Arcturus Therapeutics Holdings Inc (ARCT) 2020 Q2 法說會逐字稿

Greetings and welcome to the Arcturus Therapeutics' Second Quarter 2020 Earnings Call. (Operator Instructions) And as a reminder, this conference is being recorded, Monday, August 10, 2020.

I'd now like to turn it over to Neda Safarzadeh, Head of Investor Relations, Public Relations and Marketing. Please go ahead.

Thank you, operator, and good afternoon, everyone. We are joined today by Joseph Payne, President and CEO; Andy Sassine, CFO; Dr. Pad Chivukula, CSO and COO; and Dr. Steve Hughes, our Chief Development Officer.

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 IND application, the CTA approval, the strategy, future operations, the status of preclinical and clinical development programs, the planned initiation 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 Factors in Arcturus' annual report on Form 10-K for the fiscal year ended December 31, 2019, filed with the SEC on March 16, 2020, and in subsequent filings with or submissions to 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. Joe, please go ahead.

Hey, thank you, Neda, and good afternoon to all, and thank you for joining Arcturus' quarterly call today, which today also happens to be Andy Sassine's birthday, our CFO. So wow, what a quarter today, it's been. Arcturus has made tremendous recent corporate progress, highlighted by the progress of two clinical programs. ARCT-021, which is our COVID-19 STARR mRNA vaccine candidate and ARCT-810, our OTC deficiency program. The company has matured into a clinical-stage company, focused on the development of infectious disease vaccines and significant opportunities within liver and respiratory rare diseases. Our corporate progress is highlighted by the advancement of ARCT-021 and ARCT-810 into clinical studies. I'd like to provide an overview highlighting why we're so excited about each of these programs.

I'll begin with ARCT-021, which is also known as LUNAR-COV19. Our COVID-19 vaccine utilizes Arcturus' self-transcribing and replicating mRNA technology, which is trademarked as STARR. And the STARR mRNA is delivered with Arcturus' lipid-mediated delivery system called LUNAR, which is also a registered trademark. By combining these 2 technologies, we're developing an extraordinary potential vaccine product for this extraordinary pandemic with our partner Duke-NUS Medical School. And these technologies, when combined, and based on what we have seen in preclinical testing, may provide an improved safety and efficacy profile in the clinic. This clinical candidate has the potential to be an effective and well-tolerated vaccine with a highly differentiated profile characterized by a very low dose and a potential single-shot administration.

We may observe a lowered incidence of ISRs, or injection site reactions, due to the anticipated low dose of ARCT-021, and we may observe improved efficacy and durability of the vaccine since we observed robust humoral and cellular immune responses in our preclinical studies, particularly with CD8 T cell induction. ARCT-021 is supported by a strong preclinical package. We've demonstrated a robust cell-mediated immune response, including CD8 T cells and a balanced Th1/Th2 response following a single administration of ARCT-021. We have seen a strong antibody response, resulting in potent virus neutralization at a very low vaccine dose, again, after just a single administration. Further, neutralizing antibody titers continue to increase out to 60 days after dosing. Our vaccine is beautifully simple, completely devoid of viruses. There's no viral vectors, no adjuvants or no co-adjuvants. The Phase I/II study of ARCT-021, which we're conducting in up to 108 healthy volunteer adults in collaboration with Duke-NUS Medical School, has initiated screening, and we anticipate dosing the first cohort imminently within the next few days. This study will evaluate safety and immune response of the vaccine in both young and older adults.

We continue to advance our COVID vaccine manufacturing activities. We successfully completed the technology transfer processes and providing sufficient vaccine product to support our clinical studies. Our process is now proven and serves as a foundation to support larger manufacturing campaigns to come. With our manufacturing partners, Arcturus is now well positioned to manufacture millions of doses in 2020 and potentially hundreds of millions of doses annually thereafter.

We recently signed a binding term sheet with the Israeli Ministry of Health to supply ARCT-021, and we are pleased with the progress we have made towards the definitive supply agreement, which is expected to be completed shortly. Israel is the second country in addition to Singapore to reserve supply of Arcturus' COVID-19 vaccine. Discussions with additional countries pertaining to stockpiling and supply agreements continue to progress.

