Arcturus Therapeutics Holdings Inc. (ARCT) Earnings Call Transcript & Summary

Greetings, and welcome to the Arcturus Therapeutics call. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce our moderator, Neda Safarzadeh, Director of Investor Relations. Thank you. You may begin.

Thank you, operator, and good afternoon, everyone. We are excited for this opportunity to discuss the allowance of IND and approval of Clinical Trial Application, CTA, for ARCT-810, a first-in-class investigational mRNA medicine to treat OTC deficiency. We are joined today by Joseph Payne, President and CEO; Andy Sassine, CFO; Dr. Steve Hughes, Chief Development Officer; and Dr. Pad Chivukula, CSO and COO. Joe will kick off the call with a high-level overview of Arcturus, then Steve will discuss the OTC clinical plan, and Andy will provide information on value proposition with respect to our potential COVID-19 vaccine. Finally, we will open the call to questions and answers. 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 or other products 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 end-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 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 submissions at the SEC. Except as otherwise required by law, Arcturus disclaims 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. I will now turn the call over to Joe.

Okay. Thanks, Neda. And to those listening in, it's good to be with you. Last week, we communicated that our COVID-19 vaccine, also known as LUNAR-COV19, is slated to initiate a clinical trial in Singapore this summer under the guidance of the Health Sciences Authority or HSA. Our COVID-19 vaccine utilizes Arcturus' self-transcribing and replicating mRNA, or STARR, S-T-A-R-R, technology. And the STARR mRNA is delivered with Arcturus' lipid-mediated delivery system, which we call LUNAR. By combining these 2 technologies, we are developing an extraordinary potential vaccine product for this extraordinary pandemic. A very low dose, potential single-shot vaccine, completely devoid of viral material with no additional adjuvants or co-adjuvants. In conversations with media, investors, foundations and government agencies here and abroad, it has become clear that many groups are seriously considering ordering and stockpiling vaccines at risk, even before COVID-19 vaccine is approved for public distribution. Why are they doing this? Well, they're doing this, so that they will be in a position to move quickly to distribute vaccines to their respective citizens immediately after appropriate regulatory approval. Because of potential stockpiling efforts, several have asked if Arcturus will be preselling our COVID-19 vaccine to support these stockpiling initiatives. And if so, what does this mean for Arcturus? What assumptions should we be making as to any value proposition? Well, I've asked our CFO, Andy Sassine, to provide more thoughts pertaining to these open questions later in the call. Today, we announced that our flagship program, an intravenously dosed investigational liver therapeutic, called ARCT-810 also known as LUNAR-OTC has received allowance from the FDA to proceed into human clinical testing and approval for Medsafe to begin a second clinical trial in New Zealand. This is great news for several reasons. Well, first of all, it means that Arcturus is now a clinical stage messenger RNA medicines company. This is a significant milestone for Arcturus. It's our first IND allowance, it's our first CTA approval. Meaning, we are entering into multiple clinical trials to evaluate our flagship program, ARCT-810 in both healthy volunteers and patients. ARCT-810 is truly a first-in-class investigational mRNA medicine for OTC deficiency. This is not your run-of-the-mill pharmaceutical. I'll remind everyone on this call that ARCT-810 is intended to be an intravenously dosed or systemically administered mRNA therapeutic. If this program is proven effective and safe in the clinic, it will open the door of opportunity to many, many liver diseases that can use the same platform. When a milestone like this is achieved, I find it valuable to reflect on why and how did we even get here, I want to highlight just some of the innovative achievements by Dr. Pad Chivukula, our CSO, and his team of exceptional scientists. We needed to discover, properly design and modify the mRNA drug substance. In addition, we had to discover a new manufacturing process that could produce large amounts greater than 10 grams at a time of messenger RNA that's suitably purified for intravenous applications. And last but not least, we had to discover a nonaccumulating biodegradable lipid delivery system that was suitable for regular and monthly intravenous administrations. A remarkable suite of innovation wrapped up in 1 potential therapeutic that we call ARCT-810 or LUNAR-OTC. ARCT-810 is a low dose, systemically administered, investigational mRNA medicine that utilizes Arcturus' novel mRNA construct and proprietary LUNAR delivery system to deliver OTC messenger RNA to liver cells. In 2019, the FDA granted orphan drug designation to the drug substance of ARCT-810 for the treatment of OTC deficiency, and it was supported by promising results of preclinical studies. The GMP manufacturing campaign for ARCT-810 is complete, sufficient to support all early clinical trials. ARCT-810 batches were manufactured, utilizing Arcturus' proprietary processes for both the mRNA drug substance and the LUNAR formulated drug product. While our Chief Development Officer, Dr. Steve Hughes, is with us on the call today, he will speak in more detail regarding the ARCT-810 clinical plan, which involves the recruitment up to 30 healthy volunteers in New Zealand and up to 12 OTC-deficient patients across several sites in the United States. Before I pass the mic over to Steve, I recognize that this is his first call with the investors. So I thought it would be appropriate for me to provide some of his background. It is my distinct pleasure to introduce you all to Dr. Steve Hughes. Dr. Hughes brings over 20 years of clinical development experience with him, including successes in 3 commercial rare disease RNA medicines. Steve provides seasoned leadership at Arcturus in clinical operations, clinical affairs, clinical sciences and drug safety. He is an officer of the company. He's been involved in more than 50 clinical trials with more than 25 drugs across multiple therapeutic areas in the U.S. and globally. He played a key role in the submission of multiple NDA and MAA applications. He recently served as the CMO at Organovo. And prior to that, he was the Chief Clinical Development Officer at Ionis. He held positions at Biogen Idec, CSL Behring and Sanofi. Dr. Hughes is Board-certified in pharmaceutical medicine and received his medical degree from Imperial College in London. He also has an MBA from Imperial College Business School. We're fortunate to be working with him. And Steve, why don't you take it from here?

