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spk02: Greetings and welcome to the Arcturus Therapeutics fourth quarter and full year 2020 earnings call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Nita Savardzada, Head of Investor Relations, Public Relations, and Marketing. Thank you, Nita. You may begin.
spk01: Thank you, Operator, and good afternoon, everyone. We are joined today by Joseph Payne, President and CEO, Andy Sassin, CFO, Dr. Pat Chivikula, CSO and COO, Dr. Steve Hughes, our Chief Medical Officer, and Professor Wing-Ying Yang, Deputy Director of Emerging Infectious Diseases Program from Duke-NUS Medical School, who is also in Arcturus' Vaccine Platform Scientific Advisory Board. Before we begin, I would like to remind everyone that except for statements of historical facts, the statements made by management and any responses to questions on this conference call constitute forward-looking statements that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements other than the statements of historical facts included in this communication including those regarding the company's supply agreements and potential supply agreements, the potential future manufacturing and other operations, the status and results of clinical development programs, the planned initiation, design or completion of clinical trials, the likelihood of success of the company's coronavirus COVID-19 vaccine candidate or other product candidates and the company's current and future cash and financial position are forward-looking statements. Actual results and performance could differ materially from those projected in any forward-looking statements as a result of many factors including without limitation, an inability to develop and market product candidates, unexpected clinical results, and general market conditions that may prevent such achievements or performance. Such statements are based on management's current expectations and involve risks and uncertainties, including those discussed under the heading risk factor in ArcTrace's most recent annual report on Form 10-K with the SEC and in other filings that ArcTrace makes with the SEC. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements which speak only as of the date they were made, whether as a result of new information, future events, or circumstances, or otherwise. Now it is my pleasure to pass the call to Joe Payne, President and CEO of Arcturus. Joe, please go ahead.
spk13: Hey, thank you, Netta, and good afternoon to all. Thank you for joining the Arcturus' quarterly call today. I'd like to begin by congratulating J&J on their recent approval of their one-shot COVID vaccine. I'm sure their team has been working very hard and it's great to see their efforts being rewarded with success. No doubt the world wants access to one-shot vaccines this year in 2021. And it appears that COVID is here to stay for years to come. It's now a global pathogen, very contagious, airborne, and new challenging variants are arising. The endemic market will very likely be addressed through periodic single administrations. Therefore, a vaccine that is redosable is also important. A vaccine with an immunological profile that could potentially provide broader variant coverage is important. A vaccine technology that is rapidly updatable as needed is also important. Arcturus is developing differentiated next generation class of mRNA-based medicines. and we're very excited about the prospects for our company and our rapidly maturing pipeline. We believe that mRNA therapeutics have now come of age as a therapeutic modality to provide enormous benefit to human health, not just in vaccines, but also for a wide range of transformative medicines for serious diseases. During the last several months, there has been an increasing appreciation for the promise of mRNA approaches with the clinical successes and widespread use in tens of millions of individuals of the first wave of mRNA vaccines. We believe that this is only the beginning and that our platform has the potential to generate vaccines with a differentiated profile compared to those in use today, as well as to create medicines for numerous other diseases. Arcturus has made substantial progress during 2020 and during the beginning of this year with our lead clinical pipeline candidates, our promising preclinical candidates, and in advancing Arcturus' core capabilities and underlying science. We have continued to move our leading chemistry forward, expanded our intellectual property estate, and rapidly advanced our CMC, our manufacturing capabilities. I'll begin with an overview for ARCTO21. That's our differentiated COVID-19 vaccine candidate based on a self-transcribing and replicating mRNA, also known as self-amplifying mRNA technology. When we consider the COVID-19 pandemic at a macro level, our expectation is that it will be a prolonged global issue that will require the vaccination of billions of individuals for years to come. RNA coronaviruses are well known to mutate rapidly, and while we're not surprised with the emergence of viral variants during this global pandemic, We are carefully monitoring the situation. We're carefully evaluating these variants as they arise. We believe that because of the specific type of cellular immunogenicity that ARCTO21 promotes, that our vaccine candidate may provide broad protection to many of the SARS-CoV-2 variants in circulation. It is also possible that these variants may require periodic adaptation of vaccines administered. as is already done with vaccines for influenza. One of the benefits of an mRNA approach is that our vaccines are easily and rapidly able to be modified as needed. Furthermore, we believe that ARCTO21 could have a differentiated and highly attractive profile, a vaccine product that is not a frozen liquid, one that is lyophilized and requiring only a single administration. ARCTO21 has the potential over time to become a favoured vaccine option for many countries. We continue to rapidly advance our clinical development program for ARCTO21, and based on the highly promising clinical and preclinical data that we've obtained to date, we have recently made the decision to move forward with a single administration regimen and phase three development. Our decision to advance the single administration regimen is based on our phase one slash two study data that show favorable tolerability and both substantial humoral and cellular immunity observed after a single injection. In addition to our clinical data, we have supportive data from both primate and human ACE2 transgenic mouse challenge models that demonstrate robust protection with a single dose regimen. We