Now moving on to ARCT-810. We continue to advance our Phase I ARCT-810 clinical study in healthy volunteers. ARCT-810 is being developed for ornithine transcarbamylase deficiency. It's a serious disease with limited treatment options. ARCT-810 utilizes Arcturus' LUNAR lipid-mediated delivery platform to deliver OTC messenger RNA to the liver. Expression of ornithine transcarbamylase enzyme in the liver of patients with OTC deficiency is expected to restore normal urea cycle activity and potentially prevent neurological damage and the need for liver transplantation.

I'd like to remind all on the call that ARCT-810 is a program that's been supported by strong preclinical data in OTC deficiency murine models, demonstrating that dosing of LUNAR OTC results in robust ornithine transcarbamylase protein expression and activity, resulting in improvements in ureagenesis and plasma ammonia, and increased survival. Our OTC program is now in the clinic, now 2 months into the Phase I study and no infusion-related reactions have been observed. No steroid pretreatments have been required. So we are understandably excited about the progress being made for our flagship intravenously dosed mRNA therapeutic.

Steve will provide more details pertaining to our clinical programs for both ARCT-021 and ARCT-810 later in this call. We've also recently initiated 2 new programs, LUNAR-FLU and LUNAR-CV targeting influenza and cardiovascular disease, respectively. Influenza vaccines and familial hypercholesterolemia are significant commercial opportunities, and we believe our technology is ideally suited to address each condition.

Driving our R&D engine certainly requires significant resources, and the company has been very successful in raising approximately $280 million in gross proceeds this year to enable us to advance our promising therapeutic programs, and Andy will provide more detail in a few minutes.

In addition to the progress we have made in our R&D pipeline, we have strengthened our leadership team and appointed Lance Kurata, as our Chief Legal Officer. Lance is a nationally recognized leader in corporate and life sciences transactions. Lance joins us from Mintz, where he was a partner in the corporate group and a member of the life sciences practice group. Lance is recognized across the life sciences legal profession as a leading biotechnology-focused attorney with transactional and intellectual property expertise. I'm certainly pleased to welcome him to the company.

We have also added Dr. Kelly Lindert, who has agreed to lead our vaccine franchise, including our COVID-19 and influenza vaccine programs. We're thrilled to have her join our team. Dr. Lindert joins us from Moderna. And prior to that, she led the influenza vaccine development at Novartis. We expect the remainder of the year to be a very exciting period for Arcturus. We look forward to obtaining initial clinical data from our 2 development stage programs, ARCT-021 and ARCT-810.

I'll now pass the call to Steve to provide more detail on our ongoing clinical programs. Steve, on to you. You might be on mute.

Thanks, Joe. Yes, I was on mute. I'll start with ARCT-021, our vaccine candidate for COVID-19. To remind you, ARCT-021, we selected a self-replicating mRNA that encodes the full-length, unmodified, spike protein after a comprehensive evaluation of multiple candidates expressing different modifications and different domains of the spike protein in a preclinical screening process as well as assessment of both conventional mRNA and self-replicating mRNA versions.

Our preclinical data has demonstrated both robust neutralizing antibody response and a cellular immune response with the single administration at low doses. We have seen 100% data conversion with a single low 2 microgram dose in our animal studies and a robust CD8 and CD4-plus response with a pH1 biopsy helper response. These data have enabled accelerated discussions with the Singapore Health Sciences Authority, allowing us to move rapidly into clinical studies. The ongoing Phase I/II study is being conducted in close collaboration with Duke-NUS Medical School in Singapore. The study includes 2 parts. In Phase I, escalating doses will be administered as a single injection to younger adults, age 21 to 55 years old. And then in the Phase II parts, selected doses will be tested in a larger number of younger adults as well as in older adults greater than the age of 55. The study has commenced screening, and we anticipate dosing of subjects imminently.

We're looking forward to obtaining initial clinical data in the Q4 time frame. And with favorable data, we plan to rapidly transition to initiation of late-stage clinical trial.

