish coverage criteria through this are telling me one program.

Joseph Hulihan: Thank you, Scott, and hello, everyone.

As we evolve to a commercial stage company, we look forward to continuing to update you on our launch progress and the opportunity to make a difference in the lives of patients suffering with C. D D.

Joseph Hulihan: I'd like to begin by discussing our IV development programs.

Joseph Hulihan: We currently have two trials in refractory status epilepticus, or RSE, RAISE and RAISE-2. Both Phase III trials are designed to demonstrate a rapid onset of action and durable SE cessation. In the RAISE study, which is ongoing, durability will be measured by prevention of progression, to IV anesthesia, which is associated with high rates of morbidity and mortality.

Joseph Hulihan: In the RAISE-2 study for European registration, which is planned to begin in the first half, of 2023, durability of effect will be assessed by prevention of any escalation of treatment, IV anesthesia or otherwise, which can also prolong hospital stays and intensive medical, care.

The approval of the Tommy provided us with the potential for significant non dilutive funding in the near term to execute on our business strategy and invest in our future programs.

Joseph Hulihan: In addition to demonstration of efficacy, both studies are designed to allow us to assess, the health economic impact of Ganaxalone treatment and its potential benefit on healthcare utilization and cost.

Joseph Hulihan: As mentioned, we announced earlier this month that screening and recruitment have resumed, in the RAISE trial, which we paused after routine stability monitoring showed visible particulates of aluminum phosphate in the IV solution. The Chair of the Independent Data Monitoring Committee for the trial reviewed the clinical, safety data and reported that there were no concerning safety events identified. The study is now utilizing new batches of the current IV formulation.

Joseph Hulihan: The current clinical trial supply has a shelf life of 12 months, and we are working toward, developing a commercial supply with at least two years of shelf life. There are several ongoing strategies to achieve this goal, including modification of the buffer, for Ivegan-Axelone.

Joseph Hulihan: We don't believe that changing the buffer will require bridging studies, and we anticipate, using this improved formulation in our global registration studies. We plan on putting these new batches on stability in the third quarter of this year, with the, data from the stability batches included in the NDA filing for status epilepticus.

Joseph Hulihan: With the resumption of the RAISE study, screening, recruitment, and U.S. site activations continue, to advance, with over 50 sites now open. We expect to have over 60 sites activated by the end of the third quarter. Extensive discussions with advisors and study staff have provided insights to inform site-specific, approaches to enrollment. Study sites were eager for the trial to resume, and they expressed enthusiasm for continuing, to identify and enroll patients to address the considerable unmet need and provide the first high-quality evidence to guide the treatment of refractory status epilepticus. Additionally, a number of sites previously experiencing resource constraints due to COVID-19, have come back to us, expressing their interest in participating in the study.

Joseph Hulihan: To support recruitment and enrollment, we are expanding the study to include sites in, Canada, Israel, and Australia, and we continue to expect top-line data in the second half of 2023.

As previously disclosed we received an additional $30 million in funding under our existing credit agreement with Oaktree capital, which became available upon the approval of the Tommy.

Joseph Hulihan: Our second ongoing status epilepticus trial, the Phase 2 RESET study, is focused on established, status epilepticus, an earlier stage in the status continuum. While the annual incidence of refractory status epilepticus is approximately 35,000, the number, of patients presenting with established status epilepticus in the U.S., those failing initial treatment with benzodiazepines, is approximately 75,000 per year.

Joseph Hulihan: By investigating gonaxalone and established status epilepticus, we have the potential, to broaden its utilization in the status continuum. I would note that this broadening to established status is not expected to reduce the eligible, population for treatment of RSE with gonaxalone.

In addition, we were awarded a rare pediatric disease priority review voucher by the F D. A.

Remain committed to monetizing this P. R V and we have seen recent voucher sales continue to exceed $100 million.

Joseph Hulihan: First, the RESET study is evaluating convulsive status epilepticus, whereas most patients, with RSE have nonconvulsive status.

I'll now move to our financial results.

Joseph Hulihan: Additionally, the RESET study will be focused on emergency department treatment, whereas, the RAISE trial will predominantly enroll patients from the ICU.

For the first quarter of 2022, we recognized $14 2 million in revenues for the period ending March 31, 2022, as compared to 1.8 million in the same period in the prior year the.

Joseph Hulihan: The RESET study will investigate gonaxalone as an adjuvant to the standard therapies for, established status, to determine whether it can shorten the time to onset of effect, as well as improve the overall proportion of patients having complete cessation of status. The study uses a novel sequential cohort design to identify the optimal dose of Ganaxolone, in terms of both efficacy and tolerability. The response of each patient cohort will inform the dosing for the next, and the design will, provide solid evidence for an optimal dose and duration of infusion to utilize in a double-blind placebo-controlled study.

Joseph Hulihan: We're currently working through the Community Consent Process, known as Exception from Informed, Consent, or EPIC, a pathway for clinical research in patients requiring urgent treatment.

Joseph Hulihan: We're on track to begin U.S. enrollment in the second half of this year and expect top-line, data from the first dosing cohorts by year-end 2023.

Joseph Hulihan: Patient enrollment in our Phase III RSE trial for European registration, RAISE-2, is expected, to begin in the first half of 2023.

Joseph Hulihan: This trial is designed to serve as a critical piece of the European approval strategy, and, we believe it has the potential to further broaden the use of IV Ganaxolone in the U.S. Moving to our oral Ganaxolone programs, since Scott provided an update on our TRUST-PSC, trial in tuberous sclerosis complex, I'd like to spend some more time on our second-generation formulations.

The increase in revenue was driven by a onetime revenue recognition of $12 7 million related to the previously received Orion collaboration upfront payment, which is no longer subject to clawback provision as a result of successful completion of acquired M. Two metabolite testing.

Joseph Hulihan: We believe the new formulation will be the future of the Ganaxolone franchise. The goal of this initiative is to deliver a Ganaxolone formulation with an improved, pharmacokinetic profile, including better bioavailability and more predictable and durable drug exposure. We've started a Phase I study of the initial second-generation formulation candidate and, look forward to announcing top-line data by the middle of this year.

Joseph Hulihan: Following evaluation of this Phase I data, we expect to initiate a Phase II study in, Lennox-Gastaut syndrome in the second half of the year using reformulated Ganaxolone. Lennox-Gastaut syndrome is a rare epileptic encephalopathy that can result from many structural, or genetic causes. It's highly treatment refractory, and we believe a new oral formulation will provide more consistent, and predictable exposure to Ganaxolone, which should allow physicians to individualize dosing to achieve an optimal response for each patient.

Joseph Hulihan: In parallel to initiation of the clinical program in Lennox-Gastaut syndrome, our CMC, team is developing a modified release formulation to potentially allow twice or even once daily dosing. This will permit Ganaxolone to be utilized in a broader range of conditions with greater, convenience and adherence to treatment.

Joseph Hulihan: Additionally, a second candidate formulation has been identified, which may have a PK profile, to allow for reduced dosing frequency and improved efficacy and tolerability without additional modification of its profile. Phase I studies with this formulation candidate are planned to begin early next year.

Joseph Hulihan: Finally, we've identified two pro-drug candidates that we anticipate advancing into IND-enabling, studies in the second half of the year.

Excluding the Orion collaboration revenue, we recognized $1 5 million in BARDA federal contract revenue for the three months ended March 31, 2022, as compared to $1 8 million for the three months ended March 31 2021.

Research and development expenses decreased slightly to 18 million for the three months ended March 31, 2022, as compared to $18 6 million for the same period in the prior year.

The change versus the prior year was due primarily to reduced CBD development and safety study activities in 2022, partially offset by increased headcount costs and T. S E clinical development costs.

General and administrative expenses increased to $11 7 million for the three months ended March 31, 2022, compared to $10 4 million for the same period in the prior year.

The primary drivers of the change over the prior year were increased support for scale up of the Companys operations as well as preparation for commercialization.

Yeah.

During the quarter, a onetime cost of IP license fee of $1 2 million was recognized as expense associated with the recently signed agreement with avid therapeutics to license patents and patent applications for the use of <unk> in the treatment of CDK, all five deficiency disorder.

The company reported a net loss of $19 4 million for the three months ended March 31, 2022, compared to $27 1 million in the same period a year ago.

These totals include noncash stock based compensation of $3 4 million and $5 million in Q1, 2022, and 2021, respectively. The.

The first quarter of 2021 included $2 1 million of stock based compensation related to a severance agreement with our prior CFO Cal.

Cash used in operating activities increased to $27 1 million for the three months ended March 31, 2022, compared to $16 2 million for the same period a year ago.

As of March 31, 2022, we had cash and cash equivalents of $126 $3 million. We believe this balance is sufficient to fund our operations and maintain the minimum cash balance required under our debt facility into the first quarter of 2023.

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

Steve Pfanstiel: Now I'd like to turn the call over to Steve for updates on our commercial launch plans for ZTALMI and a review of our financial results for the first quarter of 2022.

Steve Pfanstiel: Thanks Joe, and good afternoon to everyone.

