Earnings Call Transcript - ARCT Q4 2024

Operator, Operator

Good day, everyone, and welcome to Arcturus Therapeutics Fourth and Full Year 2024 Earnings Call. Please note, today's call will be recorded. It is now my pleasure to turn the conference over to Neda Safarzadeh, Vice President, Head of Investor Relations, Public Relations and Marketing. Neda, please go ahead.

Neda Safarzadeh, Vice President, Head of Investor Relations, Public Relations and Marketing

Thank you, operator. Good afternoon, and welcome to Arcturus Therapeutics quarterly financial update and pipeline progress call. Today's call will be led by Joe Payne, our President and CEO; and Andy Sassine, our CFO. Dr. Pad Chivukula, our CSO and COO, will join them for the Q&A session. Before we begin, I would like to remind everyone that the statements made during this call regarding matters that are not historical facts are forward-looking statements within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, performance and achievements to differ materially from those expressed or implied by the statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier today as well as the Risk Factors section in our most recent Form 10-K 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.

Joseph Payne, President and CEO

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 KOSTAIVE. We're very pleased to receive European Commission approval for KOSTAIVE, the world's first approved self-amplifying mRNA COVID-19 vaccine. The centralized marketing authorization of KOSTAIVE provided by the European Commission is valid in all 27 European Union member states and 3 additional European economic area countries. The approval is based on positive clinical data from several studies, including an integrated Phase I/II/III study, demonstrating KOSTAIVE's efficacy against COVID-19, safety and tolerability and a Phase III COVID-19 booster trial, which achieved higher immunogenicity results compared to conventional mRNA COVID-19 vaccine comparators. The European regulatory approval results and milestones from CSL Seqirus, our global vaccine partner. These milestones will be disclosed in coordination with CSL. Our team continues to work diligently with CSL to prepare KOSTAIVE registration for the United States and the United Kingdom. The KOSTAIVE U.S. BLA filing is anticipated for later in 2025. On the manufacturing front, Meiji Seika Pharma, our Japanese vaccine partner, submitted a manufacturing and marketing application in February for a new vial presentation of KOSTAIVE provided in a vial containing 2 doses to the Pharmaceuticals and Medical Devices Agency, or PMDA, in Japan. Meiji Sika Pharma aims to receive approval for the 2-dose vial in time for the autumn season of 2025. The new 2-dose vial presentation will enhance convenience in daily practice and improve ease of vaccination in an individualized setting such as medical clinics. In January, Meiji, along with our manufacturing joint venture, ARCALIS, received approval from the Ministry of Health, Labor and Welfare, or MHLW, to add domestic commercial manufacturing sites in Japan for KOSTAIVE. Domestically produced products with active pharmaceutical ingredients manufactured at ARCALIS' facilities and formulated at Meiji Sika Pharmatech are now able to be shipped for commercial use in Japan. We continue to progress our STARR self-amplifying mRNA platform pipeline in other infectious disease targets. In January, the company announced the initiation of a Phase I study of ARCT-2304. 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 bird flu. The randomized placebo-controlled Phase I 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 Biomedical Advanced Research and Development Authority, also known as BARDA. Interim data will be available later this year in the second half of 2025. Moving now to our exciting pipeline of mRNA therapeutics. I will begin with an update on ARCT-032. This is our messenger RNA therapeutic candidate for cystic fibrosis. In December 2024, the company dosed the first participant in an open-label Phase II 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-032 over a period of 28 days. Our Phase II trial involves a relatively low number of study visits, only 8 study visits and 12 weeks of follow-up, easing the burden of participation for patients across all sites. Safety and tolerability data will be important given that ARCT-032 is likely to be a daily or every other day inhaled treatment. With respect to efficacy and based on historical precedents in the CFTR modulator space, an FEV lung function improvement of 3% in our Phase II trial would likely justify advancing ARCT-032 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 ARCT-032 Phase II study by the end of Q2 2025. The interim data will likely include multiple subjects at multiple dose levels. Moving on to our ARCT-810 program. This is our messenger RNA therapeutic candidate for ornithine transcarbamylase deficiency. In December 2024, the company initiated dosing of the first OTC deficient participant in a Phase II multiple ascending dose study. Each adult and adolescent participant in the open-label Phase II study is expected to receive 5 intravenous infusions of ARCT-810 over a period of 2 months. The company previously announced the completion of the dosing phase in a placebo-controlled European study enrolling 8 OTC deficient individuals. The company expects to provide interim data from participants who completed dosing in the ARCT-810 U.S. Phase II study by the end of Q2 2025. Finally, we are excited to have announced the appointment of Dr. Moncef Slaoui as Chair designate in February. Dr. Slaoui 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. We look forward to working with him in this exciting year for Arcturus, with multiple clinical studies and their associated data readouts. So with that, I will now pass the call to Andy.