are particularly encouraged by the robust cellular immune response seen in phase one slash two study subjects that were administered our vaccine. A growing body of clinical data provides support for the important role of CD8 cells in providing protection against COVID-19, and our data gives us additional confidence in the potential efficacy of our vaccine. We are currently conducting final analysis on the results of the Phase 1-2 study, and we plan to submit the results for publication in the second quarter. I also want to mention new data that has been submitted for publication based on work from Dr. Uy and his colleagues. We have been seeing several reports emerging that conventional mRNA vaccines may be highly effective after the first shot. So it begs the question, how does ARCT021, a self-amplifying mRNA vaccine, compare to the single shot of an approved conventional mRNA vaccine? Directly comparing vaccines has been challenging for investors and scientific community. because everyone uses different methods and assays to measure immunogenicity. But to help us all, to help all of us with this challenge, the Duke NUS Medical School and their colleagues have recently collected immunogenicity data from participants receiving a single injection of an approved conventional mRNA vaccine. And the data collected utilized the same assays and methods that we used for determining the immunological profile of ARCTO21. The research examined the adaptive immune responses following administration of the approved conventional mRNA vaccine based on a cohort of 20 healthcare workers. The key results from the study are included in our press release issued just recently this afternoon. The data suggest that following a single administration of an mRNA vaccine, Binding antibodies and cellular immunity, or T cells, are associated with protection against COVID-19 at early time points. Interestingly, at these same time points where clinical protection is observed, neutralizing antibodies or antibody levels have been found to be negligible, suggesting that these are not necessarily required for clinical efficacy. The findings from our ARCTO21 single-shot immunogenicity based on our phase one slash two study results compares favorably with the findings from Dr. Uwe's study examining the correlates of protection based on conventional mRNA vaccines. We believe these data provide additional support for the potential efficacy of the ARCTO21 vaccine. Following our phase one slash two study, we have now dosed over 500 subjects in our ongoing phase two study. This is a multicenter, randomized, observer-blind study, which is designed to evaluate the safety and immunogenicity of the study vaccine in younger and older adult participants. The study is being conducted in both the United States and Singapore. It is evaluating two dose levels, 5 micrograms and 7.5 micrograms. We are also evaluating prime boost regimens. By evaluating a prime boost regimen, we'll be studying the redosability of our approach. We believe that a redosable vaccine that utilizes the novel lunar non-viral vector delivery system is important, and that a single-shot mRNA vaccine that is more easily distributable, like lyophilized or non-frozen liquid, would be a valuable option for many countries. We plan to finalize the specific ARCT021 dose for our Phase III study, to be confirmed by the pending interim analysis data from this ongoing phase two study, which we expect to get during the second quarter. Our clinical team in parallel is already preparing to advance a five microgram single dose regimen for phase three development. And we continue to track towards Q2 study start. We believe that we have the potential to obtain data in the second half of the year and could obtain ARCTO21 EUA or Emergency Use Authorization in at least one jurisdiction in the second half of this year or H2 2021. Well, we are fortunate to have Dr. Uy, the Professor of Emerging Infectious Diseases at Duke NUS Medical School. He's here on the call today to present the recent data. Dr. Uy, the time is now yours. And we here in San Diego will advance the slides per your direction.
spk11: Thanks very much, Joe. Next slide, please. As you may recall, at the last investor conference call that we had, I showed this slide on the Phase III trial data of BNT162b2. And the onset of vaccine efficacy of this RNA, conventional RNA vaccine, was at day 12 after the first dose which, as you can see on the red line, the curve for the vaccinated arm pretty much flattened from that point onwards. The adaptive immune responses that coincides with this onset of efficacy could be very informative, therefore, on the necessary elements of immunity against COVID-19. Next slide, please. So we took advantage of the rollout of this conventional RNA vaccine in Singapore to define what components of the adaptive immune responses that develop coincidentally with vaccine efficacy onset. We found that BNT162b2 vaccination produced binding IgG responses in 80% of the participants at this time. Interestingly, there's very few antibodies that were neutralizing or even blocking the SARS-CoV-2 and the ACE2 interaction, and 15% were positive on SARS-CoV-2 PRNT. In contrast, 85% were positive for virus-specific T-cells on our L-spot assay. Median number of spots per 1 million cells were 28 and 13 on days 10 and 21, respectively, after the first dose. These data suggest that virus-binding antibodies and virus-specific T-cells are sufficient to protect against COVID-19. Findings are also consistent with many other studies that show that neutralizing antibodies are not absolutely required for protection. Our findings with the conventional RNA vaccine provide a context for us to compare what we have found in our Phase 1-2 trial with ARCT021. This vaccine also produces high seroconversion rate at day 14 after the first dose, 81%. which, by the way, was actually done using a more stringent serodilution series rather than optical density readings, which we used for the conventional RNA vaccine analysis. Moreover, seroconversion was 100% by date 36, so the antihumoral response were very encouraging. All of our participants developed virus-specific T-cell responses on the same ELISPOT assay, Although there is a four-day difference, the counts from the self-replicating RNA vaccine are 10 times greater than conventional RNA vaccine. These results, again, demonstrate the strong potential of ARCT021 being a single-shot vaccine against COVID-19. This data is being under review right now. It should be available as a preprint online soon. I'll hand this time over to Dr. Steve Hughes, Chief Medical Officer of Arcturus. Thanks.
