Arcturus Therapeutics Holdings Inc. Price & Performance (ARCT)

Please see the forward looking statement disclaimer on the press release issued earlier today as well as the Risk Factors section our most recent Form 10 ks and in subsequent filings with the SEC. In addition, any forward looking statements represent our views only as of the date such statements are made. Arcturus specifically disclaims any obligation to update such statements. And with that, I will now turn the call over to Joe.

Thank you, Neda.

It's good to be with you again everybody. We look forward to providing our updates today on our quarterly investor call.

I will begin my remarks with an update on progress with our vaccine franchise led by Kosave.

We're very pleased to receive European Commission approval for Co Stave, the world's first approved self amplifying mRNA COVID-nineteen vaccine. The centralized marketing authorization of CoSave provided by the European Commission is valid in all 27 European Union member states three additional European Economic Area countries. The approval is based on positive clinical data from several studies, including an integrated Phase onetwo three study demonstrating CoSave's efficacy against COVID-nineteen safety and tolerability, a Phase three COVID-nineteen booster trial, which achieved higher immunogenicity results compared to conventional mRNA COVID-nineteen vaccine comparator.

The European regulatory approval results and milestones from CSL Securis, our global vaccine partner These milestones will be disclosed in coordination with CSL.

Our team continues to work diligently with CSL to prepare co stage registration for The United States and The United Kingdom. But the Coast AVE U. S. BLA filing is anticipated for later this year 2025. On the manufacturing front, Meiji Sikea Pharma our Japanese vaccine partner, submitted a manufacturing and marketing provided in a vial containing two doses. To the Pharmaceuticals and Medical Devices Agency or PMDA in Japan.

Meiji Sekafarma aims to receive approval for the two dose vial in time for the autumn season of 2025. The new two dose bio presentation will enhance convenience and daily practice and improve ease of vaccination in an individualized setting such as medical clinics. In January, Meiji along with our manufacturing joint venture Arkallis, received approval from the Ministry of Health, Labor and Welfare or MHLW to add domestic commercial manufacturing sites in Japan for CoSave. And formulated at Meiji Seika PharmaTek, are now able to be shipped for commercial use in Japan. We continue to progress our STAR self amplifying mRNA platform pipeline in other infectious disease targets In January, the company announced the initiation of a Phase one study of ARCT [indiscernible] This is a self amplifying mRNA vaccine candidate for active immunization to prevent pandemic influenza disease caused by the H5N1 virus also known as the BRIDFlu. The randomized placebo controlled Phase one trial is ongoing at multiple sites in The U. S. And designed to enroll approximately 200 healthy participants. Screening of study participants began in November 2024, with the first participant enrolled in December 2024. The clinical study is fully funded by the the Biomedical Advanced Research and Development Authority, also known as BARDA.

Interim data will be available later this year. In the second half of twenty twenty five.

Moving now to our exciting pipeline of therapeutics, will begin with an update on ARCT-thirty two. This is our messenger RNA therapeutic candidate for cystic cystic fibrosis. In December 2024, the company dosed the first participant in an open label Phase two multiple ascending dose study in adults with CF who are not eligible for CFTR modulator therapy or are not taking CFTR modulators due to drug intolerance poor response or lack of access to modulators. Each adult participant in the Phase II CF study is expected to receive daily inhaled treatments of ARCT-thirty two over a period of twenty eight days. Our Phase two trial involves a relatively low number of study visits. Only eight study visits and only twelve weeks of follow-up. Easing the burden of participation for patients across all sites. Safety and tolerability data will be important given that ARCT-thirty two is likely to be a daily or every other day inhaled treatment.

With respect to efficacy, and based on historical precedence in the CFTR modulator space, an FEV lung function improvement of 3% in our Phase two trial would likely justify advancing ARCT-thirty two further into development. Deteriorating lung function is a significant challenge in CF subjects that do not benefit from modulators. Reversing this deterioration would address a very significant unmet medical need in this subset of the CF community.

The company expects to provide interim data from CF participants who completed dosing in the ARCTO-thirty two Phase two study the end of Q2 twenty twenty five.