I'll now transition to discuss the ARCT-810 program. Our ongoing Phase I study is being conducted in 30 healthy volunteers in New Zealand. In this study, we are evaluating 5 dose levels of ARCT-810. We have completed dosing of the first 3 cohorts with no significant adverse events, no clinically significant changes in lab values and no infusion-related reactions, despite the fact that no steroids premedication is being given. Dosing with the fourth cohort will occur this week, and we expect to complete the study by year-end. Phase Ib study, which is being conducted in OTC-deficient patients at multiple sites in the U.S. is on track to start screening the first subject in September. In this study, we plan to evaluate 3 dose levels with all dose levels selected to be therapeutically relevant based on our preclinical data. In this study, all subjects will remain on background therapy and dietitians will help guide the subjects' diets. Phase Ib study will evaluate multiple biomarkers and other exploratory endpoints, including ureagenesis, plasma OTC activity, plasma ammonia and orotic acid in the urine.

Finally, for our cystic fibrosis program, we have promising data showing that our LUNAR delivery platform technology is able to effectively deliver messenger RNA to bronchial epithelial cells in the rodents, pellet and nonhuman primates and this mRNA is effectively translated into CFTR protein that is expressed on the cell surface. And we look forward to selecting a development candidate later this year and filing an IND in 2021.

I'll now pass the call on to Andy.

Thank you, Steve, and good afternoon, everyone. I would like to thank our existing shareholders for their support, and I would like to welcome all of our new institutional investors to this call. A number of highly new sophisticated biopharma investment fund became new shareholders in Arcturus as part of our recent public offerings. On behalf of the management team and the Board, we are grateful for their investment and validation, which helped us raise approximately an additional $200 million last month. Without the support of our existing and new shareholders, we would not have been as successful with our raise.

We have obtained a very strong and diversified shareholder base through our recent public offerings, including our April offering. The combined capital raises of approximately $280 million will provide essential resources to enable the company to advance its pipeline and continue driving shareholder value. The press release issued earlier today includes financial statements for the second quarter of fiscal year 2020, which I will briefly summarize.

Arcturus' primary source of revenues is currently from license fees and collaborative payments received from research and development arrangements with our pharmaceutical and biotech partners. For the second quarter of 2020, the company reported revenues of $2.3 million, compared with $10.2 million in the 3 months ended June 30, 2019. The primary reason for the decline in collaboration revenues primarily relates to a $3.1 million decrease in reimbursement from CureVac associated with the OTC collaboration that ended in the second quarter of 2019. Additionally, in the 2019 quarter, we recorded a onetime sublicense revenue of $3.1 million related to our Synthetic Genomics agreement.

Total operating expenses for the 3 months ended June 30, 2020, were $12.4 million compared with $10.7 million for the same period of 2019. The current quarter operating expenses were partially offset with $3.8 million of funds earned under the Singapore vaccine contract and approximately $1 million in funds awarded by the CF foundation.

Our cash balance totaled $136.1 million as of June 30, 2020, compared to cash and cash equivalents of $71.4 million at December 31, 2019. Subsequent to the end of the quarter, the company added net proceeds of $186 million from our successful public offering at $53 per share. Our pro forma cash balance, including the subsequent raise, would have been $322.4 million. Based on our current pipeline, the company's current cash position is expected to be sufficient to support operations for more than 2 years. We continue to add highly regarded biotech institutional investors to a strong shareholder base from our recent public offering, and we are comfortable with our current cash position. We believe the company has the resources needed to drive our pipeline forward to achieve several meaningful value creation milestones.

I would like to provide an update on our manufacturing progress for our COVID-19 vaccine ARCT-021. We have previously discussed the importance we have placed on ensuring we have the manufacturing capacity to meet the anticipated demand of our vaccine. And in May, we expanded our base by entering into a manufacturing partnership with Catalent, a leading producer of advanced biologic products. We have successfully completed the planned technology transfer to Catalent and plan 30-gram batch of drug substance. Our manufacturing activities have been proceeding to plan, and we continue to expect to have the capacity to produce millions of doses of ARCT-021 this year and hundreds of millions of doses of ARCT-021 annually thereafter. For more details, please refer to our 10-Q, which will be filed shortly.

I'll now pass the call back to Joe.