spk12: I'll begin with ARC810, our therapeutic candidate for ornithine transcarbamylase OTC deficiency. ARC810 utilizes Arcturus's lunar lipid mediated delivery platform to deliver OTC messenger RNA to the liver, the primary target tissue in OTC deficiency. Expression of the normal ornithine transcarbamylase enzyme in the liver of patients with OTC deficiency has the potential to restore normal urea cycle activity, preventing neurological damage and the need for liver transplantation. Our ARCT810 program is supported by preclinical data in OTC-deficient murine models, demonstrating that dosing of lunar OTC results in robust ornithine transcarbamylase protein expression and activity, resulting in improvements in ureogenesis, plasma ammonia, and increased survival. We have already completed a phase one dose escalation study in healthy volunteers. That study demonstrated that administration of ART810 was associated with favorable tolerability and an attractive pharmacokinetic profile, going up to the top dose of 0.4 milligrams per kilogram, which is well within the anticipated therapeutic range based on data from our animal studies. Importantly, the lipid was not detectable beyond 48 hours after dosing, but we could actually still detect the messenger RNA at the last time point that we assessed, which was two weeks after dosing. The persistence of messenger RNA gives us optimism that we can potentially extend the dose interval beyond a few weeks. We have also initiated a phase one dose escalation study evaluating ARK810 for the first time in patients with OTC deficiency. We've been enrolling this study in the US, but have recently received approval from Health Canada to also enroll subjects in Canada as well. We look forward to obtaining initial results in this study during the coming year. We are on track to submit a clinical trial application for a multiple dose phase two study in OTC deficiency patients in Q2 of 2021. Turning now to ARCT032, our therapeutic candidate for cystic fibrosis. ARCT032 is designed to result in the expression of a functional copy of messenger RNA encoding the transmembrane conductance regulator, or CFTR, in the lungs of CF patients. CFTR is a membrane protein and chloride channel that is deficient in CF patients, causing severe pathology, including lung dysfunction. ARCT032 utilizes Arcturus's lunar lipid-mediated aerosolized platform to deliver CFTR messenger RNA to the lungs. We believe that this platform has the potential to restore normal lung CFTR activity, thereby correcting the underlying defect causing the disease. The ARCT032 program is supported by preclinical data from a variety of models, including human and ferret bronchial epithelial air-liquid interface cell cultures, ferrets, non-human primates, and a CFTR-deficient murine model. These studies have demonstrated the ability to efficiently deliver R-lunar mRNA technology to the airway epithelial cells following topical and aerosol administration. Additionally, intranasal administration has demonstrated the ability to restore chloride channel activity in the nasal epithelial cells in the so-called nasal potential difference studies in the CFTR deficient mass and suggests that our approach has the potential to fundamentally address the underlying deficit associated with CF lung disease. We recently successfully completed pre-IND interactions with FDA to enable advancement of the ARCT032 program into the clinic. Our expectation is to submit a CTA for the ARCT032 program in Q4 2021. We are excited about the potential of this program to benefit patients regardless of the underlying specific genetic abnormality causing their disease, and we are very much looking forward to moving ARCT032 forward to the clinic. I will now pass the call on to Andy, our CFO.