Thanks, Steve This is an extremely exciting time for our company and we are hard at work preparing for our first commercial launch while remain diligently focused on driving forward our clinical programs.

Steve Pfanstiel: Before diving into our financial results for the first quarter of 2022, I would like to begin with an update on our commercial preparations for the U.S. launch of ZTALMI. As Scott mentioned, we are on track for a July commercial launch of ZTALMI in the U.S. following scheduling as a controlled substance by the U.S. Drug Enforcement Administration, which is expected in mid-June.

Steve Pfanstiel: ZTALMI will be available through a designated specialty pharmacy and specialty distribution partner.

Steve Pfanstiel: Our commercial launch leadership is in place with 16 field representatives on board and beginning to engage with customers. The team comprises diverse backgrounds with deep promotional and rare epilepsy experience from over 10 organizations.

Operator can you now open the call for questions.

Steve Pfanstiel: With an average of 23 years of sales experience, all with either epilepsy or rare disease expertise, and with multiple product launches under their belts, we are confident in the team's ability to hit the ground running.

Steve Pfanstiel: To support the launch, we are pleased that results from the Pivotal Phase III marigold trial for ZTALMI were recently published in the Lancet Neurology and will be available for use by our sales team.

Steve Pfanstiel: A now-approved marketing campaign with fully integrated marketing materials featuring authentic patient stories is on track for our planned July launch.

Thank you at this time I would like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad will pause just a moment to compile the Q&A roster.

Steve Pfanstiel: The ZTALMI.com website is also now active, with designated sections to inform and educate patients and caregivers, as well as healthcare providers on ZTALMI.

Steve Pfanstiel: Preparations continue to advance for a simultaneous launch of the ZTALMI One Program, a comprehensive patient services program to provide assistance to healthcare providers, patients, and caregivers with product access and ongoing product support, and offers programs for eligible patients who need financial support for their ZTALMI prescription.

Steve Pfanstiel: We are working closely with advocacy organizations to increase awareness and provide information about access to ZTALMI.

Steve Pfanstiel: We are committed to patients and their families and plan to continue our work with patient advocacy groups throughout our drug development and commercialization efforts.

Steve Pfanstiel: Our market access team has been deeply engaged with both commercial and government payers with a focus on genetically confirmed CDD rare disease patient populations and positioning of ZTALMI. The CDD ICD-10 code, which was established in November 2020, is being implemented into practice by physicians and continues to increase month by month.

Steve Pfanstiel: We believe this consistent and high usage of the code will help ensure access alignment with payers and validate our commercial launch planning and preparedness strategies.

Steve Pfanstiel: We will initiate the conversion of patients on the expanded access program and open label extension to reimburse therapy upon commercial product availability in July while supporting a smooth transition.

Steve Pfanstiel: Most commercial and state Medicaid programs are expected to provide access and coverage over a period of six to eight months, driven by both patient need and physician demand through medical necessity requests. However, we can support patient access prior to established coverage criteria through the ZTALMI I program.

Steve Pfanstiel: As we evolve to a commercial stage company, we look forward to continuing to update you on our launch progress and the opportunity to make a difference in the lives of patients suffering with CDD.

Yeah.

Steve Pfanstiel: The approval of ZTALMI provided us with the potential for significant non-dilutive funding, in the near term to execute on our business strategy and invest in our future programs. As previously disclosed, we received an additional $30 million in funding under our existing, credit agreement with Oaktree Capital, which became available upon the approval of ZTALMI.

Steve Pfanstiel: Excluding the Orion Collaboration revenue, we recognized $1.5 million in BARDA federal, contract revenue for the three months ended March 31, 2022, as compared to $1.8 million for the three months ended March 31, 2021.

And we will take our first question from Joseph Thome with Cowen.

Steve Pfanstiel: In addition, we were awarded a Rare Pediatric Disease Priority Review Voucher by the FDA.

Steve Pfanstiel: Research and development expenses decreased slightly to $18 million for the three months, ended March 31, 2022, as compared to $18.6 million for the same period in the prior year. The change versus the prior year was due primarily to reduced CDD development and safety study, activities in 2022, partially offset by increased headcount costs and TSC clinical development costs.

Steve Pfanstiel: We remain committed to monetizing this PRV, and we have seen recent voucher sales continue, to exceed $100 million.

Steve Pfanstiel: General and administrative expenses increased to $11.7 million for the three months ended, March 31, 2022, compared to $10.4 million for the same period in the prior year. The primary drivers of the change over the prior year were increased support for scale-up, of the company's operations, as well as preparation for commercialization. During the quarter, a one-time cost of IP license fee of $1.2 million was recognized, as expense associated with the recently signed agreement with Avid Therapeutics to license patents and patent applications for the use of Ganaxolone in the treatment of CDKL5 deficiency disorder.

Steve Pfanstiel: I'll now move to our financial results. For the first quarter of 2022, we recognized $14.2 million in revenues for the period ending, March 31, 2022, as compared to $1.8 million in the same period in the prior year. The increase in revenue was driven by a one-time revenue recognition of $12.7 million related, to the previously received Orion Collaboration upfront payment, which is no longer subject to a callback provision as a result of successful completion of required M2 metabolite testing.

Steve Pfanstiel: The company reported a net loss of $19.4 million for the three months ended March 31, 2022, compared to $27.1 million in the same period a year ago. These totals include non-cash stock-based compensation of $3.4 million and $5 million, in Q1 2022 and 2021, respectively. The first quarter of 2021 included $2.1 million of stock-based compensation related to a severance, agreement with our prior CFO.

Yes.

Joe We can't hear you.

Yeah.

And it looks like still can't hear you Joe.

Looks like he may have disconnected and south let's move next.

Steve Pfanstiel: Cash use and operating activities increased to $27.1 million for the three months ended, March 31, 2022, compared to $16.2 million for the same period a year ago.

To Marc Goodman at SBB.

Steve Pfanstiel: As of March 31, 2022, we had cash and cash equivalents of $126.3 million. We believe this balance is sufficient to fund our operations and maintain the minimum cash, balance required under our debt facility into the first quarter of 2023.

Yeah.

Scott Braunstein: Now I'll turn the call back to Scott, who will provide concluding remarks.

Yes can you talk about any learnings from Genesis launch with current capillary gw's launch without the dialects.

Scott Braunstein: Thanks, Steve.

Scott Braunstein: This is an extremely exciting time for our company, and we are hard at work preparing, for our first commercial launch while remaining diligently focused on driving forward our clinical program.

And apply to.

Tommy.

And then secondly.

Talk about just raised for one second just enrollment trends I heard you mentioned that a lot of these sites that previously had issues with Covid are now back up.

And coming back to you.

Can you just give us some anecdotal information.

What's going on out there with respect to actual enrollment and how many patients per site or are happening relative to how youre thinking about it. Thanks.

Operator: Operator, can you now open the call for questions?

Joe do you want to take rate is.

And then we'll turn it over the commercial.

Operator: Thank you.

Peace and Mark I think the only comment I'll make before I turn it over to Joe is we we are still we are at.

Operator: At this time, I would like to remind everyone, in order to ask a question, press star, then, the number one on your telephone keypad.

We actively opening more sites, we're very comfortable with where we are.

And right now, we're very comfortable with our guidance.

But I think well and so we're not going to talk specifically about sites.

Sites and and per enrollment per site, but certainly our estimates include our expectation on.

On a certain patient per site number which is.

So about.

About 20% to 25% of what we saw in the phase II.

Operator: We'll pause just a moment to compile the Q&A roster.

But Joe why don't I turn it over to you.

Operator: And we'll take our first question from Joseph Tone at Cowan.

Yeah, No Mark we have had a lot of interest from sites, they're very excited to be going and getting going again.

The sites that initially had declined or coming back to us to participate.

Sites are screening.

And.

Yeah.

Active in getting up and running quickly as I mentioned, we have over 50 sites.

That are ready to go we're active now and expect to have.

Probably 60 or more by the third quarter.

And we spent the time.

The pause really getting to understand what's going on at the site level, we have some new staff, particularly someone who came from.

M G H.

Hospital pharmacy with neuro ICU experience.

She has been reaching out to sites and there has been great.

Pharmacists turn out to be probably a key contact at the site level.

Insight regained along the way.

So very optimistic about having targets for enrollment and.

Keeping this thing going.

Yeah, and let me just add mark.

I think you know.

We were really disappointed that we had a positive trial in February but at the same time.

We're now in the middle of May Covid numbers from a hospitalization point are as low as they've been in two years I see us are less burden than they've been in two years now we are still facing real personnel challenges physicians, leaving their posts.

Coordinators, leaving I think we all read that in the New York Times and the Wall Street Journal every day.

But now with what we think are our key sites.

The hospital systems not overrun.

Everyone ready to go I really feel like these since several months are the.

A very fair way to judge how what we're expecting in terms of enrollment and what what we should see going forward through the conclusion of the study. So we'll make sure to keep you very up to date on that over the coming months, but I will say I kind of I feel like this has been now the best opportune.

We have to to really achieve given where hospitalizations are today and where are we are in terms of the numbers. So I'm excited about the next few months. It's been it's been a slow start it's been a terrible pandemic and much worse than we would have ever thought from an ICU perspective.