Andrew Sassine, CFO

Thank you, Joe, and good afternoon, everyone. The press release issued earlier today includes financial statements 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-K, 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 KOSTAIVE vaccine program and our Japanese JV partner, ARCALIS. We are thrilled about the European Commission approval of KOSTAIVE, and I'm happy to announce that we have achieved several milestones related to this approval. More details regarding milestones will be provided on the first quarter earnings call. CSL reported to Arcturus that our share of gross profit from the sale of KOSTAIVE during the quarter ended December 31, 2024, was approximately $28 million. This amount will be credited against Arcturus' share of the COVID-19 development costs paid by CSL. When CSL recoups 40% of the total development cost of KOSTAIVE 19 programs, Arcturus will begin to receive shared net profit payments from CSL for all future sales of KOSTAIVE. ARCALIS remains an important strategic manufacturing asset for Arcturus concerning our vaccine and cystic fibrosis programs. We are very pleased with the recent $20 million investment by Meiji Seika Pharma as well as their involvement on the ARCALIS Board of Directors. ARCALIS and Meiji Seika Pharma are committed to advancing the development, production and supply of mRNA vaccines in line with the strategy for strengthening vaccine development and production systems adopted by the Japanese government. This is highlighted by the recent manufacturing and marketing approval of KOSTAIVE to include domestic manufacturing sites in Japan. Meiji and ARCALIS are in the process of obtaining approval for a 2-dose vial KOSTAIVE vaccine targeting the latest COVID strains. I will now provide a quick summary of our financial results. For the year ended December 31, 2024, we reported revenues of $152.3 million, a decrease of $14.5 million from the $166.8 million 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 3 months ended December 31, 2024, we reported revenues of $22.8 million, a decrease of $8.1 million from the $30.9 million reported in the same period in 2023. The decline was attributable to lower milestone achievements from the CSL agreement during the fourth quarter of 2024. Total operating expenses for the year ended December 31, 2024, were $248 million compared to $245 million for the year ended December 31, 2023. Total operating expenses for the 3 months ended December 31, 2024, were $56.2 million compared to $49.1 million for the 3 months ended December 31, 2023. Research and development expenses were $195.2 million for the year ended December 31, 2024, compared to $192.1 million for the year ended December 31, 2023. Additionally, research and development expenses were $43.8 million for the 3 months ended December 31, 2024, compared to $36.6 million for the 3 months ended December 31, 2023. The increase in R&D expenses for both the quarter and the full year was primarily driven by higher clinical trial costs associated with our OTC and CF programs as well as the COVID-19 and LUNAR-FLU programs in collaboration with CSL. However, the increase was partially offset by a reduction in manufacturing expenses related to clinical trials and drug supply agreements as part of the COVID-19 program. General and administrative expenses were $52.8 million for the year ended December 31, 2024, compared with $52.9 million for the year ended December 31, 2023. Additionally, G&A expenses were $12.4 million for the 3 months ended December 31, 2024, compared to $12.5 million for the 3 months ended December 31, 2023. These expenses remained relatively consistent between the 2 periods. We expect general and administrative expenses to decrease slightly during the next 12 months, driven by lower share-based compensation costs and a reduction in general and administrative expenses related to the commercial manufacturing transition of the COVID program to CSL. For the year ended December 31, 2024, Arcturus reported a net loss of approximately $80.9 million or $3 per diluted share, compared to a net loss of $29.7 million, or $1.12 per diluted share for the year ended December 31, 2023. Additionally, for the 3 months ended December 31, 2024, Arcturus reported a net loss of approximately $30 million, or $1.11 per diluted share, compared with a net loss of $11.7 million, or $0.44 per diluted share for the 3 months ended December 31, 2023. Cash and cash equivalents and restricted cash was $293.9 million as of December 31, 2024, and $348.9 million on December 31, 2023. Arcturus achieved a total of approximately $473.1 million in upfront payments and milestones from CSL as of December 31, 2024 and expects to continue to receive future milestone payments from CSL supporting the ongoing development of the vaccine program. For fiscal year '24 and '23, we burned about $55 million and $45 million, respectively, which was within our internal expectations. We anticipate that our burn will increase in the next 2 years, driven by our CF and OTC programs as they progress through their respective Phase II multiple ascending dose trials. Furthermore, as our COVID program transitions 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 2027. In summary, we believe the company remains in a strong financial position and has the resources to achieve multiple near-term value-creating milestones for the vaccine and therapeutic programs. We look forward to an exciting year in 2025, and we anticipate potential interim Phase II data readout for our OTC and CF programs, along with the continued development of the vaccine programs. I will now pass the call back to Joe.