spk10: Thank you, Steve, and good afternoon, everyone. The press release issued earlier today includes financial statements for the fourth quarter of fiscal year 2020, which I will briefly summarize. Arcturus' primary source of revenue is currently from license fees and collaborative payments received from research and development arrangements with our pharmaceutical and biotech partners. For the year ended December 2020, the company reported revenues of $9.5 million, which is down from $20.8 million for the prior year. The decline in collaboration revenues primarily relate to three factors. First, a $5.6 million decrease in reimbursements from CureVac associated with the OTC collaboration that ended in the third quarter of 2019. Second, we received a one-time license revenue of 3.3 million from Synthetic Genomics in 2019. And finally, we had slightly lower activity with other collaboration partners. On a quarterly basis, total revenue for the fourth quarter was 2.2 million, which was relatively flat when compared to the 2.3 million in the third quarter. Total operating expense for the year ended December 31st, 2020 were $81.1 million compared to $46.3 million for the prior year. The current year operating expenses were partially offset with $15.2 million of funds earned under the Singapore vaccine grants and funds awarded by the CF Foundation. The increase in net expenditures for the year ended December 31st, 2020 as compared to the prior year, were due primarily to the increased activity in clinical and manufacturing expenditures related to the company's COVID-19 and OTC programs, as well as increased personnel costs and other facility costs related to the organizational growth of the company. On a quarterly basis, total operating expenses for the fourth quarter with $33.3 million compared to $23.3 million for the third quarter and $13.8 million in the same period of 2019. Approximately $8 million of the sequential increase in operating expenses was due to the ramp in the COVID-19 program related expenses, which included additional personnel, manufacturing, and clinical trial expenses. The current quarter operating expenses were partially offset with a $2.7 million of funds awarded under the Singapore vaccine grants and funds awarded by the Cystic Fibrosis Foundation. Our cash balance totaled $463 million as of December 31, 2020, compared to cash and cash equivalents of $301.1 million on September 30, 2020. The increase in cash and cash equivalents compared to the September quarter is primarily due to the receipt of approximately $162 million in net proceeds from our December 2020 public offering. Subsequent to the end of the year, we received a $46 million loan from Singapore EDB to help fund the manufacturing of our COVID-19 vaccine program. Based on our current pipeline, the company's cash position is expected to be sufficient to support operations for more than two years. A strong cash position enables us to fund our phase two and three clinical trials for ARC-21, as well as advance our additional promising pipeline candidates. We hope that ARC-21 will receive emergency use authorization later this year in one or more countries. Along with our global manufacturing partners, we have laid the foundation to produce hundreds of millions of doses of ARC-21 annually, and we have ongoing manufacturing campaigns to both meet clinical needs and to stockpile lyophilized ARC-21 for potential commercial use. I'll now pass the call back to Joe.
spk13: Hey, thanks, Andy. ARC Tourist has continued to make progress with our mRNA-based therapeutic platform and development stage pipeline. We believe we are on track to rapidly progress ARCTO21 into a phase three study and potentially gain emergency use authorization this year. We believe that ARCTO21 as a single administration investigational vaccine could have a differentiated profile to other available vaccines, positioning the product for potential widespread uptake in the years to come. We're also aggressively moving forward with our broader pipeline and anticipate reports reporting important clinical milestones from our other programs. We expect that later this year we will obtain initial safety, PK, and biomarker activity data from our ARCT 810 clinical study being conducted in patients with OTC, and we look forward to starting a Phase II multiple-dose study later this year. I've also been very pleased with the progress our R&D team has made in advancing ARCTO32 for cystic fibrosis. This program utilizing an aerosolized administration of our lunar lipid mediated mRNA technology demonstrates the breadth of potential application of our platform. Our aspiration with this program is to correct the core underlying deficiency seen in cystic fibrosis and to provide a meaningful new treatment approach for the tens of thousands of individuals living with cystic fibrosis. In addition to these advanced programs, our team is also working hard to apply our mRNA platform to develop vaccines and therapeutics for many other life-threatening diseases and we look forward to providing further updates on additional programs at a later time. At this point, we can go ahead and open the line for questions. Operator, please proceed.
spk02: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions. Our first question comes from Yasmine Rahimi with Piper Sandler. Please proceed with your question.
spk08: Hi, team. Thank you so much for all the great updates. A number of questions for you. The first one is directed to Dr. Uy. Dr. Uy, thank you for sharing the new data with us. Can you comment on if you looked at T cell responses post day 28? specifically maybe at least at day 60 and how those compare to BNT162B2. And then the second question is for Joe. Joe, can you maybe comment on if Arcturus is equipped and ready to go to incorporate new constructs to provide coverage of the variants in phase three? And then the third question is to you, will we be seeing the phase two data before you start commencing phase three? And thank you for taking my questions.
spk03: Great.
spk13: Thanks, Yaz. Professor Hui, the first one's yours.
spk11: Okay. Thanks very much. Those are great questions. Yes, we have looked at longer time points for ARCT021, you know, at day 28 and beyond, up to, I forget actual exact time points, but the work is actually in progress. I mean, the high-level summary is that you do see some level of contraction, which is normal for T cells as they switch into memory. But that will be something that we're also going to go and examine further in an open-label long-term follow-up, look at how well these memory responses will be elicited upon re-exposure to the antigen. clear though is that the levels both at the acute stage as well as at the contraction stage, in this case for BNT162b2 is at day 21, they are all quite a lot lower than what we've seen with ARCT021. Thank you.