So we really think this is our best chance to move this study along actively.

Chris do you want to you want to jump on the commercial question.

Sure Hi, there Martin good afternoon.

We've done a lot of work to really try and best understand what our key launch priorities should be and we certainly used.

The comparator onshore friends gigantic container.

Some key learnings, but and you know not unlike traditional rare disease launches really early engagement with both the kols community as long as that as well, but they advocacy groups and of course, the payers has been very very insightful to help guide a lot of the assumptions that we have.

And to inform any near decisions that we had in addition to that really understanding what the patients and their caregivers and the advocacy organizations.

We're going to be looking for from a patient support model.

We have learned and really felt that an exclusive specialty agreement in this patient population to ensure seamless access we're gonna be pivotal to our success and then obviously for US we're going to really need to ensure and we have to really get the Meredith name out there similarly with GW.

And they go down next launches.

Big Pharma names, we had to create some trucks in the community with a new name on the market and again that early and outreach and and early engagement has it really helps support that.

We'll go next to Joseph <unk> at Cowen.

Joseph Tone: Joe, we can't hear you.

Hi, there good afternoon.

Erin.

We can Joe good to have you back alright, sorry about that good afternoon, congrats on the progress and thanks for taking my question.

Operator: We still can't hear you, Joe.

Maybe just as we're thinking about the follow on candidates we have.

The modified release and then.

The two.

Pro drugs and then the two kind of secondary candidates here.

Should we think about advancing or did they also intriguing data would you move them all forward for different indications would you try them prioritizing one or the other kind of how do we think about it.

And then I'll have a follow up question.

Operator: Looks like he may have disconnected himself.

Operator: Let's move next to Marc Goodman at SVB.

Marc Goodman: Yes.

Yeah, why don't I start and then I'll turn it over to Joe Joe.

Marc Goodman: Can you talk about any learnings from Zogenics' launch with Pentapolar, GW's launch with Epidialyx, that you can apply, you know, to Tommy?

So what we want to see in a proof of concept study is there a correlation with clinical efficacy.

And blood levels.

And we believe that's a very strong correlation from marigold.

And we would expect to see that in whatever formulation, we tests, but hopefully that will be our first formulation that's moved into the clinic.

That's our goal.

And then I think what where we decide to ultimately go in and in the epilepsy space is really going to be dependent on which of the three platforms.

I would say certainly we have a.

Good tolerability issues, which will be I would presume some form of a blunted C. Max good.

Good good a good half life, which will get us to twice a day or better dosing.

And certainly we want this to be a pediatric friendly formulation, so whether its suspension whether it's.

A sprinkle.

Or a solution, we want it to be friendly for the pediatric community.

Certainly we're building a strong IP platform around all of those if we are fortunate to.

See those things with more than one candidate.

That would really give us the luxury about.

As an example, using one of our new <unk> formulations in in in epilepsy in pediatric epilepsy, and then potentially using a pro drug as an example, which right. Now are early data also has a blunted a blunted C Max and what looks to be a very prolonged half life.

And in other disease state so that would be the perfect outcome here I think that we'd have more than one candidate with the with the potential of more than one indication I think will be very closely monitoring what we see in the depression space as an example, today, but certainly are key.

Focus is an epilepsy, Joe any Joe Houlihan any other thoughts that I didn't hit that you'd like to add.

No just maybe a little bit more about the PK, we're looking for and.

There are a lot of branch point in the.

The decisions for the clinical programs when we see the profiles.

These re formulations and I think the one as Scott mentioned, but one that gives us the best.

Exposure in terms of area under the curve and the lease kind of variability you.

He can trough.

On the peak side, presumably lowering the suezmax will improve tolerability.

And increasing the trough will give us more even efficacy.

And that's really what we're looking for I think that'll be the choice to move into either phase <unk> or phase III.

With one of those the.

More.

Favorable looking PK.

Perfect and then maybe one just to follow on a little bit on the commercial side, maybe I don't know if Chris you would be the best one for this but I know in the prepared remarks, there was some mention of pair.

Marc Goodman: And then secondly, talk about, just raise for one second, just enrollment trends.

Adoption in populations coming online, but maybe if you could just go into a little bit more detail on how that's going to play out with the launch.

Progress toward any sort of codes that that would help.

<unk> access and maybe kind of a key inflection points that we should be looking for in the first kind of six to 12 months. Thank.

Marc Goodman: I heard you mention that a lot of these sites that previously had issues with COVID are, now back up and coming back to you.

Thank you very much.

Marc Goodman: Can you just give us some anecdotal information, you know, just what's going on out there with, respect to actual enrollment and how many, you know, patients per site are happening relative to how you're thinking about it?

Marc Goodman: Thanks.

Absolutely.

Joseph Hulihan: Joe, do you want to take raise?

Afternoon, gentlemen, and thanks for the question and as I spoke earlier, we we've been engaging quite significantly already.

With the payer community not only just the large conferences that has nice recently kind of app like P CMA AMC and <unk>.

Recently Assembly I believe just last week, but.

And we're really also deeply engaged directly with the largest pbms and commercial payers and of course, the state Medicaid plans and those engagements are focused on ensuring coverage criteria and making sure that that criteria is consistent with our label and therefore, we expect pretty rapid adoption of autonomy.

As the first and only treatment for Caesars dotted shaded with D. D D.

The ICD 10 code was established in November of 2020, So we've gotten some most recent data collection that our operations team is pulling together and even prior to our approval. The ICD 10 code is being utilized and quarter over quarter, we're finding that that you know.

<unk> is growing which is extraordinarily encouraging to us.

There will of course being another inflection point once the sales team is live in the ICD 10 code is being educated on specifically from a promotional standpoint, so that ICD 10 code is going to be key and that diagnosis code along west.

Yet the failure of two potential ASN.

It's going to be the two hurdles that quite frankly for us don't seem like big hurdles right now to get them to access for patients.

And does that answer your question yes.

Okay Christy.

Christine maybe maybe a little timing on what you expect for Medicaid reimbursement across the board since you're the biggest player.

Absolutely. So just as a quick reminder, we believe that about 60% of the patients.

Going to be utilizing access through our state Medicaid plan and so with that it's going to be really important for us.

Not only internally, but with external partners.

Between you know at the at our July launch till the end of the year. We think we'll have access to between 40 and 50% of those payers and then the majority done about 90% in Q1 of 2023, we are targeting 22 major states and those states will be the most populous state.

And as well as those states that overlap with our centers of excellence. So by next year, we'll have pretty much full coverage from a Medicaid standpoint.

Yeah.

Yeah.

Excellent. Thank you so much.

Scott Braunstein: And then we'll turn over the commercial piece.

Okay.

Scott Braunstein: And Marc, I think the only comment I'll make before I turn it over to Joe is, you know, we are still, we're actively opening our sites.

Scott Braunstein: We're very comfortable with where we are.

We will take our next question from Andrew <unk> at Jefferies.

Scott Braunstein: And right now we are very comfortable with our guidance.

Scott Braunstein: But I think we'll, and so we're not going to talk specifically about sites and per enrollment, per site, but certainly our estimates include our expectation on a certain patient per site number, which is still about 20, 25% of what we saw in the Phase 2.

Okay. Thank you good afternoon, thanks for taking my questions.

Joseph Hulihan: But Joe, why don't I turn it over to you?

My question is actually on a T. I S. T. S C. Our RSC your phase III programs I noticed in the CBD publication, there were two interims built in.

Joseph Hulihan: Yeah.

Joseph Hulihan: No, Marc, we have had a lot of interest from sites.

Joseph Hulihan: They're very excited to be going, getting going again.

Joseph Hulihan: Some of the sites that initially had declined are coming back to us to participate.

When at 50% or 75% of enrollment. So are there similar interim analysis built in four T. S C and RSC and if not would you consider doing an interim for either program. Thanks.

Joseph Hulihan: Sites are screening and, you know, they're very active in getting up and running quickly.

Joseph Hulihan: As I mentioned, we have over 50 sites that are ready to go or active now and expect to, have probably 60 or more by the third quarter.

No. Thanks for the question.

We do have an interim built into the RSV study.

And that would be at approximately two thirds of the way through.

We looked at all.

Statistical modeling for that.

At what point, we would.

You know I expect to be able to stop the trial for efficacy. If we showed a signal and also show statistical significance on some of the secondary endpoints health economic end points and so on and.

So.

That's.

That's what we're doing for RFC now if it's enrolling very quickly you know the enrollment curve typically.

You know start more slowly pick up speed and there is the potential we wouldn't be able to get an interim done.

Two thirds of the way through before the trial is fully enrolled and it's a short study.

Inpatient study totally a few days.

And so.

Joseph Hulihan: And, you know, we spent the time during the pause really getting to understand what's, going on at the site level.

Joseph Hulihan: We have some new staff and particularly someone who came from the MGH Hospital Pharmacy with, no ICU experience, and she's been reaching out to sites and has been great.

We did leave open the option to cancel the interim analysis, if things are going to quickly.

Joseph Hulihan: You know, pharmacists turn out to be probably a key contact at the site level, which is, an insight we gained along the way.