Thanks for the kind introduction, Joe. I've been fortunate to work with a great team here at Arcturus for almost a year now, first in a consulting role and then transitioning to Chief Development Officer at the beginning of this year. As a company, we are very pleased to be taking a significant step further in bringing this important new potential therapy to patients with ornithine transcarbamylase deficiency, an unmet genetic disease that reduces activity of an important enzyme system in the liver called the urea cycle. OTC deficiency is one of a number of the so-called urea cycle disorders, each one being due to a deficiency of a different enzyme within the urea cycle. And OTC deficiency is one of the most severe and the most common of the urea cycle disorders, affecting about 10,000 patients worldwide. At the end of March, we have received approval from the New Zealand regulator, Medsafe, to commence our Phase I study in healthy volunteers. And last Friday, we received an allowed to proceed notification from FDA for our Phase Ib clinical trial in patients with stable OTC deficiency. These events mark a milestone in the evolution of Arcturus from a discovery to a clinical supply technology company. I would like now to take a little bit more time to go over some of the design elements of the clinical trials and also to give a brief mention about our anticipated timings for beginning enrollment and availability of data. Both studies are single ascending dose studies and the randomized placebo control are blinded. The healthy volunteer study, we will be testing up to 5 dose levels. And in the patient study, we'll be testing 3 dose levels, with the highest dose in the patient study being the same as the highest dose in the healthy volunteer study. All studies lower than the anticipated range of therapeutic biological -- or I should say, all doses lie within the anticipated range for therapeutic biological effect predicted by the results of our studies in animal models. The primary goal of these studies is to find the safest doses to take forward into subsequent multiple dose clinical trials. Therefore, the primary endpoints are measures of safety and tolerability. We will also be evaluating a number of potential biomarkers as indicators of biological and clinical effect. These include [Technical Difficulty] with the ability of the urea cycle to form urea, called the ureagenesis assay, plasma ammonia levels, plasma OTC enzyme activity and urine orotic acid. However, LUNAR-OTC is intended as a chronic multiple dose therapy. And based on what we've seen in our animal studies, the levels of the OTC enzyme would likely to continue to increase in the liver over the first few doses in subsequent multiple dose studies. Also, as with most first-in-human studies, the cohort sizes are relatively small. Therefore, we may not be able to detect statistically significant changes in these biomarkers in these first studies. For that reason, the biomarkers are exploratory endpoints and the results will not affect whether or not we continue to move forward, that will be based on the safety profile that's observed. The next study in patients will be a multiple ascending dose study, and the dose levels tested will be guided by the results of these single dose studies. We anticipate that because several doses will be administered in the multiple dose study, the OTC enzyme will be able to achieve higher levels in the liver, and the biomarkers should therefore be more informative in that study. Now to the timing of these first studies. New Zealand is currently at Alert Level 4, which mean nonessential workers must stay at home and no social gatherings are possible. Under these conditions, initiation of the clinical trial is not allowed. Level 4 is continuing in New Zealand until the 23rd of April, at which time we are hoping that the restrictions will be eased so that we can -- so that we would then be allowed to get things going. The reason we are optimistic for the Level 4 restrictions being eased is that the number of new cases in New Zealand has flattened and now seems to be declining. This means that we are hoping to be able to start enrolling healthy volunteers pretty soon. In North America, the delays are due to both social distancing measures and also due to the burden that COVID-19 disease is placing upon the health care system. Additionally, many academic institutions are prioritizing research STARR onto STARR's COVID-19 studies. However, we are hoping to be able to start enrolling patients in the Q3 or Q4 2020 time frame. Finally, I would like to talk about the likely timing of the data from these initial clinical trials. We expect that the healthy volunteer study will evolve pretty quickly since all subjects within the cohort will be dosed within a couple of days of each other. We should also start seeing results within a few weeks of dosing the subjects. The first results will be those of the safety evaluations, and these should be available within about 6 weeks of starting each cohort. This is based on the fact that subjects are [Technical Difficulty] for 4 weeks after each dose, and we then need to consolidate and evaluate the data. However, we can dose escalate from 1 cohort to the next just a couple of weeks after dosing. So we don't need to wait for the final safety results from 1 cohort before we can proceed with the next. This is typical for healthy volunteer studies. The biomarker results are evaluated in batches, so we need to wait a little bit longer for these. We hope that this study will be completed by the end of the year. The study in patients will take a little longer to recruit due to the very rare nature of OTC deficiency and the results will take a little bit longer, too. As with the healthy volunteer study, the initial results will be based on the safety evaluations with the biomarker results following afterwards. And again, we do not have to complete the 30-day follow-up for all patients in a cohort before initiating the next cohort. Once the study gets going, we will be in a better position to estimate the likely timing of the data readout. Andy, I'd now like to turn the call over to you. Thank you.