Sure. Thanks, Andy. It's definitely been a remarkable period of progress for Arcturus. And before we just proceed with Q&A, I think we got some feedback that during Steve's portion of the call that it was difficult for him to hear. So we've been asked by a few investors, if you could reread the script that he just went through. So if it's okay, Steve, if you can give it a second, and hopefully, the connection will be a little bit clearer at this time. All right, Steve, and then we'll proceed with Q&A thereafter.

Okay. No problem. Can you hear me better this time?

Yes. It's great. Thank you.

Yes.

Okay. Yes. I've unplugged my headphones and put some different ones in. So apologies for just now. So I'll start again. So starting with the ARCT-021 program or vaccine for COVID-19. With ARCT-021, we selected a self-replicating mRNA that encodes the full-length, unmodified, spike protein after a comprehensive evaluation of multiple candidates expressing different modifications and different domains of the spike protein in a preclinical screening process as well as an assessment of both conventional messenger RNA and self-replicating messenger RNA versions.

Our preclinical data has demonstrated both robust neutralizing antibody responses and a cellular immune response with a single administration at low doses. We've seen 100% data conversion with a single low 2 microgram dose in our animal studies and a robust CD8+ and CD4+ response with a pH1 biopsy helper response. These data have enabled accelerated discussions with the Singapore Health Sciences Authority allowing us to move rapidly into clinical studies. The ongoing Phase I/II study is being conducted in close collaboration with Duke-NUS Medical School in Singapore. The study includes 2 parts.

In Phase I, escalating doses will be administered as a single injection to younger adults, age 21 to 55 years old. In the Phase II part, selected doses will be tested in a larger number of younger adults as well as in older adult cohort greater than 55 years of age. The study has commenced screening, and we anticipate dosing of subjects imminently. We are looking forward to obtaining initial clinical data in Q3 or early Q4. With favorable data, we plan to transition rapidly through initiation of our late-stage clinical trials.

I'll now transition to discuss ARCT-810. In the ongoing Phase I study, we are enrolling 30 healthy volunteers in New Zealand. In this study, we're evaluating 5 dose levels of ARCT-810. We have completed dosing of the first 3 cohorts with no significant AES, no clinically significant changes in lab values and no infusion-related reactions, despite the fact that no steroid premedication is being given. Dosing of the fourth cohort will occur this week, and we expect to complete the study by year-end.

The COVID situation in New Zealand is under control, and there haven't been any local cases for over 100 days now, which means that we don't anticipate any difficulties in completion of the rest of the study. The Phase Ib study, which is being conducted in 12 OTC-deficient patients at multiple sites in the U.S. is on track to start screening the first subject in September. In this study, we plan to evaluate 3 dose levels with all those levels predicted to be therapeutically relevant, based upon our preclinical data. In the study, all subjects will remain on background therapy and dietitians will help guide the subjects' diets. Phase Ib study will evaluate multiple biomarkers and other exploratory endpoints, including ureagenesis, plasma OTC activity, plasma ammonia and orotic acid in the urine.

Finally, turning to our cystic fibrosis program. We have promising data showing that our LUNAR delivery platform technology is able to effectively deliver messenger RNA to bronchial epithelial cells in the rodents, pellet and nonhuman primates and that this messenger RNA is effectively translated into CFTR protein that is expressed on the cell surface. And we look forward to selecting a development candidate later this year and filing an IND in 2021.

I'll now pass the call on to Andy.

Well, it's fine to come back to me. This is Joe. Thanks, Steve. And clearly, we have exciting milestones ahead and clinical data readouts anticipated later this year. We look forward to continuing to provide you with updates on our progress.

And operator, I think now is an appropriate time to open the call for questions.

(Operator Instructions) The first question is from Seamus Fernandez from Guggenheim.

Great. Thank you for repeating the script. Joe, I guess, from my perspective, if you could just -- can you help us understand a little bit, a couple of things. Number one, I think the prospect of having a single dose is something that is particularly attractive and would be helpful to just talk a little bit about how your construct could actually achieve that? And then separately, can you just help us understand a little bit better that you said that timing will be imminent for dosing. Just hoping to get a little bit of a sense of some brackets around that, it's imminent this week. And then finally, can you just give us a general sense of when we see the data? How many patients' worth of data should we anticipate seeing? Is that towards the end of the third quarter and the beginning -- or beginning of the fourth quarter, I think, is what you guys said? So can you just clarify a little bit of what you would hope to incorporate into a press release or an announcement? And then I had one last question that I'll follow-up with.