The interim data will likely include multiple subjects at multiple dose levels. Moving on to our 10 program. This is our messenger RNA therapeutic candidate for ornithine transcarbamylase see. In December 2024, the company initiated dosing of the first OTC division participant zero point in a Phase two multiple ascending dose study. Each adult and adolescent participant in the open label Phase two study is expected to receive five intravenous infusions of ARCTA10 over a period of two months. The company previously announced the completion of the dosing phase in a placebo controlled European study enrolling eight 10 U. S. Phase two study the end of Q2 twenty twenty five. Finally, we are excited to have announced the appointment of Doctor. Monceth Sloughie as Chair Designate in February. Doctor. Sloughi has been serving on the company's Board of Directors since June 2024 and he has a strong proven track record in the biotech and pharmaceutical industry. With that, I will now pass the call to Andy. Thank you, Joe. And good afternoon, everyone. The press release issued earlier today includes financial for the fourth quarter and fiscal year ending December 31, 2024, and provides a summary and analysis of year over year financial results.

Please also reference our Form 10 ks which will be filed today for more details on the financial performance. Before we begin the financial review, I wanted to give you some highlights from our Coaste vaccine program and our Japanese JV partner, Arkalis, We are thrilled about the European Commission of approval of Coasteve and I'm happy to announce that we have achieved several milestones related to this [indiscernible] More details regarding Myel will be provided on the first quarter earnings call. GSL reported to us, Taurus, that our share of growth profit from the sale of CoSave during the quarter ended 12/31/2024 was approximately $28,000,000 This amount will be credited against our ura's share of the COVID-nineteen development costs paid by CSL When CSL recouped 40% of the total development cost of Co Stage-nineteen program, Arcturus will begin to receive shared net profit payments from CSL for all future sales of Co Ocalysts remains an important strategic manufacturing asset for Arcturus with respect to our vaccine and cystic fibrosis program. We are very pleased with the recent $20,000,000 investment by Maji Saikawa as well as their involvement on the Akalis Board of Directors. Arcalis and Meiji Sica Pharma are committed to advance the development, production and supply of mRNA vaccines in line with the strategy for strengthening vaccine development and production system adopted by the Japanese government.

This is highlighted by the recent manufacturing and marketing approval Road Coast to include domestic manufacturing sites in Japan Meiji and Arkalis are in the process of obtaining approval for a two dose Lyle CoV-eight vaccine targeting the latest COVID strain. I will now provide a quick summary of our financial results For the year ended December 31, 2024, we reported revenues of $152,300,000 dollars a decrease of $14,500,000 from $166,800,000 reported for the year ended 2023, The decrease was due to lower milestone achievements from the CSL agreement. Offset by increased BARDA revenue due to progress of the pandemic flu program. For the three months ended December 31, 2024, we reported revenues of $22,800,000 dollars a decrease of $8,100,000 from the $30,900,000 reported in the same period in 2023 The decline was attributable to lower miles achievements from the CSL agreement. During the fourth quarter of twenty twenty four. Total operating expenses for the year ended 12/31/2024 were $248,000,000 compared to $245,000,000 for the year ended 12/31/2023, Total operating expenses for the three months ended 12/31/2024 were $56,200,000 compared to $49,100,000 for the three months ended 12/31/2023. Research and development $200,000 for the year ended 12/31/2024, compared to 102 hundred and $92,100,000 for the year ended 12/31/2023 Additionally, research and development expense were $43,800,000 for the three months ended 12/31/2024 compared to $36,600,000 for the three months ended 12/31/2023, [indiscernible] The increase in R and D expenses for both quarter and the full year was primarily driven by higher clinical trial costs with our OTC and CF programs as well as the COVID-nineteen and lunar flu program DFL However, the increase was partially offset by a reduction in manufacturing mix related to clinical trials and drug supply agreements as part of the COVID-nineteen program.