Joseph Hulihan: So, very optimistic about, you know, hitting the targets for enrollment and keeping this, thing going.

In terms of PSC.

I think you know, we're not really considering an interim for PSC.

But.

No I think thats, something we could reconsider I think you know.

You pay a bit of a price on statistical power with these interim analyses.

And we actually ended up not doing the interim for C. D. D. The second interim analysis because of what I mentioned by the time. It would have been done the trial would be finished so we ended up actually canceled and the second one.

Scott Braunstein: Yeah, and let me just add, Marc, I think, you know, we were really disappointed that, we had a positive trial in February.

Scott Braunstein: But at the same time, you know, we're now in the middle of May. COVID numbers from a hospitalization point are as low as they've been in two years. ICUs are less burdened than they've been in two years.

Right, Thanks and.

Right.

And the second question is you know given the volatility in the market. Today, you know I can argue the cost of capital has gone up. So I guess the next question is maybe you talk about your confidence and your ability to get your P. R. I V E vouchers sold and possibly even striking a synthetic royalty deal.

Scott Braunstein: Now, we are still facing real personnel, challenges.

I'm just curious what the landscape is out there for you guys. Thank you.

Scott Braunstein: Physicians leaving their posts, nurse coordinators leaving.

Yeah, Hi, Andrew this is Steve.

We're actively engaged in a process to monetize the peer V. We're working with a financial advisor on the process we've.

We've seen we've seen these numbers stay above $100 million with the last couple of being solid at $110 million. So we're pretty confident that we'll be able to execute an agreement here in the near term on that.

In terms of a royalty monetization that is available to us under the Oaktree agreement.

That allows us to monetize up to 5% revenue stream from our our business in the U S. That's something where we're actively looking at as well I think thats, how we structured that deal to be able to have that additional flexibility.

Scott Braunstein: I think, you know, we all read that in the New York Times and the Wall Street Journal every day.

Scott Braunstein: But now with what we think are our key sites, the hospital system's not overrun, everyone's ready to go.

Scott Braunstein: I really feel like these next several months are a very fair way to judge how what we're expecting in terms of enrollment and what we should see going forward through the conclusion of the study.

I think there's there is a good opportunity to get something done on that in fairly short order as well.

And and I should add.

If we're able to execute both of those you know I would anticipate that gives us a po.

A minimum of another year's worth of cash run way if not more.

Okay. So right. These two potential revenue cash inflows can boost.

Your cash towards 2024 time frame basically.

Yeah absolutely.

Scott Braunstein: So we'll make sure to keep you very up to date on that over the coming months.

Okay very good thank you.

We'll go next to directly sell at H C Wainwright Wainwright.

Hi, good afternoon, thanks for taking my questions.

Just.

Just to confirm on the first new formulation, the one that would be advance into for lgs.

It sounds like that focus is going to be on the bioavailability and that would still be three times dosing and that it's in the second round of next generation formulations that we would potentially look at the reduction in dosing frequency.

That's the first the first formulation.

Actually won't be intended to have the.

The the smoother.

Smoother PK curve.

It's really going to move into a proof of concept for some initial safety and PK information.

And it would be the modified release that wood.

Of that formulation.

Or the or the second formulation that would move into full clinical development.

And when we think about.

The next generation formulation.

Do you have any thoughts in how because obviously it was in some ways be preferable to the original <unk> formulation and I would think patients.

Or C D patients would be interested in it how do you approach that or if you've given that much thought from a regulatory standpoint, and I've got one more quick question.

Scott Braunstein: But I will say I kind of I feel like this has been now the best opportunity we have to really achieve given where hospitalizations are today and where we are in terms of the numbers.

Scott Braunstein: So I'm excited about the next few months.

Well, let me, let me kick it off and then I'll turn it over to Joe and maybe Christine, but first and foremost Doug.

Scott Braunstein: It's been a slow start.

Scott Braunstein: It's been a terrible pandemic and much worse than we would have ever thought from an ICU perspective.

Scott Braunstein: And so we really think this is this is our best chance to move this study along actively.

I'm really happy with the IP estate that we've been building around the the call me franchise and I think that will give us a lot of flexibility down the road and my hope with our lead indication in lgs. It will we'll see a meaningful improvement.

Men and efficacy, so where we are very comfortable with our 30% Delta in TDD, we'd look for 35 or 40% Delta is the goal, we're really striving for in lgs.

When you look at the subset of patients in the <unk> study, who had blood levels close to 150 to 175 nanograms.

Those efficacy results were well north of 40% in terms of seizure reduction. So I think first and foremost we have to see a delta and in efficacy that we would hope to see.

To Joe's earlier comments, we have to smooth the PK. So that tolerability is not an issue I think thats, an easy one for us to manage and I think if we hit those parameters.

It's going to be a really interesting interesting discussion for us about what's the right approach.

<unk> I mean, my general thought is our PSC studies in a highly refractory population, we continue to hear the unmet need in earlier lines of therapy in PSC and I, certainly think that's a real possibility there.

<unk> CTD, we're always going to be looking at a highly refractory refractory population by the nature of the Beast.

But I think that we're already thinking about strategies.

In in smaller ways that we can continue to build on the strength of the franchise. So I'll stop there I think we've got some time, we've got some economic decisions, Joe or Kristy anything that you guys want to add on top of that.

Christy: Christy, you want to you want to jump on the commercial question?

Christina Okay got that.

Just real quickly I mean, I think Scott said, where we've been taking quite a bit about that looking at the options for patients who want to convert.

But.

As Scott also mentioned, we have a bit of luxury of time to do that.

And you can get some more data in there.

There are a number of options for you to evaluate kind of the regulatory feasibility of some of those too.

To do that in the most efficient way.

So it's still on the table, but we have time to look at that.

Yes.

And then just one.

Go ahead Scott.

Just one quick question Christy noted that the ICD 10 code is being used more I'm just curious.

Why that might be and what does that necessarily.

What's your take on that to the market.

Okay.

You know it's a great question, one that we don't have an answer tailing well will most likely be able to read back once we.

Once we're out in the field more deeply and gaining some insight, but I'm you know parent hypothesis is that this is that if a refractory patient population and there are certain pockets of the country that a lot of these patients are centralized and and these kols are driving this kid I liked.

To think that the fact that the Tommy was approved and on the horizon that there was a lot of disease awareness and education are already going on from the Kols to the Caribbean and so I do think that we've created a bit of noise out in the community already and just with the development program and now with the approval. So we're hopeful that our sales team will just even.

Now grow that from there.

Okay got.

Can I add yeah, I feel really fortunate that we have great Alliance partners here.

The Lulu Foundation, who really drove the ICD 10, becoming a standard code. The first few months. It was quite slow it really started to pick up not surprisingly, but now they've done a lot of the heavy lifting so we have a lot to be thankful for in that regard.

Really as the ICR really collects.

Families and an understanding of patients out there so different than other disease launches, we have a lot of terrific partners that are helping us prepare.

And I think the ICD 10 code is just one of those tools. So we have a lot to be thankful for particularly from the Lulu Foundation in that regard.

I think Doug I don't know if that's your background I don't think Thats mine, but.

Oh.

Christy: Sure.

Alright, just opening my desk drawer.

Well, that's okay, because they're shipped.

She thought I was doing terrible things on the line. So I'm glad that you first up to it.

Thanks Pat.

Pat.

[laughter].

Yeah.

And next we'll move to Brian <unk> with Baird.

Christy: Hi there, Mark.

Hey, good afternoon, everyone. Thanks for taking my question. My question is probably for Joe on the reset study just looking at the study design with a five patient cohorts getting dosed and evaluated before selecting the dose for the next five patients just wondering if you'd help us understand how you sort of think about optimizing here I'm looking at safety and efficacy for the bolus then.

They're in the infusion and then durability I guess based on your experience so far with either you can ask alone.

Sort of an order of prioritization for those three like you can figure out Oh less on sort of a stable IV that youre comfortable with and then once you maximize that they need to optimize tid side of things and and are you committed to doing all all 40 patients or might you got three.

Horton and feel like it's fully optimized and then move into the double blind phase.

Christy: Good afternoon.

Yeah, that's a great question, Brian Thanks.

Christy: You know, we've done a lot of work to really try, and best understand what our key launch priorities should be. And we certainly used the comparator launches from Zogenix and GW to have some key learning.

Christy: But, you know, not unlike traditional rare disease launches, really early engagement with both the KOL community, as long as as well as with the advocacy groups, and of course, the payers has been very, very insightful to help guide a lot of the assumptions that we had and to inform any mere decisions that we had.

Operator: We'll go next to Joseph Tome at Cowen.

Yes, so we will be evaluating this is actually called a bayesian optimal interval design and.

Christy: In addition to that, really understanding what the patient, their caregivers and the advocacy organizations were going to be looking for from a patient support model.

Christy: We learned and really felt that an exclusive specialty agreement in this patient population to ensure seamless access, we're going to be pivotal to our success.

Christy: And then obviously, for us, we're going to really need to ensure and we have to really get the Marinus name out there.