Joseph Payne, President and CEO

Thanks, Andy. 2024 was a historical year for Arcturus as we transition to a commercial company with the launch of KOSTAIVE. And 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 questions.

Operator, Operator

And we'll take our first question from Lili Nsongo with Leerink.

Lili Nsongo, Analyst

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 milestones within the CSL collaboration? And are there been any updates in terms of the expectation for the flu vaccine program and a potential combo program with COVID flu?

Joseph Payne, President and CEO

I can address the flu question, Lili, thanks for calling in, and then Andy can discuss the cadence of milestones. CSL is generally responsible for providing guidance on the flu program. We have completed our Phase I for the quadrivalent version of the vaccine, and it's important to note that CSL holds a global license for the flu program, which is a significant focus for them. They will offer specific updates regarding the next steps in the flu area, including any potential trivalent or COVID flu combinations. So, we’ll be deferring to them. Andy, would you like to speak about the milestone cadence?

Andrew Sassine, CFO

Sure, Lili. Thanks for the question. Yes, we will continue to receive milestones from CSL throughout the year. And as we've articulated, we have earned milestones related to the European regulatory filing, and we'll provide more details with respect to that in the first quarter call. Hopefully, that will answer your question.

Lili Nsongo, Analyst

And maybe just a quick question moving on to the revenue pipeline, especially as it relates to the CF program. How should we think about potential differentiation from competitors in development, especially within the mRNA, the aerosol mRNA competitors?

Joseph Payne, President and CEO

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 differences. So what do I mean by mRNA? I 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 meaningful. And all of these differences were 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 and the LUNAR technology, but also take into consideration the know-how and IP associated with manufacturing and purification of the messenger RNA.

Operator, Operator

We'll move next to Yasmeen Rahimi with Piper Sandler.

Yasmeen Rahimi, Analyst

I would like to take some time to discuss the anticipation surrounding the CF interim data expected in the second quarter. Can you provide details about the cohort size for the 12 CF patients that have been dosed at this interim look? Will there be one or two doses administered? What key points do you want to demonstrate at this interim point to firmly establish its strong proof of concept in this market? I apologize for the multiple questions, but I would appreciate your insights on this.

Joseph Payne, President and CEO

Sure, sure. So I think in clinicaltrials.gov, we've communicated that the size of the Phase II 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 FEV lung function improvement of 3% in our Phase II trial would likely justify advancing ARCT-032 further into development. And this is simply based on historical precedents in the CFTR modulator space. And I believe that's the color you were looking for, Yas. Is there a follow-up question?

Yasmeen Rahimi, Analyst

I was going to ask, do you plan to present this data when it becomes available? Or do you hope to get that in at a key conference? I don't know if you have any visibility in terms of.

Joseph Payne, President and CEO

Yes. We haven't guided how to... 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.

Operator, Operator

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

Boran Wang, Analyst

This is Evan Wang filling in for Seamus Fernandez. I have two questions. First, regarding cystic fibrosis, could you update us on the progress of enrollment? Given the focus on complete dosing, what is the anticipated distribution of Class I and CFTR intolerable patients? Additionally, what are the next steps to advance the pivotal study? Secondly, concerning KOSTAIVE, it's good to see the European approval and the initial royalties from Japan. When can we expect to gain visibility into orders for 2025?