Sure. Seamus, thanks for joining the call and for the questions. With respect to the word imminent, I actually looked at up prior to the call today in the dictionary, and it said very, very soon. So what does very, very soon mean, I use the vernacular of the next few days, but just stay tuned. It's very soon. And we -- so it's imminent by the true definition of the word with respect to dosing. With respect to timing of the data, what we're messaging is that weighty data will be provided in Q4. And you heard the language on the call today by Steve and the team that there may be some preliminary data in Q3, but the substantial data will be Q4.

With respect to addressing why this is potentially a first shot. I do have Pad with me, but I'll begin to address that question. Our vaccine contains 2 technologies, a self-replicating mRNA technology and a delivery system called LUNAR. If the self-replicating mRNA kinetics expresses the COVID-19 or the full link spike protein over a period of 2 to 3 weeks, so that extended duration of expression has shown in our preclinical dataset that neutralizing antibodies continue to increase for 60 days. You just do not see that data in any other vaccine, especially with our experience internally with conventional messenger RNA vaccines. So that extended durability or duration of action. May remove the requirement for a second shot because the kinetics continues to proceed. With respect to the delivery technology, how that delivery technology has been optimized for delivery to dendritic cells may play a role as well. But I'll leave it at that.

And just as a follow-up question. I know that you guys are just entering the safety study. Can you just give us a little bit of a structure for the trial, the dose escalation? And then where your preclinical studies would predict enough expression to really drive a robust immune response? I know we're seeing very low levels in your preclinical studies. But just wanted to get a little bit of -- if you could provide any color in that regard with regard to kind of what you would characterize as or think is likely to be the effective dose?

With respect to what's the effective dose, I can comment that the initial dose will be a single microgram, a 1 microgram dose, to initiate the study. But I'll -- Steve is on the call. I'll let him address the remainder of your question.

Thanks, Joe. Yes. So as I said, we're starting with a 1 microgram dose, and then we're dose escalating from there. The highest dose that we're testing is actually still lower than all of the other messenger RNA vaccines. So they have chosen for their Phase III dose. So we're escalating within the low single and low double-digit microgram range. So still very, very low doses. As previously stated on, I think, in the last earnings call, we were anticipating the therapeutic effect is going to be somewhere in the 1/10 microgram range. And that's the dose that we're hoping to take forward into subsequent clinical trials. But until we've tested the dose range and seen the responses in humans, it's difficult to comment further than that. Does that answer your question?

Yes. No, that's great.

The next question is from the line of Madhu Kumar with Baird & Co.

So starting out with ARCT-021. To what extent is the single dose robust versus the idea of doing a prime plus boost, but having a better safety profile from the existing messenger RNA vaccines? Like how do you think about those 2 possibilities and kind of both likelihood of one versus another and kind of potential for your vaccine for one versus another?

Well, based on -- yes, thanks for the question, Madhu. It's appreciated. This is Joe. I think it's important to realize that both of these scenarios that you highlighted could happen, right? But based upon the preclinical data that we've collected, the likelihood of each of them is reasonable. What we've seen preclinically is that a single administration was sufficient. And that's what every single bit of data we've collected has suggested. But if for whatever reason, there's subpopulations that do not respond, either as expected or due to some sort of immune suppression and some sort of subpopulation, we want to be prepared to have a shot plus booster for those individuals as well, whether it's the elderly or people with comorbidities, et cetera. So we are collecting single administration data and 2 shot administration in the clinic. But ultimately, which one are we focusing on, I think, both would be fantastic scenarios, we'd be happy with either. But the single administration, at least, we have to give that our best shot, no pun intended, because that would be very differentiating to all the other vaccines.

Okay. Joe, I don't believe that -- I believe the pun was intended. But secondly, these are the datasets we have out there, what do you think is a good both antibody like humoral clinical profile and T-cell clinical profile for a single shot? Like, what is the profile you would need to see to be like, yes, the single shot works for us.