spk03: Thanks.
spk13: Did you have a follow-up question for Professor Uyiyaz or would you like me to address your second question?
spk08: I guess just as he has maybe, if I may, can you elaborate on the contraction that he was referring to?
spk11: So, yeah, the contraction actually, when you have this acute exposure, you get a lot of expansion of the T cells, right? So that's the acute response. And then over time, then some proportion of which will switch over to become memory T cells, and then they hone into the lymphoid tissues or possibly even where the exposure of the antigen occurs, and in this case could well be the skin and muscles and all that, and mucosa. Then at that point when you measure the T cells in the blood, you see a contraction. But the important thing is that as long as these T cells can be rapidly recalled upon antigen exposure, it looks like there will be protection.
spk13: i hope that that answers the question i'm not sure whether it's a scientific question you're asking what is the amount itself um thank you um that was helpful i'll move on to uh joe yeah if you want to yeah yeah now with respect to variant coverage i mentioned earlier that we're closely monitoring and closely evaluating the covid variants that are potentially escaping or evading neutralizing antibodies that is in the literature and there's getting reports on those right but cellular immunity may provide broader variant coverage cellular immunity may actually be very important for resistant variants that evade these neutralizing antibody titers I refer you to Dan Barouch's work at Harvard Medical School you know he was quoted to say I'm just looking at my notes here but he was quoted to say that vaccine induced T cell responses are important for COVID vaccines, particularly for resistant variants that might partially evade neutralizing antibodies. So this is becoming a more well-understood and accepted principle that cellular immunity is important for resistant variants. So that's point number one. Now, having said that, even though ARCTO21, as just was shown by Professor Uy, generates a robust T cell response that may be broadly protective, If there is any variant that happens to escape our vaccine, then we're still a messenger RNA vaccine, and it's a readily updatable technology, and we can move quickly if needed.
spk05: Thank you, Joe.
spk08: And will we be seeing the Phase II data before Phase III?
spk03: Yes.
spk12: Steve, do you want to address that question? So we'll definitely be seeing the Phase 2 data before Phase 3. We've got some interim analyses that are going to be conducted fairly quickly and they'll go to our Data Safety Monitoring Board for review prior to finalisation of our Phase 3 dose. Depending on the nature of the evaluation will depend on whether it's worthwhile sharing as an update in any level of detail because we're conducting more than one interim analysis and they're looking at different things. Some are just looking at early safety responses, and then others are looking at immunogenicity responses. So it's quite likely that we'll issue something brief about the safety and something more detailed about the immunogenicity as that data reads out.
spk05: Thank you, Steve. Thank you. Our next question comes from Seamus Fernandez with Guggenheim.
spk02: Please proceed with your question.
spk07: Thanks for the question. So, a few questions here. First off, can you guys please talk about your solution to variants and how you're approaching that in the context of correlates of protection that are emerging, you know, with the FDA's guidance, the EU's guidance, and then some folks are implying that the WHO may come up with a standardized correlative protection that crosses vaccines. So just hoping that you would comment on your approach to variants and then the correlative protection. The second question is on your phase three trial design Can you just give us a sense of the size of the study and how you're planning to execute it? Would this be a head-to-head type study, a crossover study? Just give us a general sense of the size. Then I have a couple of additional questions.
spk13: Sure, Seamus. It's good to talk to you. This is Joe. You too. Thanks, Joe. Plan A with respect to variants, just to reiterate, is that our present vaccine, because of the cellular immunity profile, is sufficient to capture or cover any variants that are out there. If there are variants that are challenging or escape or evade protection with our vaccine, we're preparing. We mentioned we're not only monitoring but evaluating the variants that are that are escaping these neutralizing antibodies and will be well-positioned to swap out any manufacturing run with an upgraded variant if needed. Does that address your question?
spk07: I guess the question is sufficient to cover in what way, though, Joey? There's a number of different approaches that we're talking about, disease prevention, prevention of severe disease. There's a lot of different ways to define that.
spk13: Right, I understand. Steve, do you want to give the first crack at that?