Christy: Similarly, with GW and the Zogenix launches, you know, not big pharma names, we had to, create some trust in the community with a new name on the market.

Christy: And again, that early outreach and early engagement has really helped support that.

Joseph Tome: Hi there.

I got the idea was looking at a trial of hypothermia treatment or into infants with hypoxia and they needed to look at efficacy and safety at the same time and.

Make decisions based on that.

Joseph Tome: Good afternoon.

So we have an algorithm.

It looks concurrently at the bolus.

The infusion dose and the infusion durations. So for example, if a patient gets the bolus and then they start on the infusion and the seizures recurred during the infusion we go up on the infusion dose for the next cohort.

If they get the bolus and it's overly sedating at that dose.

We go in and the status stops we go down on the.

On the bolus dose.

And then look at seizure recurrence, whether their seizure recurrence at each stage and look at Tolerability. Each stage and then we can come up again from a predetermined algorithm.

What the dose and the duration of infusion would be for the next cohort.

And to answer the second part of your question no well if we if we have a good handle on the dose will stop for 40 patients.

Got it thanks that's helpful.

Operator: Can you hear me?

Yeah.

Well move next to Jim Lee at true Securities.

Operator: We can, Joe.

Operator: Good to have you back.

Hi, Thanks for taking our question.

Operator: All right.

In the prior comments to a question you said you may consider doing an interim for tuberous sclerosis study, what would determine that and for the ongoing trust TSV.

Do you and the Kols in the U S hurdle for commercial success in terms of percent seizure reduction or a responder rate. Thank you.

Joseph Tome: Sorry about that.

Joseph Tome: Good afternoon.

So for the PSC study one of the things we're going to do.

Is oh in terms of medical monitoring stay in close touch with the physicians about tolerability.

Joseph Tome: Congrats on the progress and thanks for taking, my questions.

Joseph Tome: Maybe just as we're thinking about the follow-on candidates, we have the modified release and then the two pro-drugs and then the two kind of secondary candidates here.

Joseph Tome: How should we think about advancing those?

I don't have a predetermined sense of of an interim.

Joseph Tome: If they all show intriguing data, would you move them all forward for different indications?

It's a blinded study so we won't have an idea about.

Efficacy the one thing well knows.

Joseph Tome: Would you try and prioritize one over the other?

Tolerability and we're going to need to manage that closely and look at the data and see if there's any relationship potentially between tolerability and efficacy that may make us want to do an interim.

Joseph Tome: Kind of how do we think about that?

Scott Braunstein: And then I'll have a follow-up question.

Scott Braunstein: Yeah, why don't I start and then I'll turn it over to JoJo.

And so there are.

You know, we don't have set criteria about an interim but we'll be looking at an ongoing basis, mainly at tolerability.

Sorry could you repeat the second part of the question I didn't catch it.

Yes, so for what they.

You are dead.

Kols view as a hurdle for commercial success.

<unk> in tuberous sclerosis, how do you think.

Scott Braunstein: So what we want to see in a proof of concept study is there is a correlation with clinical, efficacy and blood levels.

What are you thinking to show in the trial in terms of efficacy or safety or Tolerability that was set up for success commercially.

Scott Braunstein: And we believe that's a very strong correlation from Marigold.

Well I could start and then I can turn it over to Christy, but I mean, as Scott mentioned the effect size, we want to see goods.

Scott Braunstein: And we would expect to see that in whatever formulation we test, but hopefully that will, be our first formulation that's moved into the clinic.

Good separation between.

Excellent and placebo and the.

And the CVV study.

The main side effect was somnolence Budd.

But patients didn't drop out.

Scott Braunstein: That's our goal.

There were very few dropouts in the study and I hope we see the same in the.

Scott Braunstein: Then I think where we decide to ultimately go in the epilepsy space is really going to, be dependent on which of the three platforms.

Scott Braunstein: I would say certainly we have good tolerability issues, which will be, I would presume some, form of a blunted C-max, a good half-life, which will get us to twice a day or better dosing.

Scott Braunstein: And certainly we want this to be a pediatric-friendly formulation. So whether it's suspension, whether it's a sprinkle or a solution, we want it to be friendly, for the pediatric community.

Scott Braunstein: And certainly we're building a strong IP platform around all of those.

Scott Braunstein: So that would be the perfect outcome here.

Scott Braunstein: If we are fortunate to see those things with more than one candidate, then I think that, would really give us the luxury about, as an example, using one of our new Ganaxone formulations in epilepsy, in pediatric epilepsy, and then potentially using a ProDrug as an example, which right now our early data also has a blunted C-max and what looks to be a very prolonged half-life in other disease states.

TLC stuff I don't know Christy if you have any comments about COVID-19 and Joe just just to remind you and the powering and the 160 patient study powered for the 90% power I believe it's 20% Delta, 20% to 25% up I think 20.

'twenty 'twenty present Delta if I recall, it was 20% start on 20% of the fleet.

Yeah.

Scott Braunstein: I think that we'd have more than one candidate with the potential of more than one indication.

So maybe if you wanted to talk a little bit commercially what youre, hoping to see.

Sure so.

When speaking to physicians first we know that there are still a very large population and the TSA community that is refractory to current on Madison. So we do know that there is there is a large need on our 30% reduction in C. D. D has been.

Really received nicely and Scott's point earlier about LG as the goal will be.

Even more once we get to a new formulation, but if we find 30%, 35% and an ultra refractory patient population and TSA I think that that will be received very nicely.

Great.

Yeah, Julian the only thing I would add one or two things just to be crystal clear given our enrollment curves and really site activations with so many global sites coming on in the fall summer fall.

Scott Braunstein: I think we'll be very closely monitoring what we see in the depression space as an example, today.

Scott Braunstein: But certainly our key focus is in epilepsy.

Scott Braunstein: Joe Houlihan, any other thoughts that I didn't hit that you'd like to add?

Joseph Hulihan: No, just maybe a little bit more about the PK we're looking for.

Joseph Hulihan: I think there are a lot of branch points in the decisions for the clinical programs when, we see the profiles of these reformulations.

I think it will be in the middle of a very robust enrollment kind of third fourth quarter and so.

Joseph Hulihan: And I think the one, as Scott mentioned, the one that gives us the best exposure in terms, of area under the curve and the least variability to peak and trough on the peak side, presumably lowering the C-max will improve tolerability and increasing the trough will give us more even efficacy.

Joseph Hulihan: And that's really what we're looking for.

Joseph Hulihan: I think that'll be the choice to move into either phase 2B or phase 3 with one of those, you know, the more favorable looking peak A.

I'm struggling to see the real possibility of us doing an interim kind of when are all 70, plus sites are up and running it's a possibility, but I think it's much lesser so.

Whereas with RSC, that's an easier decision given the incidence population and the monthly enrollment numbers being more similar than different right wearing a TLC study, where you're really dealing with a prevalence population as we get our sites up the number should increase pretty nicely. So that that's the least way.

Thinking about enrollment so I do think that.

You really.

It's unlikely that we would do an interim unless there was a specific reason or a signal that we were looking for.

And I think the last piece on the commercial side as I think you know better than anyone the F&I <unk>.

25% Delta is kind of the bar and TSMC, but I think we'll continue to show really strong durability data in the CBD population. That's clearly very important we've actually had very nice durability in the open label phase two PSC to those patients responding.

Still staying on drug we've seen that in our open label open label extension of <unk> 19, as well. So we've got multiple data points on the durability of <unk> alone and I think we have no reason to believe that's going to differ tremendously in TSV and I think that's also going to factor into the equation.

So just in terms of just one or two other thoughts yes.

Is there any mechanistic rationale why.

Targeting Gaba would have more durable effect than at the time.

Alex or other mechanisms.

Okay.

Yeah, well I.

I think if anything.

We wonder whether it's the extra extra synaptic activity.

Activity at the extra synaptic Gaba a receptor that differentiates that from the benzodiazepines.

Yeah. So yeah in the open label C D D.

It looks like we're seeing good maintenance of effect, so, especially in that we're very happy to see that.

Great Okay.

Yeah.

Joseph Hulihan: Perfect.

Thanks Sharon.

Well go next to Jay Olson of Oppenheimer.

Oh, Hey, congrats on the progress and thanks for taking the questions.

As you prepare for those are telling me launch can you talk about your plans for physician education and.

Specifically any speaker programs are.

Any events that you might sponsor at medical meetings.

And also what.

The key messages that you want to.

Delivered to these physicians.

<unk> specifically.

Since you have a very broad label.

And I guess most of the patients in the Marigold study.

Multiple lines of therapies.

It is the opportunity to to.

Move to told me up into earlier lines of treatment.

Joseph Tome: And then maybe one, just to follow on a little bit on the commercial side, maybe, I don't, know if Christy would be the best one for this, but I know in the prepared remarks, there was the mention of pair kind of adoption and populations coming online.

This is Christie J. Thanks for the question Theres a lot in there so you'll remind me if I Miss anything, but first just talking about the traditional outreach to physicians.

Joseph Tome: But maybe if you could just go into a little bit more detail on how that's going to play, out with the launch, progress toward any sort of, you know, codes that would help ease access and maybe kind of the key inflection points that we should be looking for in the first kind of 6 to 12 months.