Right. Well, you're seeing -- and I would fully expect additional vaccines as they enter the clinic that we're going to see a humoral antibody response. And this is what you've been seeing to date. But what we're not seeing from vaccines in the clinic is a strong cellular immunity response, especially with respect to CD8 induction. So focusing on humoral immunity, how we're different there is we've shown preclinically that our neutralizing antibody titers continue to increase over 60 days. That's different. So does that mean that we'll see the same thing in humans? We hope so, but we've got to prove that. Does it mean that we'll ultimately have higher neutralizing antibody titers than other vaccines out there? It sure could be, and we've got to prove that out as well. But what is even more differentiating is the robust T cell response, the CD8 response that we saw in our preclinical animal models and studies there. Because that is something we haven't seen to date with other vaccines. And if we see that, that means that a higher percentage of people will respond to this vaccine. So our efficacy rates go up. And it will also mean that the durability of the vaccine or the duration of the protection will extend as well. So that will be something that will be very interesting to learn as early as we can in this early clinical trial is that CD8 induction data, in addition to the growing and increasing neutralizing antibody data or the humoral immune response.

Okay. Great. And then a question for Steve. So thinking about the OTC program, so you haven't seen any ISRs, you haven't seen any need for steroids so far in healthy volunteers. Is there any reason to think that patients with OTC deficiency and then urea cycle disorders could have a different profile in terms of infusion reactions and a need for steroid regimen therapy as compared to healthy volunteers, such that there might be a difference that would require steroids in the course of treatment?

Thanks. That's a great question. No, there's no reason at all to believe that the patient population is going to react in a different way from the point of view of their immune system or the infusion. So we're confident that the data we're seeing in healthy volunteers in terms of the safety and tolerability of the drug will translate directly to the patient population.

Okay. And then from the healthy volunteer study, what kind of PK or PD assessments are being done? You mentioned in the patient study that you're looking at urea cycle and all that kind of stuff. What is being done in the healthy volunteers? Was there any data from that, that you feel could be interesting to you to kind of help give people a sense of how 810 is working ahead of data from the kind of the Phase Ib in OTC patients?

Yes. Again, it's a very good question. The -- in the healthy volunteer population, obviously, a lot of the factors -- all of the factors relating to the urea cycle are normal. So several of the biomarkers, such as urinary or orotic acid, et cetera, ammonia level, just aren't applicable. They're not going to change in a healthy volunteer because they're tightly regulated and urea cycle kicks up (inaudible). We are looking at ureagenesis. As we said previously, this is a single-dose study. It will be great if we did see something move, and that would be incredibly informative, and we're hopeful that we do see something move. But in our animal studies, what we saw was that the biomarker data improved with successive dosing over 4 or 5 doses administered. And so even if we don't see anything in the healthy volunteer study, that doesn't ring any alarm bells or anything. And similarly, in the patient population, we're going to expect biomarkers in a multiple-dose study to move more substantially than in a single-dose study. So it's quite possible that in single-dose studies, we just don't see enough of a bump to achieve statistical significance on the biomarker. Does that answer your question?

But there's no way PK readout that you think would be meaningful from the healthy volunteer study in terms of just how good exposure you're getting kind of over time?

So we do have PK readouts from the healthy volunteer study in both plasma and urine while assessing PK. I'm not sure that anything from the PK is going to give us a really good idea of what the protein expression is like. We're trying to get a handle on that with some of the biomarkers. But for that particular biomarker, it's one that where we're working with a vendor to actually develop to give it enough sensitivity to be able to protect the changes in a normal person. That's the critical constraint for the healthy volunteer that everything is normal. So trying to see changes in a tightly regulated system in a normal person is challenging. But as yet, we don't have the biomarker data back. That's taking a little bit longer than the safety data to come out. So we'll have to provide you with an update on that at a later call, I think.

The next question is from the line of Wangzhi Li with Ladenburg.

My first question is about the COVID-19 vaccine, ARCT-021, I think, is now the new name. With the data, I think, that you expect in the fourth quarter this year, just to clarify, should we just expect dose-escalation data or we also include dose-expansion data?