Joseph Payne, President and CEO

We are on track to provide interim data at the end of the second quarter regarding enrollment for CF. Multiple sites are already open and active, and we are engaging several more, which are highlighted on various CF tracking platforms from the CF Foundation. You can check for updates there and also on clinicaltrials.gov. Activity is ongoing, and we remain on schedule. Regarding the KOSTAIVE visibility on Japanese sales, could you clarify that for Andy?

Boran Wang, Analyst

Yes. For KOSTAIVE, just with the kind of ordering dynamics that may be typical in Japan or Europe, any kind of comments on, I guess, when that ordering pattern happens and what point you or CSL would get more visibility into, I guess, quantity of orders for the next flu season? And then on cystic fibrosis, I also wanted to ask on, I guess, split of Class I versus CFTR intolerable patients expected.

Andrew Sassine, CFO

Sure, Evan. As you probably noted recently, the Meiji and our Catalyst and CSL have petitioned the Japanese PMDA to get a 2-dose vial approved here in order to be ready for the next COVID strain. Consequently, as they go through that process, hopefully, it will happen in the first half of this year. With respect to their orders, 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.

Joseph Payne, President and CEO

And with respect to the Class I and non-Class I, really, it's one group. There's several, several genetic versions of this disease. Class I 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 subclasses, these are folks with multiple mutations or just very challenging characteristics that do 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 I subjects. So they're bundled together to represent one group where there's a very significant unmet medical need, and we're addressing them all. With respect to statistically, if there's 18% approximately 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 I null patient population. So you would anticipate approximately half of our the folks in our Phase II trial to be from Class I. 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.

Operator, Operator

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

Myles Minter, Analyst

Congrats on the progress and the EU approval for KOSTAIVE as well. 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? That's the first one. The second one is this is an open-label study. I believe you're adding albuterol into the administration process here. So would that have any potential impact on FEV1 readouts alone? And just wondering whether you're factoring that into the interpretation of your data?

Joseph Payne, President and CEO

Yes, the first question refers to a well-established precedent in the modulator space, which is an absolute improvement of 3%. It's important to note that deterioration rates in the non-Delta 508 community are more rapid and significant. Therefore, the Delta improvement would actually be more substantial, making that 3% absolute improvement more noteworthy. Regarding your question about albuterol, pretreatment with albuterol will not affect the analysis of the FEV response. When subjects come in to have their lung function measured, it is done before they receive albuterol for the next treatment. Since albuterol is very short-acting and lasts only a few hours, it will not impact measurements taken the following day.

Operator, Operator

We'll take our next question from Whitney Ijem with Canaccord Genuity.

Joohwan Kim, Analyst

This is Joohwan Kim on for Whitney Ijem. Maybe 2 quick ones from us. First, can you give any clarity on the magnitude of cost that CSL needs to recruit before Arcturus will begin to receive profit payments? We know you said the 40% of cost, but any specifics on development costs to help flush out that math? And secondly, now that KOSTAIVE 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?

Joseph Payne, President and CEO

Andy, go ahead.

Andrew Sassine, CFO

No, thanks for the question. We are excited about the European approval and so is CSL. And the good news is they're in charge of the commercialization process in Europe. With all of their experience in the flu program, we're in a good position here to rely on them to lead 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 amount that we reported that they shared with us, the $28 million 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 KOSTAIVE. And as you've heard, our guidance is until the end of the first quarter of 2027.

Operator, Operator

We'll move next to Pete Stavropoulos with Cantor Fitzgerald.

Pete Stavropoulos, Analyst

And congratulations on the progress and including the EU approval. I have a question for ARCT-032 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 1 or 2 or a high threshold Grade 3 and 4?

Joseph Payne, President and CEO

Yes. Well, just as a recap, thanks for the question, Pete. Thanks for calling in. There were no serious or severe adverse events observed even at the highest administered doses in our Phase I study in healthy volunteers and CF patients. The first dosed patients in the Phase II study are obviously ongoing. And if there were any major events, then we'd have to update the market accordingly there with respect to safety. In Phase II, we are reviewing safety and tolerability at predetermined time points. We 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 major lung or pulmonary-based adverse events, there's 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.

Pete Stavropoulos, Analyst

All right. Moving on to ARCT-810. 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? And any genetic subtypes and age range?

Joseph Payne, President and CEO

Great. Yes. For OTC, as we've transitioned to a Phase II 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 are. But I can comment and confirm that, generally speaking, we're starting to get access into younger and more advanced disease patients.