spk12: Yes, I think there's a couple of parts in answer to the question. One is the FDA very recently, I think within the past week, has given updated guidance that includes specific appendix on how to bring forward new vaccines or variations on existing vaccines for emerging variants. And then the second piece is effectiveness of the current vaccine against emerging variants. So maybe just dealing with the second piece first, which is really you need to conduct a clinical trial with efficacy-based outcomes in order to address that. And then people that have been vaccinated that end up contracting COVID, then actually sequencing the virus that they've got to see whether it's a variant or not. And that can give you an idea of whether you have active... adequate coverage for all of the variants or whether there's one or more particular variants that are escaping your vaccine. And we intend to do that. The second piece is being able to rapidly pivot with your vaccine platform to cover new variants. And we're seeing some of this with the other mRNA vaccines at the moment where they're rapidly retooling, manufacturing a vaccine with a slightly different sequence and then taking that forward into early phase clinical trials to generate immunogenicity data, which then hopefully can be used to show activity against the variant. In order to really go down that route, which is the route that's been put forward by the FDA, you require efficacy data from your vaccine platform. So we're moving aggressively forward with our phase three clinical trial that will generate the body of efficacy data that we need to then to be able to then very, very rapidly pivot to utilize that data to fast track subsequent vaccines if they're necessary. And at this point, we don't know whether we're going to need different vaccines for at least the variants that are out there at the moment. We believe that the T cell coverage that we're seeing with our vaccine positions us well for coverage against all of the variants. But if it turns out that we do need additional coverage, then we can leverage the clinical data that we'll have from our phase three program that we're about to kick off to very rapidly bring forward new variants based upon immunological correlates of protection as they emerge.
spk04: Great.
spk07: And as we look at the design of the phase three, can you just help us understand, you know, there are different points in time from where you can start counting events, a number of the you know, sort of two-dose companies certainly seem to benefit from that quite a bit in terms of the disclosed and sort of trumpeted efficacy. As we think about design of phase three and the endpoints and your discussions with the agencies in the countries that you're going to pursue, can you just give us a sense of how you're going to execute your phase three study?
spk12: Yeah, sure. So it's going to be a randomized study. placebo-controlled study, so I'll compare it to placebo. It will be a one-to-one randomization, the same as the other studies, or most of the other studies at least, that have moved forward and got emergency use authorization or conditional approval at the moment. It's going to be several thousand participants in the region of 10,000 to 15,000, and it's going to be several different countries. We're not disclosing the actual countries at the moment because we're going through the process of discussion with the regulators and doing feasibility at individual sites to choose from our short list the countries that are most tractable for a rapid study startup. But in general terms, we're looking at countries that have a high incidence of COVID at the moment so that we can collect events quickly, that have a very short regulatory approval process in terms of approving the clinical trial startup, and also countries that have a low vaccine penetrance and are predicted to continue to have a low vaccine penetrance at least through the first four to six months of the study that allows us to collect all of our events that are needed and the safety follow-up that we require to get registration. I think it's inevitable that after a period of time participants that have been vaccinated with placebo are going to have to cross over and we've seen that with the studies that have where they've already got emergency use authorization they're now allowing crossover but the important thing is that we don't cross over until we've collected all of our events and that's what we're planning at the moment great and maybe just as a one follow-up question in terms of just the phase two study data that you guys know so far
spk07: Can you just give us an update on, you know, how many patients have been dosed? You know, is the safety actually known to the team, and is it unblinded? And is there anything that you would comment on with regard to the Phase 2 study? Thanks.
spk12: So, I can tackle that question as well. So, we've vaccinated over 500 people at the moment. I don't have the most up-to-date figures from today, but it was definitely over 500 as of Saturday. No dosing was performed on Sunday. We haven't unblinded the data at the moment, but we do have a safety review committee that is actively looking at the data in an ongoing fashion, but in a blinded fashion. In broad terms, we haven't seen anything in the Phase 2 data that is markedly different from what we've seen in our Phase 1-2 study. Although, of course, we're blinded to dose, so we don't know what's happening at the different doses. But at a very high level, the data looks very similar to what we've seen in the Phase 1-2 study.
spk07: Okay, great. And this will be my last question. Any second doses? Have any of the second doses been executed in the study as yet? Yeah. Or is it still too early?
spk12: Yeah, so a number of people have received a second dose already. I don't have that number to hand at the moment, but it's more than a few. And even with the second dose, we're not seeing anything remarkable.
spk05: Okay, great. I'll jump back in the queue. Thanks. Thanks, Seamus.
spk02: Thank you. Our next question comes from Nick Abbott with Wells Fargo Securities. Please proceed with your questions.
spk05: Hey, Nick.
spk06: Hi, guys. It's Joe on for Nick. Congrats on all the progress and appreciate you taking the questions. Two from us, you know, maybe just further on the phase three design, without disclosing specific countries, you know, how do you think about site distribution in terms of major geographies? I'm assuming it's primarily ex-U.S. and, you know, what consideration will be given to you know, the prevalence of variant strains within the countries you select. And then, you know, beyond that in the phase three design, you know, to what extent do you intend to characterize the T cell immunity component to the story? And then secondly, you know, on the recent licensing deal with Alexion, you know, is there any additional detail you can provide in terms of the specific technology that was licensed and you know, if and when you expect the technology will be transferred to your manufacturing partners, and could this technology potentially accelerate your prior guidance of, you know, hundreds of millions of doses annually?