Thanks, Steve, and hello, everyone. We have received a lot of questions related to our COVID-19 vaccine program and we will try to address some of those questions today. Many government agencies here and abroad and foundations like the Bill & Melinda Gates Foundation are funding the stockpiling of vaccines from many countries and companies. They are providing funding to companies for the manufacturing of millions of vaccine prior to regulatory approvals. At this time, we have only received financial commitment from the Singapore government to manufacture the vaccine. We will not be providing any revenue guidance today. We will share some vaccine assumption that will help investors understand the potential opportunity. The assumptions I will share with you today assumes we are successful in the development of vaccine and the vaccine is approved by the Singapore Health Science Authority. We currently do not know what the indicated doses per vaccine will be until we complete our animal and human studies. We do not currently know what the vaccine prices will be, which will depend on HSA approval and the competitive landscape. Accordingly, we cannot predict with certainty when we can begin marketing any vaccine, if approved, or if and when we would receive any revenues from any sales. However, we believe other respiratory vaccine prices are representative, such as a pneumonia vaccine would be a reasonable assumption for your model. I will remind everyone, these are assumptions from the best available information we have today, and will change as we learn more about our optimal target dose level. We anticipate providing frequent updates to investors to help educate the market on our progress in developing the product candidate. We anticipate we will have total commitments from our existing suppliers to deliver 2 10-gram batches this year for a total of 20 grams. Based on the information we have today, we can assume potential vaccine dose ranges of 5 to 10 micrograms per vaccine. Based on this dose range, we can assume that each manufactured 10-gram batch can support approximately 1 million to 2 million doses. As mentioned earlier, we do not yet know the exact dosing levels nor the exact price per vaccine. But we wanted to share with you some assumptions to help you model this opportunity. I hope this was helpful, and I will now turn the call back over to Joe.

Thanks, Andy. It looks like now is a good time to open the call for questions.

[Operator Instructions] Our first question comes from Yasmeen Rahimi with Roth Capital.

Congrats on the update, very happy for you to see this. Couple of questions. Can you enlighten us or give us color a little bit in detail what the doses are? You mentioned there are 5 doses in the healthy volunteer and 3 in the OTC patients. So what is the dose ranges and how they vary between the 2 patient population? And then the second question I have is, you didn't discuss sort of the length of duration of the study especially in the OTC patients. When will these biomarker analysis be completed to get data? And then if you can give us some comments in regards to your how long your animal tox package is and what is the longest duration study you can run? And then I have 1 last follow-up in regards to OTC.

Thanks, Yas, for calling in. I'll pass that question on to Steve.