Pete Stavropoulos, Analyst

Okay. And one last question, if you don't mind. The Phase I study for the H5N1 vaccine. Interim data are expected in the second half. What should we expect to see there? Is it data from multiple dosing cohorts and different vaccination schedules or piece-wise?

Joseph Payne, President and CEO

We initiated dosing in December, and more than 80% of the patients have already been enrolled. We aim to complete enrollment by the end of this first quarter, so we are on track with recruitment.

Pete Stavropoulos, Analyst

So the interim data, what do we expect to see there? That's something you're waiting for.

Joseph Payne, President and CEO

Yes. Interim data will include multiple doses and multiple administrative 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, fulsome data set. It will be a couple of 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 and different dose levels, different prime boost regimens, etc.

Operator, Operator

We'll move next to Tom Shrader with BTIG.

Thomas Shrader, Analyst

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 there'll be as to why? And then I have a vaccine follow-up.

Joseph Payne, President and CEO

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

Padmanabh Chivukula, CSO and COO

Yes, I think it's a great question. In our initial preclinical work, we focused heavily on how mucus and clogging affect the delivery of our nanoparticles and the expression of mRNA. We optimized our formulations to ensure they are stable in sputum, allowing them to diffuse and reach the appropriate cell type. This foundational work led us into our initial clinical trials. It's important to note that when patients enter the study, they come from diverse genetic backgrounds. As a result, lung function varies among patients. However, we expect that after the initial dosing and clearance of mucus, these nanoparticles will become more effective over time, allowing for deeper delivery into the lungs and targeting the root cause of the disease.

Thomas Shrader, Analyst

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?

Joseph Payne, President and CEO

Yes. The evolving nature of viruses presents significant commercial opportunities for the mRNA vaccine sector due to advantages in manufacturing and distribution speed. Self-amplifying mRNA positions us well in markets where viruses like COVID and flu are changing. Our competitive edge lies in our self-amplifying mRNA technology, which allows for a much lower dose. Clinical trial data and peer-reviewed studies have demonstrated that our immunogenicity lasts longer, allowing for an annual administration instead of several throughout the year. Many people would prefer a lower-dose option that offers a more sustained immune response and comprehensive protection all year round, rather than just seasonally. This is how we maintain our competitive advantage in the mRNA field.

Operator, Operator

We'll take our next question from Ed Arce with H.C. Wainwright.

Wing Yip, Analyst

This is Thomas Yip asking a couple of questions for Ed. Congratulations on the achievement in 2024. So first question on CF. Clearly, a lot of interest there. And given the evolving landscape for combination treatments in CF, how do you see 032 fitting in either as a competitive or complementary agent? And also, can you remind us how large is your total addressable market estimate?

Joseph Payne, President and CEO

Yes. We're very excited about the opportunity in cystic fibrosis. We believe that transient mRNA therapeutics and protein replacement therapeutics are particularly suitable, especially for those patients who do not respond to existing modulators. When considering the potential market size, recent estimates suggest that around 15% to 18% of the cystic fibrosis community would be very interested in a solution that could meet their unmet medical needs. This represents a substantial commercial opportunity, particularly for a company of our size. You can also look at the competition in the field to understand the scope of the opportunity. Did I answer your question, Ed?

Wing Yip, Analyst

Yes, yes. Perhaps switching gears to ARCT-810, one more question from us for the interim readout and also coming into the second quarter. In addition to safety and PK, what would you consider to be a bar for success from an efficacy standpoint in OTC?

Joseph Payne, President and CEO

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 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 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 transcarbamylse 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.

Operator, Operator

We'll move next to Yanan Zhu with Wells Fargo.

Yanan Zhu, Analyst

I was curious, as we approach the CF data readout, how we should consider variability in the data. I want to note that in your Phase I study, there is some variability, and in certain patients, it might exceed 3% from one measurement to the next. It appears that this will involve multiple patients and doses, but since this is not a very large study, it might be somewhat easier to identify a signal.