Christy: Thank you very much.

Yes, we will have a full bag speaker.

Program and and speakers Bureau, if you will I do foresee that that is going to look a little bit different than the traditional nature, you know with H E. B D centers of excellence and scale out pension know each other quite well and we will be targeting key physicians and national epilepsy centers that are more.

Or out in the community. So there may not be that traditional you know.

20 physicians at a dinner program versus where we will be focusing quite significantly or there is one on one interactions when they're appropriate and in addition to that and moving into Q4 of this year into the beginning of 2023 and will be doing something similar with caregivers and patients.

Joseph Tome: Absolutely.

Christy: Good afternoon, Joe, and thanks for the question.

Okay.

Patients and Theres a lot of word of mouth.

Christy: As I spoke earlier, we've, been engaging quite significantly already with the payer community at not only just the large conferences that have most recently come up, like PCMA, AMCP, and most recently Assembly, I believe, just last week.

Specifically in the city count five community and we want to ensure that I had the opportunity to speak to folks on.

One on one basis for it tomorrow.

Really talking about.

What we're doing from a communication standpoint, so right now we're really really focused on awareness right. So the awareness that the economy has been approved.

Christy: But we're really also deeply engaged directly with the, largest PBMs and commercial payers, and of course, the state Medicaid plans. Those engagements are focused on ensuring coverage criteria and making sure that that criteria is consistent with our label.

Christy: And therefore, we expect pretty rapid adoption of the TAMI as the first and only treatment for seizures associated with CDD.

Christy: You know, the ICD-10 code was established in November of 2020.

Christy: So, we've gotten some most recent data collection that our operations team is pulling together.

Christy: And even, you know, prior to our approval, the ICD-10 code is being utilized.

Christy: And quarter over quarter, we're finding that that utilization is growing, which is extraordinarily encouraging to us.

A little bit.

Christy: There will, of course, be another inflection point once the sales team is live and the ICD-10 code is being educated on specifically from a promotional standpoint.

Christy: So, that ICD-10 code is going to be key.

Disease Education. However, these folks again and the larger centers are typically.

Christy: Does that answer your question?

Christy: That diagnosis code, along with, you know, the failure of two potential ASMs, is going to be the two hurdles that, quite frankly for us, don't seem like big hurdles right now to get to access for patients.

Christy: Yep.

Joseph Tome: Christy, maybe a little timing on what you expect from Medicaid reimbursement across, the board since it's going to be the biggest payer.

Christy: Absolutely.

Christy: So, just as a quick reminder, we believe that about 60% of the patients, are going to be utilizing access through a state Medicaid plan.

Christy: So, with that, it's going to be really important for us, not only internally, but with external partners.

Typically you have been keeping us rather than us teaching them about CDK outside.

Christy: Between, you know, at our July launch until the end of the year, we think we'll have access to between 40% and 50% of those payers, and then the majority of them about 90% in Q1 of 2023.

Operator: We'll take our next question from Andrew Tai at Jefferies.

Christy: We are targeting 22 major states, and those states will be the most populous states, as well as those, states that overlap with our Centers of Excellence.

Christy: So, by next year, we'll have pretty much full coverage from our Medicaid standpoint.

Joseph Tome: Excellent.

Christy: Thank you so much.

Andrew Tai: Okay.

Christy: Thanks.

But really what we're dealing with this molecule is we wanted to make sure that we're establishing an excellent and are central to comprehensive CBD management.

Andrew Tai: Thank you.

Andrew Tai: Good afternoon.

Andrew Tai: Thanks for taking my questions.

Andrew Tai: My question is actually, on TSC or RSC, your phase 3 programs.

Andrew Tai: I noticed in the CDD publication, there were two interims built in at 50% or 75% of enrollment.

Andrew Tai: So, are there similar interim analyses built in for TSC and RSC?

Joseph Hulihan: And if not, would you consider doing an interim for either program?

Joseph Hulihan: Thanks for the question.

Joseph Hulihan: We do have an interim built into the RSE study and that would be, at approximately two-thirds of the way through.

Joseph Hulihan: We looked at statistical modeling for at what point we would expect to be able to stop the trial for efficacy if we showed a signal and also show statistical significance on some of the secondary endpoints, health economic endpoints, and so on.

These kids tend to have lots of different.

Okay.

Billing on with their disease.

One of them.

And the one that tends to be the most <unk>.

<unk>, so bringing the attention back.

Joseph Hulihan: And so that's what we're doing for RSE.

Joseph Hulihan: Now, if it's enrolling very quickly, the enrollment curves typically start more slowly and pick up speed.

Joseph Hulihan: And there's the potential we wouldn't be able to get an interim done two-thirds of the way through before the trial is fully enrolled.

Just maybe back to the senior management is really core to what we're doing here.

And then obviously that the rapid access to be able to get to that Tom is the next portion of that education that we need to do.

Joseph Hulihan: And it's a short study.

Joseph Hulihan: It's an inpatient study. It's only a few days.

Yeah.

Okay great.

Joseph Hulihan: And so, you know, we did leave open the option to cancel the interim analysis if things are going too quickly.

Yeah, No I'll just quickly add you know we have the medical science liaison team out there.

Joseph Hulihan: In terms of TSC, I think, you know, we're not really considering an interim for TSC.

Joseph Hulihan: But, you know, I think that's something we could reconsider.

Not only gathering a lot of information about <unk>.

Current state of treatment, but also.

Joseph Hulihan: I think we, you know, you pay a bit of a price on statistical power with these interim analyses.

They are able to manage some of the more complex scientific discussions.

Joseph Hulihan: And we actually ended up not doing the interim for CDD, the second interim analysis, because of what I mentioned, by the time it would have been done, the trial would be finished. So we ended up actually canceling the second one.

Lot of talk about.

Joseph Hulihan: Right.

This is the first drug approved in this class of compounds.

Andrew Tai: Thanks.

And theyre talking about that management of side effects and so on.

And the other thing I'll mention is.

Andrew Tai: And right.

Andrew Tai: And the second question is, you know, given the volatility in the market today, you know, I can argue the cost of capital has gone up.

Andrew Tai: So I guess the next question is maybe talk about your confidence in your ability to get your PRV voucher sold and possibly even striking a synthetic royalty deal.

Then.

Very successful with the publication plan, our head of scientific Affairs, Alex and that he has done a tremendous job we had eight.

Andrew Tai: Just curious what the landscape is out there for you guys.

Presentations at the American Epilepsy Society, and preparing close to that number for this year, we were glad to see the paper.

Andrew Tai: Thank you.

Steve Pfanstiel: Yeah.

For the <unk> study published in Lancet neurology and <unk> got a very nice editorial.

Steve Pfanstiel: Hi, Andrew.

Steve Pfanstiel: This is Steve.

We were also pleased to see so publications are going to be another big piece of things.

Steve Pfanstiel: Yeah, we're actively engaged in a process to monetize the PRV.

Steve Pfanstiel: We're working with a financial advisor on the process.

Steve Pfanstiel: We've seen these numbers stay above 100 million with the last couple being sold at 110 million.

Andrew Tai: Okay.

Steve Pfanstiel: So we're pretty confident that we'll be able to execute an agreement here in the near term on that.

Steve Pfanstiel: In terms of royalty monetization, you know, that is available to us under the Oak Tree Agreement.

Steve Pfanstiel: That allows us to monetize up to 5% revenue stream from our business in the U.S. That's something we're actively looking at as well.

Super helpful. Thank you for that and maybe if I could just add.

Steve Pfanstiel: I think that's how we structure that deal to be able to have that additional flexibility.

Steve Pfanstiel: And I think, you know, there's there is a good opportunity to get something done on that in fairly short order as well.

Steve Pfanstiel: And I should add, you know, if we're able to execute both those, you know, I would anticipate that gives us potentially a minimum of another year's worth of cash runway, if not more.

I ask one follow on.

Andrew Tai: So, right.

Patients move into the open label extension phase at Marigold are there any observations you could share with us in terms of.

Andrew Tai: These two potential revenue cash inflows can boost, your cash towards 2024 timeframe, basically. Yeah, absolutely.

Andrew Tai: Okay, very good, thank you.

Operator: We'll go next to Douglas Tsao at H.C. Wainwright.

Long term benefits or our safety observations.

Douglas Tsao: Hi, good afternoon.

Yeah.

So I mentioned briefly I don't have the numbers off the top of my head but.

Douglas Tsao: Thanks for taking the questions.

The retention for the open label has been good it's been in line I think with what you tend to see a similar.

Douglas Tsao: Just to confirm, on the first new formulation, the one that would be advanced into for LGS, it sounds like that focus is going to be on the bioavailability, and that would still be three times dosing.

<unk>.

And the efficacy.

That we're seeing is good we've had.

Some patients become seizure free.

During the open label and real durability and improvement of effect.

In terms of the patients who remain on the drug.

So.

We're very interested in seeing what happens in the open label I mentioned the durability of effect.

Joseph Hulihan: And that it's in the second round of next generation formulations that we would potentially look at the reduction in dosing frequency?