spk03: Great questions.
spk13: The first one will be addressed by Steve, and then I can handle the Alexion question.
spk12: Okay. So, thanks. All great questions. With regard to the Phase III study, We're focusing on geographies where we can do placebo-controlled clinical trials and where the COVID incidence rate is high. We're not focusing so heavily on emerging variants because it's difficult to predict and stay ahead of that. So, for instance, the UK variant has a relatively low prevalence in the United States at the moment but is predicted to be a dominant strain by the end of March based upon some models. And that timeframe would obviously be within the timeframe for recruiting a clinical trial. So trying to stay ahead of the variants I think is futile. So we'll just have to manage that within the clinical trial. And as we said, we're confident that because of the strong T cell responses that we're seeing, that we are going to actually have good coverage against the variants. In terms of the last part of the phase three clinical trial question, would you mind just repeating it?
spk06: Yeah, just in terms of, you know, to what extent, you know, will you measure and characterize the T cell immunity component to the story?
spk12: Yeah, so I think in the phase three study, that's more challenging. And we are doing more T cell work in our phase two study. So the additional T cell data is going to be coming out. Our partner that's conducting the lab work is just in the process of validating those assays at the moment. So we'll be able to provide the results of that in due course. In the phase three study, we're not currently planning to conduct any more T cell analysis. I don't think it helps us very much to get beyond the body of T cell work that we'll have by then.
spk03: Great.
spk13: With respect to the second question, the exclusive license that we acquired from Alexion helps us with the technology to support are highly efficient processes to manufacture high purity mRNA vaccines. Arcturus has three franchises, not just the vaccine franchise, but also a liver and a lung franchise. And these liver and lung areas are systemically or inhaled administrations of messenger RNA, which require a higher barrier of purity. And it's of extreme importance to have high purity messenger RNA to support those programs. But having said that, we've applied the Selexion IP to the ongoing programs, including our vaccine program. And will this provide advantages? Absolutely, with respect to more efficient processes and higher purities, which is applicable not only to our liver and lung programs, but of course also of importance to the vaccine program as well.
spk06: Great. Thank you. And, you know, in terms of has this technology already been implemented or at what point do you expect it to be transferred to manufacturing partners? I mean, is it conceivable to think that it will be involved in the manufacturing runs for phase three or is it more down the line looking at commercial supply?
spk09: Yeah, I guess, Pat, why don't you start? Yeah, no, thanks for that question. Yeah, so we're obviously, we've been in discussions with Alexion for quite a while to evaluate the specific technology, and we've evaluated that in-house, and we believe these processes can be adapted for our future batches. So that is correct. And these can, as Joe mentioned, these will be implemented for our protein replacement applications, but this can definitely be used for our commercial batches of COVID as well.
spk06: Great. Very helpful, guys.
spk05: Thank you, and congrats again on the progress. Thanks. Thank you.
spk02: Our next question comes from Yigal Nachomovitz with Citigroup. Please proceed with your questions.
spk14: Hi. Thanks. I have two questions. The first one, with respect to this pending Phase II data, what do you need to see in that data that will provide additional confidence that you selected the 5-microgram single-dose regimen? And conversely, what data from the phase two would make you revert to the two-dose regimen as well as potentially the seven and a half gram microgram dose? And then separately, could you just comment on what's different about your technology that allows for lyophilization in contrast to the other mRNA vaccines already commercialized that have the liquid formulation?
spk03: Thank you. Steve, do you want to address the first?
spk12: Okay, sure. So primarily, we're just looking for confirmation of the safety data readout from the Phase 2 study. We are collecting immunogenicity data as well, but our first readout as we move towards Phase 3 is going to be based upon safety. Since we disclosed data back in November and again in December, we've had subsequent internal reads on the data that give us a lot of confidence that the 5-microgram dose is really a sweet spot for us. And also that dose is the one for which, at least in the Phase 1-2 study, we have most exposures and most information. So we think we have sufficient data from the immunogenicity perspective to confidently select that dose. So we're primarily looking at safety data readouts in the first instance. We're also going to have a later immunogenicity interim analysis that allows us to rapidly switch tack if we need to down the road.
spk13: And just if I can interject, Steve, the likelihood of us proceeding with the two-shot vaccine is very low. Like I mentioned in the introductory comments, that in the endemic phase of COVID, we believe that it's all going to be single administrations. Whether these are unvaccinated people, whether they're COVID survivors, whether they're viral vector recipients or messenger RNA vaccine recipients, They're all just going to want a single administration, whether it's a boost or a single injection format. So we're fully intending or planning on collecting our phase three data as a single shot. And we're very encouraged by Professor Uy's recent data to show that our vaccine compares favorably. Oh, and then with respect to the second question, Padraig.