Joseph Payne, President and CEO

That's a great question, Yanan. Thank you for reaching out. Variability is something we must monitor closely. Previously, when we shared FEV data, it came from a Phase Ib safety study, which was not focused on efficacy. Therefore, there tends to be higher variability with just two administrations. Our ongoing Phase II study entails 28 daily doses and multiple measurements, which should help reduce concerns about variability since it is an efficacy study specifically designed to measure efficacy with FEV. We expect this to hold true. It's clear that a higher FEV will strengthen our statistical confidence in the significance of the data. The 3% I mentioned earlier relates to historical precedents in the modulator community, serving as a basis for us to move forward. It’s clear that we aim for a higher percentage to ensure statistical significance and address the variability concerns you raised.

Yanan Zhu, Analyst

That's great to hear. May I also ask is a potential dose response should be something we look for or maybe at this stage in time?

Joseph Payne, President and CEO

No one has ever established that or at least hasn't shared that data in the history of mankind. So we would be 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 is rationale to expect that, that could be the case. The higher the dose, the more of the coverage, the more of the CFTR, the more 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 a dose response in human beings. But I'd 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.

Yanan Zhu, Analyst

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

Joseph Payne, President and CEO

We have conducted numerous preclinical toxicology studies, specifically chronic dosing studies for injectable and inhaled therapeutics in our animal models. There have been no issues observed with lipid accumulation or with the technology in our intravenous program for OTC deficiency, as these lipids become undetectable after a brief period. Therefore, we are confident that we won't encounter significant safety or tolerability challenges. However, we need to collect data over 28 consecutive doses to confirm this. Did I answer your question, Yanan?

Yanan Zhu, Analyst

Yes, yes. If I may ask a quick question on KOSTAIVE. 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?

Joseph Payne, President and CEO

Well, yes, Meiji communicated their recent sales guidance in the second week of February on their investor call. But Andy, do you want to provide some color to address this question.

Andrew Sassine, CFO

Yes. Meiji had originally planned to sell around 4 million doses, and they basically changed their guidance to less than half of that. So that's the latest that we've heard from Meiji 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. But we're rooting for them and we anticipate that the 2-Dose Vial format will certainly help ease and improve the efficacy of the administration, certainly the logistics around Japan. But that's pretty much the latest that we have from Meiji.

Joseph Payne, President and CEO

And the only other marketing difference I would add is the last time the Meiji sales force was looking to distribute and sell this vaccine, they were the only country in the world that had approved KOSTAIVE. And now there's 31 countries that have approved KOSTAIVE. 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.

Operator, Operator

We'll move next to I-Eh Jen with Laidlaw & Company.

Yale Jen, Analyst

Congratulations on your progress. Regarding the CF mRNA development, it seems there's another competitor that may release data around the same timeframe as you. I would like to know your thoughts on the comparison between the two, before either of you reports the data. I also have a follow-up question on the COVID side.

Joseph Payne, President and CEO

Yes, it's definitely an exciting competitive space. The first round of competitive performance will be evaluated directly in Phase II trial data, and everyone will compare our data to the competitors. If any other programs advance to Phase III trials, that clearly indicates they observed improvements in FEV percentage. I fully expect that the focus—shared by others here at Arcturus—will shift towards safety and tolerability for daily treatment, but in the near term, the emphasis will be on FEV.

Yale Jen, Analyst

Okay. Great. Maybe just a follow-up here regarding the two-dose COVID vaccine for the upcoming winters, what are the key strains that the vaccine targets against COVID?

Joseph Payne, President and CEO

Yes. The application is in place for the 2-dose vial presentation, but we have not included the updated variant of concern that you typically provided in the spring by the WHO. And typically, the PMDA and the Japanese regulatory authority align 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.

Yale Jen, Analyst

Maybe one last question for Andy regarding the $28 million from the sales of your shares. I'm curious if that profit is shared equally between two parties or three, considering that Meiji is also involved in that profit sharing.

Andrew Sassine, CFO

Yes. No, very good question. It is a 3-way split between Meiji and CSL and Arcturus. And so as I alluded to in my previous call, there's a 2-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 vaccine for, and they'll be sharing that information with CSL, who will then do the calculation on the differences between the 2 prices and allocate those revenues accordingly. So hopefully, we'll have more color sometime later 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 calculations.

Operator, Operator

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

Joseph Payne, President and CEO

Just a 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. Thank you, everyone, and good night.

Operator, Operator

This does conclude today's program. Thank you for your participation. You may disconnect at any time, and have a wonderful evening.