It's a particular issue in CVD and.

Joseph Hulihan: That's right.

And there are some experimental evidence.

<unk> suggested.

This extra snapback activation has a particular benefit in terms of chronic durability. So I. Appreciate the question about the open label so far very pleased with the results.

Joseph Hulihan: The first formulation actually won't be intended to have the smoother PK curve.

Joseph Hulihan: It's really going to move into a proof of concept for some initial safety and PK information.

Joseph Hulihan: And it would be the modified release of that formulation or the second formulation that would move into full clinical development.

Joseph Hulihan: And when we think about the next generation formulation, do you have any thoughts in how, because obviously it would in some ways be preferable to the original Zotomy formulation, and I would think patients or CD patients would be interested in it.

Joseph Hulihan: How do you approach that, or have you given that much thought from a regulatory standpoint?

It sounds like it sounds like excellent outcomes. Thank you for sharing that with us and thanks. Thanks for taking the question sure.

Joseph Hulihan: And I've got one more quick question.

Joseph Hulihan: Well, let me kick it off, and then I'll turn it over to Joe and maybe Christy.

Scott Braunstein: But first and foremost, Doug, I'm really happy with the IP estate that we've been building around the Zotomy franchise, and I think that will give us a lot of flexibility down the road.

Scott Braunstein: My hope with our lead indication in LGS is that we'll see a meaningful improvement in efficacy.

Scott Braunstein: So where we are very comfortable with our 30 percent delta in CDD, we'd look for a 35 or 40 percent delta as the goal we're really striving for in LGS.

Scott Braunstein: When you look at the subset of patients in the CDD study who had blood levels close to 150 to 175 nanograms, those efficacy results were well north of 40 percent in terms of seizure reduction.

Sure thing.

Scott Braunstein: So I think first and foremost, we have to see a delta in efficacy that we would hope to see.

Scott Braunstein: To Joe's earlier comment, we have to smooth the PK so that tolerability is not an issue.

Scott Braunstein: I think that's an easy one for us to manage.

And next we'll move to Charles Duncan of Cantor Fitzgerald.

Scott Braunstein: And I think if we hit those parameters, it's going to be a really interesting discussion for us about what's the right approach in TSC and CDD.

Scott Braunstein: I mean, my general thought is our TSC studies in a highly refractive population, we continue to hear the unmet need in earlier lines of therapy in TSC, and I certainly think that's a real possibility there.

Scott Braunstein: So I'll stop there.

Scott Braunstein: I think in CDD, we're always going to be looking at a highly refractory population by the nature of the beast.

Scott Braunstein: But I think that we're already thinking about strategies in smaller ways that we can continue to build on the strength of the franchise.

Yeah.

Charles you still there.

It sounds like it sounds like we lost Charles well. Thank you everyone really appreciate you joining the call today.

Scott Braunstein: I think we've got some time.

Scott Braunstein: We've got some economic decisions.

And.

We will continue to put our heads down work very hard on our clinical trials I think kristi's got her team ready for an exciting launch so we plan on having some exciting updates over the coming months and I. Appreciate you, making the time today. Thanks everybody.

Joseph Hulihan: Joe or Christy, anything that you guys want to add on top of that?

Joseph Hulihan: I think Christy's okay with that.

Joseph Hulihan: Just real quickly, I mean, I think Scott said we've been thinking quite a bit about that, looking at the options for patients who want to convert.

Joseph Hulihan: But Scott also mentioned we have a bit of luxury of time to do that and can get some more data in.

Joseph Hulihan: There are a number of options for you to evaluate the regulatory feasibility of some of those to do that in the most efficient way.

Joseph Hulihan: So it's still on the table, but we have time to look at that.

Brian Skorney: Hey, good afternoon, everyone.

Douglas Tsao: Just one quick question, Kristi noted that the ICD-10 code is being used more, I'm just, curious why that might be, and what is that necessarily, what's your take on that for the market?

Brian Skorney: Thanks for taking the question.

Christy: You know, it's a great question, one that we don't have an answer to, and we'll most, likely be able to read back once we're out in the field more deeply and gaining some insights.

Brian Skorney: My question is probably for Joe.

Christy: But, you know, current hypothesis is that this is a super refractory patient population.

Joseph Hulihan: On the RESET study, just looking at the study design of the five patient cohorts getting, dosed and evaluated before selecting the dose for the next five patients, just wondering if you'd help us understand how you sort of think about optimizing here, looking at safety and efficacy for the bolus, then during the infusion, and then durability.

Christy: There are certain pockets of the country that a lot of these patients are centralized in, and these KOLs are driving this code.

Joseph Hulihan: I guess, based on your experience so far with IV Ganaxalone, is there sort of an order of, prioritization for those three, like you figure out bolus on sort of a stable IV that you're comfortable with, and then once you maximize that, then you look to optimize the ID side of things, and are you committed to doing all 40 patients, or might you get three cohorts in and feel like it's fully optimized, and then move into the double-blind phase?

Christy: I'd like to think that the fact that the TAMI was approved and on the horizon, that there, was a lot of disease awareness and education already going on from the KOLs to the caregivers. So I do think that we've created a bit of noise out in the community already, just with, the development program and now with the approval.

Joseph Hulihan: Thanks.

Jun Li: Thanks for taking our question.

Christy: So we're hopeful that our sales team will just even, you know, grow that from there.

Operator: And that does conclude today's conference.

Joseph Hulihan: Yeah, that's a great question, Brian.

Jun Li: In the prior comment to a question, you said you may consider doing an interim for tuberous, sclerosis study.

Scott Braunstein: And Doug, I'm just going to add, yeah, I feel really fortunate that we have great alliance, partners here.

Operator: Thank you for your participation.

Joseph Hulihan: Thanks.

Jun Li: What would determine that?

Scott Braunstein: And, you know, the Lulu Foundation really drove the ICD-10 becoming a standard code.

Joseph Hulihan: Yeah, so we'll be evaluating, this is actually called a Bayesian optimal interval design, I got the idea looking at a trial of hypothermia for treatment of infants with hypoxia and they needed to look at efficacy and safety at the same time and make decisions based on that.

Jun Li: And for the ongoing trust TSE, you know, what do you and the KOLs view as a hurdle for commercial, success in terms of percent seizure reduction or responder rate?

Scott Braunstein: The first few months it was quite slow, it really started to pick up, not surprisingly. But now they've done a lot of the heavy lifting, so we have a lot to be thankful for in that, regard.

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

Joseph Hulihan: And so we have an algorithm.

Joseph Hulihan: Thank you.

Scott Braunstein: Similarly, as ISCR really collects, you know, families and an understanding of patients, out there.

Joseph Hulihan: It looks concurrently at the bolus, the infusion dose and the infusion duration. So for example, if the patient gets the bolus and then they start on the infusion and the, seizures recur during the infusion, we go up on the infusion dose for the next cohort.

Joseph Hulihan: So, for the TSE study, one of the things we're going to do is, you know, in terms of medical, monitoring, stay in close touch with the physicians about tolerability.

Scott Braunstein: Different than other disease launches, we have a lot of terrific partners that are helping, us prepare, and I think the ICD-10 code is just one of those tools, you know, so we have a lot to be thankful for, particularly from the Lulu Foundation in that regard.

Joseph Hulihan: If they get the bolus and it's overly sedating at that dose and the status stops, we go down, on the bolus dose.

Joseph Hulihan: I don't have a predetermined sense of an interim.

Operator: You may, now disconnect.

Scott Braunstein: I think, Doug, I don't know if that's your background, I don't think that's mine, but, – Oh, it was mine, sorry.

Joseph Hulihan: And then look at seizure recurrence, whether there's seizure recurrence at each stage, and look at tolerability at each stage, and then we can come up, again, from a predetermined algorithm, what the dose and the duration of infusion would be for the next cohort.

Joseph Hulihan: It's a blinded study, so we won't have an idea about efficacy.

Douglas Tsao: I was just opening my desk drawer. I needed a new pen.

Joseph Hulihan: And oh, to answer the second part of your question, no, if we have a good handle on, the dose, we'll stop for 40 patients.

Joseph Hulihan: The one thing we'll know is tolerability, and we're going to need to manage that closely, and look at the data and see if there's any relationship potentially between tolerability and efficacy that may make us want to do an interim. And so there are, you know, we don't have set criteria about an interim, but we'll be, looking in an ongoing basis, again, mainly at tolerability.

Douglas Tsao: Well, that's okay, because Shaki was eating me up.

Joseph Hulihan: Got it.

Joseph Hulihan: And I'm sorry, could you repeat the second part of the question?

[music].

Scott Braunstein: She thought I was doing terrible things on the line, so I'm glad that you've tested, up to it.

Brian Skorney: Thanks.

Joseph Hulihan: I didn't catch it.

Douglas Tsao: No, I'll admit, I just needed a new pen.

Joseph Hulihan: That's helpful.

Joseph Hulihan: Yeah, so for what's the, you know, what do you and are the KOLs view as a hurdle for, commercial success of Gonaxalone and tuberous sclerosis?

Operator: And next, we'll move to Brian Skorney with Baird.