General and administrative expenses were $52,800,000 for the year ended 12/31/2024, compared with $52,900,000 dollars for the year ended 12/31/2023. Additionally, G and A expenses were $12,400,000 for the three months ended thirty one, twenty twenty four, compared to $12,500,000 for the three months ended 12/31/2023. These expenses remained relatively consistent We expect general and administrative during the next twelve months driven by lower shared base compensation costs and a reduction in general and administrative and the COVID program to CSL. For the year ended 12/31/2024, Altois reported a net loss of approximately $80,900,000 dollars or $3 per diluted share compared to a net loss of $29,700,000 or $1.12 per diluted share for the year ended 12/31/2023, Additionally, to the three months ended 12/31/2024, [indiscernible] or $1.11 per diluted share Cash equivalents and restricted cash was $293,900,000.0 as of 12/31/2024, and $348,900,000 on 12/31/2023. Curis achieved a total of approximately $4.00 $73,100,000 in upfront payments and milestones from CSL as of twelvethirty onetwenty four. And expects to continue to receive future mile CSL supporting the ongoing development of the vaccine program. For fiscal year 'twenty four and 'twenty three, we burned about $55,000,000 and $45,000,000 with which was within our internal expectation.

We anticipate that our burn will increase in the next two year driven by our CF and OTC programs as they progressed through their respective Phase two multi pole ascending dose trial Furthermore, as our COVID program transitioned to a commercial phase, our development milestones with CSL will decline over the next year. However, I am happy to report that based on the current pipeline and programs, the cash runway remains strong and is expected to extend until the end of the first quarter of twenty twenty seven. In summary, we believe the company remains in a strong financial position and has the resources to achieve multiple near term value creating milestones [indiscernible] We look forward to an exciting year in 2025 and we anticipate potential interim Phase two data readout for our OT and CF programs along with the continued development of the vaccine program I will now pass the call back to Joe. Thanks, Andy. 2024 was a historical year for Arcturus. As we transitioned to a commercial company with the launch of Coasteve. As we begin 2025, we look forward to another transformative year with key clinical data for our therapeutics and vaccines programs coming forward. So with that, let's turn the time over to the operator for And we'll take our first question from Lily Nesongo with Leerink.

Your line is open. Hi. Good afternoon and thank you for taking my question and for the update. FX. I had maybe one question on the vaccine pipeline and I guess another one on the rare disease pipeline. So for the vaccine collaboration, how should we think about the cadence of development milestone within the CSL collaboration? And are there any updates in terms of the expectation for the flu vaccine program and the potential combo program with COVID flu?

I can address the and hi, Lily. Thanks for calling in. But I'll address the flu question and then Andy can address the cadence of milestones. But CSL generally is providing the guidance for the flu program. We completed our Phase one for the quadrivalent version of the vaccine. And we remind people that CSL has a global license for the flu program This is an area that's very important to them. So they will be providing specific updates on what's next in that area of the flu pertaining to any sort of trivalent or COVID flu combos, etcetera? So we'll be deferring to them. With respect to the milestone cadence, Andy, do you want to address that?

Sure, Lily. Thanks for the question. Yes, we will continue to receive mild earned milestones related to European regulatory filings. And we'll provide more detail with respect to that in the first quarter call Hopefully, that will answer your question.

Thank you. And maybe just a quick question moving on to the revenue pipeline, especially as it relates to the CS program. How should we think about potential differentiation from competitors in development? Especially within the mRNA [indiscernible] Sure. Yes. We're definitely different from the gene therapy and gene editing approaches. But within the mRNA space, we're different. We're different with respect to the mRNA molecule itself. Of course, our lunar lipid nanoparticle delivery technology and even our manufacturing and purification different would say the mRNA sequence is likely to be different with increased stability and translation Our lunar lipid nanoparticle technology is proprietary and clearly different Our IP and know how in manufacturing and purification may also be meaning showcased in our preclinical animal studies and our data set there. And also in our early human clinical studies. So I think there's fundamental chemical and modification differences to both the mRNA and the lipids in the LUNAR technology. But also take into consideration the know how and IP associated with manufacturing and purification of the messenger RNA.

Thank you.

Thank you, Lily.