Wangzhi, yes. So there is definitely a dose-escalation phase in this Phase I/II study that will then transition to a dose-expansion phase, and we encourage everyone on the call to look at clinicaltrials.gov as we update it periodically. So with respect, I guess, to rephrase your question, you're just trying to tease out when the data is going to come out, correct, Wangzhi?

Just wondering because you mentioned that we've got data in the fourth quarter, just clarify, is that just the dose escalation data or will it be both the dose-escalation and the dose-expansion cohort data?

Well, in terms of timing of the data, we are escalating the dose starting from 1 microgram. And if one of the early doses is very responsive, that would improve our time line into sharing that data. But if we simply want to complete the study and then share a more hearty, fulsome, data package, then there will be multiple dose levels evaluated and people can not only see the efficacy, but the dose response, et cetera. So right now, what we're messaging is Q4, in general, for a substantial dataset to be shared. But of course, there's always a scenario where the early doses are exceptional of material value, and we'd have to share those earlier. But just for conservative messaging, Q4 is what we expect for sharing the data package.

Got it. And a follow-up on that is, when do you compare both of the single dose and -- versus the double dose, either from the beginning at the dose escalation or is it more at the dose-expansion cohorts?

Well, we -- and Steve can feel free to fill in any gaps here, Steve. But we are working under the guidance of the Health Sciences Authority. They've been wonderfully collaborative, and they've allowed us considerable flexibility, much more flexibility than you would see normally. And what do I mean by flexibility is in terms of dose levels and modifying those at the same time. So -- but Steve, do you have anything else to add?

Yes. So I -- what I can say is that the dose escalation is entirely single doses. So as we move into the Phase II part of the study, that's where we start to evaluate some 2 dose cohorts as well. But we're planning to not repeat all of the same doses in the Phase II part. That isn't very economical in terms of finding more subjects (inaudible) select few doses into the expansion cohort to evaluate those in a greater number of subjects and in more detail.

Got it. Very helpful. Now the high level, just think about -- because -- you are doing the trial in Singapore at this moment, in Singapore, the pivotal trial, where else you can conduct this, just in Singapore or you will include other countries? And also, what's the regulatory path or requirement for you to get approval in other countries, for example, Israel or additional countries if you do the pivotal trial in those countries?

Yes. Go ahead, Steve.

So maybe if I take the questions in reverse order and thanks for asking. In terms of regulatory pathways in all countries are very, very low at this point in time. If you ignore Western China, I guess, where there's been some recent announcements, we're not really clear on what those regulatory approvals were based on. But in the countries that we're considering, the regulatory pathway involves conducting an appropriately sized clinical trial to demonstrate prevention of COVID-19 disease, and that's the same in all jurisdictions. The difference with Israel and Singapore and some other regulators is that some of them will look favorably and give you a more rapid path to approval if you already have approval in, for example, Canada or the United States or Europe. So they have a particular regulatory mechanism that allows for approval (inaudible) give you a quicker approval process. In terms of our late-phase development, our Phase III clinical trial will be conducted in multiple different geographies and multiple different jurisdictions. And those will be selected primarily closer to the time at which we initiate because it requires using countries and areas where there's a substantial presence of COVID-19, so that we can enroll the study quickly and get the number of events required within a reasonable time frame to get to a fast legislation. Does that answer your question?

Yes, that's very helpful. And then maybe lastly on the ARCT-810 OTC program. Just curious for the PK, you mentioned earlier, what do you exactly look at for the PK is the component of the lipids or the messenger RNA cells in the blood? Or what do you look at for the PK?

Well, we're not measuring PK in the vaccine. So vaccine is given at -- our vaccine is given at such a low dose that there is not really a lot of point in measuring the PK, which was measured in systemic exposure, which we know is going to be extremely low as compared to the ARCT-810 program. So in the ARCT-810 program, we're measuring the PK.

Sorry, I mean, for the OTC program.

Okay. So yes, so for the OTC program, we measure both the ionizable lipid as part of the nanoparticles, and we also measure messenger RNA in (inaudible) urine, although it's not really possible to measure the messenger RNA in urine. So there we have been measuring the lipids.