Operator: We'll move next to Jun Li at Truist Securities.

Joseph Hulihan: How do you think, what do you think you need to show in the trial in terms of efficacy, or safety or tolerability that would set it up for success commercially?

Jun Li: Hi.

Joseph Hulihan: Yeah, yeah.

Joseph Hulihan: Well, I could start, and then I could turn it over to Christy, but I mean, as Scott mentioned, the effect size.

Joseph Hulihan: We want to see a good separation between Gonaxalone and placebo and, you know, in the CBD study, the main side effect was somnolence, but patients didn't drop out.

Joseph Hulihan: There were very few dropouts in the study, and I'd hope we see the same in the TSC.

Joseph Hulihan: I don't know, Kristi, if you have any comments about compensation.

Joseph Hulihan: And Joe, just to remind you, in the powering the 160 patient study powered for the 90 percent, power, I believe it's a 20 percent delta, 20, 25 percent delta, I think, 20, 20 percent delta if I recall. It's 20 percent. It's powered on 20 percent, I believe.

Joseph Hulihan: Yep.

Joseph Hulihan: But Kristi, maybe if you want to talk a little bit commercially, what you're hoping to see.

Christy: Sure.

Christy: So, you know, when speaking to physicians, first, we know that there's still a very large, population in the TSD community that is refractory to current medicine.

Christy: So we do know that there's a large need.

Christy: Our 30 percent reduction in CDD has been, you know, really received nicely.

Christy: And Scott's point earlier about LGS, the goal will be, you know, even more once we get to, a new formulation.

Christy: But if we find 30, 35 percent in an ultra-refractory patient population in TSD, I think that that, will be received very nicely.

Christy: Yeah.

Scott Braunstein: And, June, the only thing, I'd add one or two things just to be crystal clear.

Scott Braunstein: Given our enrollment curves and really site activations, with so many global sites coming, on in the fall, summer, fall, I think we'll be in the middle of very robust enrollment kind of third, fourth quarter.

Scott Braunstein: And so I'm struggling to see the real possibility of us doing an interim kind of when our all, you know, 70-plus sites are up and running.

Scott Braunstein: That's a possibility, but I think it's much lesser so.

Scott Braunstein: Whereas with RSC, that's an easier decision, given the incidence population and the monthly, enrollment numbers being more similar than different, right, where in a TSD study where you're really dealing with a prevalence population, as we get our sites up, the numbers should increase pretty nicely.

Scott Braunstein: So that's at least the way I'm thinking about enrollment.

Scott Braunstein: But I do think that you really, it's unlikely that we would do an interim unless there was, a specific reason or a signal that we were looking for.

Scott Braunstein: And I think, you know, the last piece on the commercial side is, I think you know better, than anyone, the epidiolex 25 percent delta is kind of the bar in TSC.

Scott Braunstein: But I think, you know, we'll continue to show really strong durability data in the CDD population, and that's clearly very important.

Scott Braunstein: We've actually had very nice durability in the open-label phase two of TSC, so those, patients responding are still staying on drug.

Scott Braunstein: We've seen that in our open-label extension of PCVH19 as well.

Scott Braunstein: So we've got multiple data points on the durability of Gonaxalone, and I think we have no reason, to believe that's going to differ tremendously in TSC, and I think that's also going to factor into the equation.

Scott Braunstein: So just one or two other thoughts.

Scott Braunstein: Yeah.

Joseph Hulihan: Is there any mechanistic rationale why targeting GABA would have more durable effects than, epidiolex or other mechanisms?

Joseph Hulihan: Yeah.

Joseph Hulihan: Well, I think, if anything, we wonder whether it's the extra synaptic activity.

Joseph Hulihan: Activity, Activity at the Extrasynaptic GABA-A Receptor that differentiates that from the, benzodiazepines.

Joseph Hulihan: Yeah, and so, yeah, in the open-label CDD, it looks like we're seeing good maintenance, of effect.

Joseph Hulihan: So especially in that, we're very happy to see that.

Joseph Hulihan: Great.

Jun Li: Thank you.

Jun Li: Thanks, Jim.

Yeah.

Operator: We'll go next to Jay Olson at Hoffenheimer.

Yeah.

Jay Olson: Oh, hey, congrats on the progress, and thanks for taking the questions.

[music].

Jay Olson: As you prepare for the Zotomy launch, can you talk about your plans for physician education, and specifically any speaker programs or CME events that you might sponsor at medical meetings?

Jay Olson: And also, what are the key messages that you want to deliver to these physicians?

Jay Olson: And specifically, since you have a very broad label, and I guess most of the patients in, the Marigold study failed multiple lines of therapies, what is the opportunity to move Zotomy up into earlier lines of treatment?

Christy: So this is Christy.

Christy: Jay, thanks for the question.

Christy: There's a lot in there, so you'll remind me if I miss anything.

Christy: But first, just talking about the traditional outreach to physicians, yes, we will have, a full-blown speaker program and speakers bureau, if you will.

Christy: I do foresee that that's going to look a little bit different than the traditional nature.

Christy: You know, with eight CBD centers of excellence, these KOLs tend to know each other quite well.

Christy: We will be targeting key physicians and national epilepsy centers that are more out in the, community.

Christy: So there may not be that traditional, you know, 20 physicians at a dinner program versus, where we will be focusing quite significantly or those one-on-one interactions when they're appropriate.

Christy: In addition to that, moving into Q4 of this year into the beginning of 2023, we'll be, doing something similar with caregivers and patients as well as organizations.

Christy: There's a lot of word of mouth, specifically in the CDKL5 community, and we want to ensure, that folks have the opportunity to speak to folks on, you know, on a one-on-one basis where it's more appropriate.

Christy: Really talking about, you know, what we're doing from a communication standpoint.

Christy: So right now, we're really, really focused on awareness, right?

Christy: So the awareness that the TALMI has been approved, a little bit of disease education.

Christy: However, these folks, again, in the larger centers typically have been teaching us rather, than us teaching them about CDKL5.

Christy: But really what we're doing with this molecule is we want to make sure that we're establishing, Gonaxalone at central to comprehensive CBD management, one of them.

Christy: And, you know, the one that tends to be the most debilitating.

Christy: So bringing the attention back to the seizure management is really core to what we're doing here.

Christy: And then obviously, the rapid access to be able to get to the TAMI is the next portion of that education that we need to do.

Jay Olson: Okay, great.

Joseph Hulihan: No, I'll just quickly add, you know, we have the medical science liaison team out there.

Joseph Hulihan: They're, not only gathering a lot of information about, you know, current state of treatment, but also they're able to manage some of the more complex scientific discussions.

Joseph Hulihan: A lot of talk about, you know, this is the first drug approved in this class of compounds.

Joseph Hulihan: And they're talking about that management of side effects and so on.

Joseph Hulihan: And the other thing I'll, mention is that we've been very successful with the publication plan.

Joseph Hulihan: Our head of scientific affairs, Alex Aimetti has done a tremendous job.

Joseph Hulihan: We had eight presentations at the American Epilepsy Society and preparing close to that number for this year.

Joseph Hulihan: We were glad to see the, paper for the CDD study published in Lancet Neurology, and it got a very nice editorial with it, which we were also pleased to see.

Joseph Hulihan: So publications are going to be another big piece of things.

Jay Olson: Super helpful.

Joseph Hulihan: Thank you for that.

Joseph Hulihan: Maybe if I could just ask one follow on.

Jay Olson: As patients move into the open label extension phase of Marigold, are there any observations you could share with us in terms of long-term benefits or safety observations?

Joseph Hulihan: Yeah.

Joseph Hulihan: So I mentioned briefly, I don't have the numbers off the top of my head, but, the retention for the open label has been good.

Joseph Hulihan: It's been in line, I think, with what you tend to see in similar populations. And the efficacy that we're seeing is good.

Joseph Hulihan: We've had some patients become seizure-free during the open label and real durability and improvement of effect in terms of the patients who remain on the drug.

Joseph Hulihan: So we're very interested in seeing what happens in the open label.

Joseph Hulihan: I mentioned durability of effect. It's a particular issue in CDD, and there's some experimental evidence that suggests that this extrasynaptic activation has particular benefit in terms of chronic durability.

Joseph Hulihan: So, yeah, I appreciate the question about the open label.

Joseph Hulihan: So far, we're very pleased with the results.

Jay Olson: Great.

Joseph Hulihan: Sounds like excellent outcomes.

Jay Olson: Thank you for sharing that with us, and thanks for taking the question.

Jay Olson: Sure thing.

Operator: And next, we'll move to Charles Duncan at Cancer Fitzgerald.

Charles Duncan: Charles, are you still there?

Operator: Sounds like we lost Charles.

Scott Braunstein: Well, thank you, everyone.

Scott Braunstein: Really appreciate you joining the call today.

Scott Braunstein: And we will continue to put our heads down, work very hard on our clinical trials.

Scott Braunstein: I think Christy's got her team ready for an exciting launch.

Scott Braunstein: So we plan on having some exciting updates over the coming months, and appreciate you making the time today.

Scott Braunstein: Thanks, everybody.