Move next to Yasmeen Rahimi with Piper Sandler. Your line is open. Good morning, team. Good afternoon, team. Thank you so much for the great updates. Would love to spend some time. I think a lot of investors are very much looking forward to the CF interim data that's expected. Here in 2Q. Could you maybe talk about sort of I know that you have dosed 12 CF patients sort of at that interim look like what is the size of the cohort? Will we get one or two doses? And what do you want to show at this interim look to really establish [indiscernible] strong POC in this market. Sorry, that's very lengthy on questions around it, but I appreciate if you could just Sure. Sure. So I think in clinicaltrials.gov, we've communicated that size of the Phase two trial is approximately 12 people. We do have flexibility to increase that number. In terms of guidance, we've mentioned that we intend to have an interim update that will involve multiple patients and multiple dose levels, but not a specific number has been guided. At the end of the second quarter this year. In terms of a bar for success or something like that, we highlighted on today's call and I'll reiterate here that an 3% in our Phase two trial would likely justify advancing ARCTO-thirty two further into development and this is simply based on historical press precedence in the CFTR modulator space.

And I believe that's the color you were looking for Yaz. Is there a follow-up question?

Yes, maybe you may need to check the mute button. Oh, sure.

Oh, sorry. I was going to ask, thank you. I was going to ask do you plan to present this data when it becomes available? Or do you hope to get that in I don't know if you have any visibility in terms of Yes. We haven't guided how to share data. That's a disclosure. Okay.

Whether it's a press release or a specific call or a conference or a publication, we haven't provided any of that guidance. Just that by the end of the second quarter, we'll be providing interim data.

Okay. Great. I'll jump back in the queue. Thank you.

Thank you.

We'll take our next question from Seamus Fernandez with Guggenheim. Securities.

Your line is open. Hi, guys. This is Evan Wang on for Shamus Fernandez. From me. First on cystic fibrosis, First, could you just comment on how enrollment has been progressing so far?

And just given the focus on those if complete dosing [indiscernible] I guess, the entity split of Class one and CFTR intolerable patients? And then also, I guess, how quickly or what in the next steps there would be to advance your pivotal studies And then on post, Dave, glad to see the European approval there.

And the first royalties attributed to from Japan. Just can you expect at what point you'd expect visibility into all your orders for 2025? Thanks.

Okay. So first of all, with respect to enrollment and an update there with CF We remain on track to provide interim data at the end of the second quarter. We have multiple sites already open and active and we're engaging several more and those are highlighted in different CF tracking sites provided by the CF Foundation. So you can follow updates there and also on clinicaltrials.gov. But it's very active and we remain on track there. With respect to the coast day visibility on Japanese sales, is that maybe you want to clarify that for Andy? But can you clarify the question?

Yes. For Kostave, just with the kind of order dynamics that may be typical in Japan or Europe, any kind of comments on, I guess, when that ordering pattern happens and [indiscernible] you or CSL would get more visibility into, I guess, quantity of orders from the next flu season.

And then on cystic fibrosis, I also wanted to ask on, I guess, split of Class one I versus GFR intolerable patients expected Okay. Andy, proceed with the first question. I'll take the next one.

Sure, Evan. As you probably noted recently, [indiscernible] Arkalis and CSL have petitioned Japanese PMDA to get a two dose LIO approved here in order to be ready for the next COVID strain and consequently as the go through that process, Hopefully, it will happen in the first half of this year. With respect to their order, we really can't comment on that. It will be Meiji that will provide that guidance and hopefully they'll share that as soon as possible. But So we're excited for the new format and and hopefully we'll enable them to have a more successful launch with with a two dose LIO format going forward.

And with respect to the Class one and non Class one, really it's one group There's several, several genetic versions of this disease. The Class one is well understood because those are considered null patients and they do not have any CFTR in their lungs. But with respect to the other subclass, these are folks with multiple mutations or just very dysfunctional not respond or benefit from modulators, you can imagine that they present in a similar manner. And their lungs deteriorate in a similar manner to Class one subjects. So they're bundled together in this to represent one group where there's very significant [indiscernible] within the CF community, that do not respond to modulators, if you take that 18 number and cut it in half, that would be 9%. That would represent the Class one null.