spk09: Sure. You know, we've been working on where's the lyophilized messenger RNA for quite a few years. We first introduced that for our protein replacement applications. And since we had the platform already working for our protein replacement applications, we decided to implement that for the COVID-19 vaccine. There's some specific know-how that goes into the lyophilization of lyophilized nanoparticles containing these, especially these large messenger RNA. But because we started our program a few months after some of the other leaders, during that interim time, we were able to develop a LiO program and implement that into our phase three.
spk13: Yeah. So the phase three study will be evaluating our lyophilized version of our vaccine. And we think this will be very important. especially for countries that have challenges with respect to just distributing frozen liquids. Forget about the cold chain. Just the challenges associated with something that once it's melted, it has to be utilized in the case of a freeze-dried product that you don't incur those challenges of distributions.
spk05: Got it. Thank you. Thank you.
spk02: Thank you. Our next question comes from Wang Chi Lin with Leidenberg. Please proceed with your question.
spk15: Hi. Thanks for taking my question. Maybe just first to follow up with the localization, could you further clarify how you've done any bridging study at this moment, or will you do a bridging study to compare the current version before the start of Phase III?
spk13: Will we need any bridging studies, Steve? Maybe you can comment. Is that what your question is, Wangzi? Yes.
spk09: I can touch on that. Wangzi, one of the things that when we started to develop the Lyo formulation is we wanted to first look at analytical comparability, of course. We wanted to ensure that pre- and post-reconstitution, the particle size, the characteristics were similar between our frozen liquid formulation and the Lyo product. That was one of the key parameters that we evaluated first. And then the second piece was looking at immunogenicity. We wanted to ensure that we were seeing similar immunogenicity in our preclinical studies for our frozen product as well as our, you know, lye product. And we've collected that data set, and now we're comfortable with moving forward with our phase three based on that data.
spk15: Okay, got it. That helps. Thank you. Then maybe also a question for Dr. Owee, just a clarifying question about the new data, very encouraging. In the press release also mentioned that the PRNT increased to 100% by day 36, and then on day 28, 59%. So maybe just a Clarifying question, how do you compare this with the PRND 50? I mean, the definition of 50, I guess, is neutralizing 50% of the virus, right? 59% doesn't mean neutralizing 59% of the virus on day 28. How, maybe... If we convert this into PINT50 so that we can compare with the previous data, can you help me with that? How do we compare this with the prior data?
spk11: That's a very good technical question actually. So the 59% is the prevalence of the proportion that test positive. So the way we did it though was slightly different. So for ARCT021, Our minimum dilution was 1 in 20, so we started at a 1 in 20 dilution, whereas for BNP162b2, we started at a 1 in 10 dilution, because we're giving it a little bit more opportunity to detect these antibodies because it's much earlier. So that's that one difference there, but you're right that actually the Another important number is the titer itself, the amount of antibody as measured by this thing called PRNT50. That basically just means that the highest dilution you can go where 50% of the virus that you put in will be neutralized. The reason why we use 50% is simply because if you do this from 0 to 100%, then the curve appears as a sigmoidal curve. And 50% is the linear part of that curve. So if you go down or you go higher up, then you start to lose that linearity. And then it becomes less sensitive. So that's the reason for using 50%. But I just want to add one more point. Right now, it's difficult to interpret the titer because we still lack a correlate of protection. We don't know if it's 1 in 10, it's 1 in 20, or it's higher. But that's why we thought it was important for us to look at the onset of efficacy from the BNT162B2 trial to understand what actually started the protection. And our findings actually are very consistent with the phase 1 data, where even the Pfizer and BioNTech could not detect neutralizing antibodies at such an early point. So I think everything is all coming together to suggest that you can get protection from other elements of the adaptive immune response beyond neutralizing antibodies.
spk15: Great. Thanks for the clarification. Very helpful. My last question is maybe also on the new variants, Ron. Have you done any preclinical evaluation just in terms of T cell response? You maybe discussed it earlier. It's challenging, but any, so far, any data or preclinical work on the T cell response against the new, any of the new variants with the current vaccine?
spk13: Yeah, preclinical evaluation. Pat, why don't you go and address that question?
spk09: Sure. No, of course, as Joe mentioned, you know, that's something that we're actively evaluating, and we hope to share the data in the near future. But that's something that we're definitely considering and collecting.
spk15: Okay, great. Thanks for taking my question, and congratulations on all the progress.
spk05: Thank you, Wangzi.
spk02: Thank you. There are no further questions at this time. I would like to turn the floor back over to Joseph Payne for any closing comments.
spk13: Hey, thanks, everyone. It looks like our time's up, and we're going to be closing the call, but feel free to reach out to our team, as always, if you have any follow-up questions. We will be as efficient as we can in our responses, and bye for now.
spk02: This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation. Have a great day.
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