Got it. And my last question is for the OTC program, when do you expect to start repeat dosing?

That's going to be sometime next year, we would anticipate just because we need to collate the results from the healthy volunteer study, selection doses and then go to the regulators with a clinical trial protocol. So as we previously said, the guidance for that is next year.

(Operator Instructions) And the next question is from the line of Steve Seedhouse from Raymond James.

This is Ryan Deschner, on for Steve Seedhouse. My question is that the self-replicating RNA and higher hurdle from a regulatory standpoint, safety database size or length of (inaudible) relative to a conventional RNA? And also, will you be benchmarking neutralizing data to a complex and 0 panel in the Phase I or Phase II studies in Singapore?

Good question. I'll address the first one. The self-replicating messenger RNA and concept has been known since actually the '90s. Some of the older generations of this technology has been evaluated in the clinic and is very familiar with a different approach using like a viral vector, for example. But -- so the agencies that we've talked with are very familiar with self-replicating mRNA. Ours is just an improved or next generation. So with respect to the second component of your question, Steve, maybe you can address that.

Yes, sure. Could you just remind me again what the second component was?

I was wondering if you will be benchmarking neutralizing antibody data of complex and 0 panel in the Phase I or II studies in Singapore?

Yes. So as with the other published studies, we would intend to do the same thing. So that our dataset is interpretable alongside the others. So yes, that is our intention.

Okay. And then one last question. I wanted to know your take on the safety events that you're seeing across these Phase I mRNA studies in terms of fever, which wasn't seen in (inaudible) protein-based vaccine and also Pfizer and BioNTech [sort of a] better safety for their second vaccine, Canada is going into Phase III. Do you think it's possible to modulate mRNA-based vaccines to reduce safety events? And how would you (inaudible) doing that?

Well, I can initially respond to that question with respect to expectations around safety. We believe that a substantially improved safety profile will be related directly to the amount of RNA and the amount of lipids that are injected. In other words, the dose level. And because the self-replicating mRNA technology combined with LUNAR has shown to be efficacious at very low doses, if we can repeat that in human clinical trials, then the dose level would be much lower, which means the lipid burden and the RNA burden would be lower and the undesired immune responses to those entities would be far less likely because the dose is much less. With respect to other aspects of the vaccine, I remind people that our vaccine is devoid of adjuvants and devoid of viruses and viral vectors as well. So we have much less to be concerned about with respect to tracking over long periods of time in the clinical trial.

The next question is from the line of Mayank Mamtani with B. Riley Securities.

This is Justin Zelin, on for Mayank. Congrats on all the progress here. I had 2 quick questions on 021. First, could you speak to publication plans for any preclinical data on 021's potential to generate sterilizing immunity or reduce viral transmission? And secondly, could you provide any color on the Israeli Ministry of Health Agreement in terms of the range of doses applied and what the implications are for discussions with other ex U.S. countries?

Okay. First of all, with respect to our cadence of data sharing and how we're going to share that data with respect to publications, we can look to what other companies have done with their other vaccines. We may share data initially in the form of a press release and then subsequent to that, in a peer-reviewed press release. We are collecting additional preclinical data in parallel with our human clinical trials here in Singapore. So we definitely intend to share this data in the cadence that you've seen with other companies do. With respect to the Ministry of Health or Israeli Ministry of Health, we just had a great experience with them. They had -- after we signed the binding term sheet with the country of Israel, they had a press conference where they clearly communicated to their citizens that the Arcturus deal is a significant one and a key part of their vaccination strategy that can potentially address a large portions of their population. So that's how they communicated it. And so I'm just reiterating their talking points from their press conference. But we also view it the same that it's a significant deal, that it can be very considerable. And any other questions?

That's great, Joe. I appreciate the color here. And congrats, once again, on the progress.

Thanks.

We're out of time for today. I'll turn it over to Joe Payne for any closing comments.

Just thanks to everyone for listening in. It looks at this point, we're going to close the call. Feel free to reach out as always, if you have any follow-up questions, and we will respond efficiently. Bye for now.

That does conclude the conference call for today. We thank you for your participation, and you can now disconnect your lines.