Patient population. So you would anticipate approximately half of our of the folks in our Phase two trial to be from Class one. But I want to reemphasize that they're all in the same boat. They're all in the same level of unmet medical need and they all want the same thing, which is a functional CFTR expressed in their lungs. Thank you, Evan.

We'll take our next question from Myles Mentor with William Blair.

Your line is open.

Hey, congrats on the progress and the EU approval for Costa over 12.

It's good to see that.

Two for me on CF. The first one is just a clarification that 3% improvement bar to take this therapy forward, if you do see that. Is that on an absolute FEV1 basis or is that on a percent predicted FEV1 basis? So the first one. The second one is this is an open label study. I believe you're adding cell have any potential impact on FEV1 readouts alone? And just wondering whether you're factoring that into the interpretation of your data? Thanks very much. Yes. Yes. It's Well, the first question, yes, this is the precedent that's well established in the in the modulator space is it was an absolute number. So that's an absolute improvement of 3%. We do remind investors that deterioration rates in the non Delta five zero eight community are more rapid and more significant. So the Delta would be actually more trying to emphasize. But yes, that's the precedent 3% there and it would be an absolute number With respect to your question about albuterol. The pretreatment with albuterol will have no I guess, effect on the analysis of the FEV response. The subjects when these subjects come in to have their lung function measured, It's timed before they receive the albuterol for the next treatment, right?

So albuterol is very short acting and only lasts few hours, so it won't have any impact or effect on any measurements on the following day.

Great. Thanks for the questions.

Yes. Thanks, Myles. Good to hear from you.

We'll take our next question from Whitney Ilim with Canaccord Genuity. Your line is open.

This is Julian Kim on for Whitney EGM. Thanks for taking our question.

Maybe two quick ones from us. First, can you give any clarity on the magnitude of cost that 40% of cost, but any specific specifics on development costs help flush out that math.

And secondly, now that Cost Safe has received approval in the EU, What are the next steps towards commercialization? Specifically, will things go country by country or will there be advanced orders or anything you can tell us about what to expect next?

Thanks so much.

Andy, go ahead.

No, thanks for the question. We are excited about the European approval and so it's DFL and the good news is they're in charge of the commercialization process in Europe and with all of their experience in the flu program, we're kind of in a good position here to rely on them to lead that that whole progress. And frankly, I think it would be immature for us to comment on that since it's their program. But we're excited and certainly looking forward to it. With respect to the the amount that we reported that they shared with us, the $28,000,000 was our share of the revenue, the gross profit that we recorded they recorded in the fourth quarter And so that's good news that we're calling away at the 40% of our total development expenses for the program. We haven't given specific guidance as to what the total is. But it is good progress for us and certainly would hope that we'd be able to achieve revenue sometime in the next few years. The good news is that it doesn't impact our guidance. And our cash runway does not incorporate any revenue from CoSave and you per our guidance is until the end of the first quarter of twenty twenty seven.

Thanks, Jeevan.

We'll move next to Pete Stravopoulos with Cantor Fitzgerald. Your line is open. [indiscernible] Congratulations on the progress and including the EU approval.

I have a question for CYR32 study. Can you just provide a little detail around the safety monitoring and what are the key parameters for triggering, let's say, a pause in the study? When it comes to lung or pulmonary based adverse events? Is there a low threshold, say grade one or two or a high threshold grade [indiscernible] Well, just as a recap, thanks for the question, Pete. Thanks for calling in. There was no serious or severe adverse events observed even at the highest administered doses in our Phase one study in healthy volunteers and CF patients. The first dosed patients in the Phase II study are obviously ongoing. And if there was any major events, then we'd able we'd have to update the market accordingly there with respect to safety. Phase two, we are reviewing safety and tolerability at predetermined time points have a data and safety monitoring committee that's staffed by the CF Foundation TDN. This network of clinical sites under the umbrella of the CF Foundation all of which have long term experience with clinical trials So when it comes to a major lung or pulmonary based adverse events, is an appropriate threshold applied but we haven't disclosed the details of that.

But I just wanted to provide some context as to our level of experience there.

Okay. Thank you for that. Moving on to 08:10, can you just briefly touch on the study design, meaning the types of patients that you're enrolling? Are they controlled, uncontrolled, standard of care, not on standard of care? Any genetic subtypes and age range?

Great. Yes. For OTC, as we've transitioned a Phase two trial here in The United States, we are gaining access to younger and more advanced disease patients. I can't share that.

But at the end of the second quarter, we look forward to sharing an update on the impact on these patients. But with respect to subtypes, I haven't had line of sight into that personally. So I don't even know what specific genetic subtype of OTC deficiency they are, but I can come generally speaking, we're starting to get access into younger and more advanced disease patients. And one last question, if you don't mind, the Phase one study for H5N1, [indiscernible] So interim data are expected in, I guess, the second half. What do we expect to see there? Is it doses for multiple cohorts? Sorry, data from multiple dosing cohorts and the different vaccination schedules or or piecewise?

Well, just first an update on on we initiated dosing in December, but greater than eighty percent of the patients already been enrolled. We're looking to complete enrollment here just at the end of this first quarter. So we're well on track there with respect to recruitment. And then with respect, what was the other element of your question?

So the interim data, what do we expect to see there? [indiscernible] multiple doses and multiple administrated types of administrations, right? Prime Boost versus others.

That are being investigated by BARDA in younger and older adults. So it's a really diverse Folsom data set will be a couple hundred people and the timing of that is likely in the second half of this year. But it will include a lot of immunogenicity data [indiscernible] different dose levels, different [indiscernible] etcetera. Yes. Thank you, Pete. We'll move next to Tom Schreeder with BTIG.

Your line is open.

Thanks for the update. Nice to be involved.

A lot of comments about deterioration of lung function. I'm curious what your preclinical data says how that interplays with your ability to deliver CFTR if the lung is too inflamed or too coated does it get very spotty? And what kind of data do you collect on patients that might inform us? I'm curious if it works well in some patients and not at all in others. How much of a theory they'll be as to why then I have a vaccine follow-up.

Well, Pat can provide some context on the preclinical data set. Yes, go ahead, Pat.

Yes. I mean, I think it's a great question.

When we did our initial preclinical work, we did a lot of work on the effect of mucus, the effect of sort of clogging on the delivery of our nanoparticles and the delivery and the expression of mRNA. And we've optimized our formulations so that they're stable in sputum for example and it can diffuse and get into the right cell type. And we did all that work pre clinically, which really led into sort of our doing our initial clinical trial work. Just so you're aware, when patients do come in, they come with a diverse genetic background, right? So So the lung function varies from different patients but we do anticipate after the initial dosing, after the clearance of the mucus, it gradually these the nanoparticles will become more efficacious over time will be more they should feel it should be delivered to sort of deeper lung and really go at the cause of the disease.

Got it. And if I can follow-up, how excited are you about a seasonal flu vaccine The other mRNA companies have shown really effective vaccines but the reactogenicity is so bad, they're not probably competitive. Is that high on your list? Or is it kind of you have enough to do? Thanks.

Yes.

Definitely, these changing viruses are attractive commercial opportunities for the mRNA vaccine space in general because of clock speed advantages and manufacturing and distribution.

So self amplifying mRNA would be considered one of those companies that would be attracted to markets where the virus is changing and that includes COVID and flu. The advantages that we bring to the table versus the competitors in the space is we're self amplifying mRNA that means the dose would be much lower. Also, we have shown [indiscernible] with clinical trial data and peer reviewed publications that the duration of immunogenicity is extended to to be once a year. Instead of multiple times a year. So I think most people would like a lower dose option that has an extended more durable immune response and that has complete coverage throughout the year. Not just for the season. And that would that That's how we would have competitive advantages within the mRNA space.

Okay. Thank you.

We'll take our next question. We'll take our next question from Ed Ayers with H. C. Wainwright. Your line is open.

Hi, good afternoon, everyone. This is Thomas Yip as asking a couple of questions for Ed. Congratulations on the achievement in 2024.

So first question on CF, clearly a lot of interest [indiscernible] And given the evolving landscape for combination treatments in CF, How do you see 32 fitting in either as a competitor or complementary agents? And also can you remind us how large your total addressable market estimate?

Yes. In terms of well, first of all, we're very excited about the transient mRNA therapeutics and protein replacement therapeutics are ideal especially for those that do not respond to modulators. And in terms of the size of the opportunity, you have to take into consideration the latest estimates whether they're 15% or 18% of the CF community. Be very interested in something that could address their unmet medical need. That is a massive commercial opportunity. Especially for a company of our size. So I think you can look to the competitors in the space. And see what the opportunity is there But did I address your question, Ed? [indiscernible] Thank you. Perhaps switching gears to A10, one more question from us. For the interim readout, and also coming to the second quarter. In addition to safety and PK, what we consider to be a par for success from an FPC standpoint in OTC.

Well, several biomarkers are being measured and evaluated in our clinical studies, so including ammonia and several amino acids and multiple methods to evaluate urea genesis. So our biomarker strategy is becoming more clear. We haven't communicated communicated that and shared that with the public. We intend to communicate this strategy in more detail later this year, likely concurrent with the interim data set We haven't promised that, but but that's likely. So you can imagine that it's not just about ammonia There's other amino acids that are implicated in urea cycle disorders like ornithine transcarbamylase deficiency. And we're one of the leading companies to understand what an mRNA therapeutic can do to not only restore a healthy urea cycle, but what impact that will have on what specific biomarkers that could drive and to establish potential clinical endpoints in pivotal studies.

Understood. Thank you, Ken, so much for taking our questions. Looking forward to the progress We'll move next to Yanan Xu with Wells Fargo.

Your line is open.

Great. Thanks for taking the questions.

So first, I was wondering, ahead of the CF data readout, how should we think about variability when we see the data I wanted to mention that for your Phase one study, there's Some variability, any in some patient, it could be greater than three percent.

From measurement to measurement. So I guess what could sounds like this will be a few multiple patient, multiple doses?

But of course, this is not a very large study that it's easier to [indiscernible] No, it's a great question, Yan, thanks for calling in. Variability is something that we have to watch closely. Now in our previous when we shared FEV data previously, that was that was from a Phase 1b safety study. It was not an efficacy study.

And so of course there would be elevated variability with just two administrations.

In the Phase two study that we're undertaking, this is twenty eight daily doses. And several measurements taken. So that will help alleviate a lot of [indiscernible] and designed as such. So we believe that will be the case. Now clearly, it the higher the FEV, the stronger your statistical conviction on how meaningful this data is. But the three percent that I referenced earlier on the call and in the Q and A session is just simply referring to historical precedents in the modulator community as justification to proceed. It states the obvious that we would like to get higher than that. To address statistical significance and variability concerns that you just shared. That's great to hear. May I also ask is potential dose response should be something we look for or maybe at this stage? No one has ever established that or at least hasn't shared that data in the So we would be your Us and our competitors would be the first company ever to show that there is a dose response for inhaled mRNA therapeutics in CF patients.

But there's rationale to expect that, that could be the case. The higher the dose, the more of the coverage, the more of the CFTR. More of the biochemical and pharmacological response. So there isn't any reason to justify that there isn't a dose response We did see a dose response in preclinical animal models as well. Especially the challenging ferret model.

So I think the general consensus is that we would expect to dose response in human beings, but I like to remind everyone this is the first of its kind and we just don't know what will happen, but that would be fantastic if we saw that.

Got it. May I also ask about safety? I think the dosing frequency is daily inhalation. How do we think about delivered product inhaled daily just in general? Thanks.

Yes.

So we've done a lot of preclinical talk studies that are chronically dosed tox studies for injectable and inhaled therapeutics our preclinical animal models. And we haven't seen any concerns pertaining to accumulating lipids for example, or accumulating technology in our intravenous program for OTC deficiency, we saw that these lipids are no longer measurable after a short period of time. So we have we have conviction or confidence that we won't see anything Too challenging in the with respect to safety and tolerability. But that's why we have to collect the data with 28 consecutive doses to clearly establish that. Did I address your question, Yanet?

Yes. If I may ask a quick question on cost saves. Could you clarify how many doses have been sold in the last quarter? And how do we think about the first quarter relative to the last quarter adjusting for seasonality? In general? Thank you. Well, yes, Meiji communicated their recent sales guidance in the February on their investor call. But Andy, do you want to provide some color to address this question?

Yes. Meiji had originally planned to sell around $4,000,000 dose and they basically changed their guidance to less than half of that. So that's the latest that we've heard from Maji and CSL. And as soon as we get more clarity, I think we'll be more than happy to share that with the market as soon as possible. We're rooting for them and we anticipate that the two dose lie on format will certainly help ease and improve the efficacy of the administration certainly the logistics around Japan, but but that's pretty much the latest that we have from AG.

And the only other marketing difference I would add is the last time the Meiji sales force was was looking to distribute and sell this vaccine. They were the only country in the world that had approved COSTAVE. And now there's 31 countries haven't approved that have approved Coasteve. And so they'll be armed with that level of confidence and conviction as they enter the 2025 market. So we're definitely cheering for them.

Great. Thanks for all the additional color. I appreciate it.

Yes. We'll move next to Yale Jin with Laidlaw and Company.

Your line is open.

Good afternoon and thanks for taking the questions and congrats on the progress. In terms of the CF mRNA development, we noticed there's another competitors probably going to report the data about a similar timeframe as yours. So I'd just like to see what do you think about the comparison between these two before they and you either one of you reporting the data. And then I will follow-up on the COVID side.

Yes.

It's definitely an exciting competitive space.

I think the first round of competitive performance will be evaluated ahead heads up in Phase two trial data.

Everyone will compare our data to the competitors. If any of the other programs make it into Phase three trials that obviously implies that they saw FEV percentage improvements. And so I fully expect the focus and this is just our May and others here at Arturais. We expect the focus will elevate on safety and tolerability for a daily treatment But in the near term, the focus will be on FEV And then as we transition to Phase three trials, I think it will be obvious for daily inhaled treatment that the focus will look towards safety and tolerability and that will leverage some of the strengths of our Lunar technology from others.

Okay, great. Maybe just a follow-up here in terms of the two dose max COVID vaccine. For the next for the upcoming, I guess, winters. What are the key strength the vaccine was against? COVID-nineteen?

Yes. The application is in place for the TUDOS file presentation, but we have not included the up updated variant of concern that she typically provided in the spring by the WHO. And typically, the PMDA and Japanese regulatory authority aligns with the WHO selection, but that should unfold in the coming months. And that's what we've seen in the past few years, and that's what we expect for this year.

Maybe one last question for Andy, which is that for the $28,000,000 your shares from the sales, I'm just Arcturus, is that just a two way or three way split because of major. So it's I assume it's part of that that sharing that [indiscernible] Yes. No, very good question. It is a three way split. Between Meiji and CSL and Artura. And so, as I alluded to in my previous call, there's a two tiered pricing system and this is the first tier. Of that mechanism. And of course, the second tier would relate to the sell through, right? And how much did they actually sell the back for and they'll be sharing that information with CSL who will then do the calculation on the differences between the two prices. And allocate those revenues accordingly. So hopefully, we'll have more color sometime maybe this year, but the mechanism is a little complex and nevertheless We're grateful that we have good partners here to help us figure out all these [indiscernible] Okay, great. Thanks a lot and congrats on the progress.

Thank you.

And this does conclude the Q and A portion of today's call. I would now like to turn it back to Joe Payne for any additional or closing remarks.

Just to thank you to everyone participating on the call. If there's any remaining questions, don't hesitate as always to reach out to our team. We'll get back to you as soon as we can. You, everyone, and good night.