Thanks, Joe. There's quite a few questions within that. So I'll try to remember all of them. If I don't, then if you can just remind me at the end. Regarding the doses, we're not disclosing details of the exact doses that we're using in our clinical trials like that. That will come at a later point. But what I can say is that all of the doses in both studies lie within the anticipated therapeutic range that predicted from our animal models. And the dose range that we're testing in each of the studies is broadly similar. But in healthy volunteers, the starting dose needs to be lower than in the patient study. So in the healthy volunteers, our starting dose is lower, i.e., the patients will start slightly higher. But both the healthy volunteer study and the patient study have the same top dose. In the healthy volunteer study, we're testing 5 different doses. So the dose increments are slightly smaller. In the patient study, we're testing 3 different doses. So there's a larger dose increment in that study. However, because healthy volunteer studies typically initiate much more quickly than patient studies and are conducted much more rapidly, we should get a readout on each of the doses that are going to be tested in the patients. We'll get a readout from the healthy volunteer study well ahead of initiating that post in the patient study. In terms of the timing, we don't need to wait for the healthy volunteer study to complete before we can start the patient study. Both studies could actually start in parallel. We have approval for both the studies to start in parallel. What dictates the start time is the length of time it takes to get the study up and running, and that's just much quicker at a Phase I unit than it is at academic institutions. I'm just trying to remember the rest of the questions that you asked. So the toxicology -- So the duration of the studies? Okay. So the -- both of the studies are single dose studies. So there isn't a dosing duration. And with single doses, you don't need to follow-up the patients for a terribly long time after you've actually dosed them. And so after dosing, each patient within the study will be followed up for 30 days. And then when -- and when the patients in the study are actually in any given cohort have been followed up for just a couple of weeks, we're able to dose escalate. So we don't need to wait until each cohort completes before we move to the next cohort, we can actually dose escalate after just a couple of weeks. In terms of toxicology data, we have enough toxicology data right now to do a multiple ascending dose study. Our toxicology studies were actually multiple dose toxicology studies. So they will cover us both for the single ascending dose and for the multiple ascending dose study that we'll do subsequently. But they won't cover, at this stage, very long-term dosing such as 1 year of dosing. We're not disclosing right now what the design of -- or the number of doses in the subsequent multiple dose study will be. Actually, it's even quite difficult to disclose that until we start to see some human pharmacology data from the single ascending dose study, and that will help to inform what we do in the multiple dose study. Did I cover off all -- on all of your questions there?

Yes. No, that was great. And then assuming that you're going to have data ahead from New Zealand, can you take the data and go back to the FDA and then begin right away, implement in that OTC patient study in multi dose arm event?

So technically, it is possible to do that. Obviously, it depends on what the FDA say and what the results of our healthy volunteer study show. So that is a possibility. Whether or not we would go down that route, I'm not able to disclose right now.

Our next question comes from Whitney Ijem with Guggenheim Securities.

This is Evan Wang on for Whitney. Just a question regarding the path towards pediatric patients. Can you discuss maybe how you guys are thinking about that, and whether any of these studies -- or the healthy volunteer study could accelerate time lines to pediatric patients?

Could you restate the question? You broke up a little bit.

I'm just wondering if you could talk a bit more on the path towards addressing pediatric patients and whether the healthy volunteer studies can help accelerate time lines there?

Great. Great question with respect to pediatric patients. Steve, can you handle that?

Yes, sure. So the FDA, as you know, and other regulators too, for most diseases, insist that you go into an adult population unless the disease only exists in the pediatric population. And in fact, even for some pediatric-only diseases, the regulators insist that you go into an adult patient with a similar disease before they let you go into patients because you need to develop that the drug -- to show that the drug is either safe and/or effective in adults before they let you start in children. So that's the primary thing that's constraining the speed at which we can get into a pediatric population. The second thing that I'd like to say is that pediatric population obviously covers a very large age range, all the way from 0 up to 18. And in some countries, up to 21. And within that, there are a number of distinct age ranges that the regulators like you to test in a stepwise fashion. So typically, you would -- after enrolling adults, you would move to adolescent patients. And then you'd moved down to progressively younger patients as the data becomes available. Certainly, the data from the adult studies will help us to accelerate our pediatric program because the safety data will be instrumental in our discussions with the regulators about the timing of initiation of those studies. And good safety data gives the regulators great confidence that you can go into children. At this stage, it will be premature to speculate on what the next studies would look like or what the pediatric studies would look like. But I can say that it might be possible that as we move to a multiple ascending dose study that we could start to include some pediatric patients in the adolescent range within a multiple dose study. But obviously, that needs to be discussed with the regulators once we have some data.

Okay. And then I have one follow up on COVID. Given the kind of deal activity we've seen there with other mRNAs based vaccines, I guess what is the interest in kind of partnerships or distribution at Singapore?

Well, that's a great question. You saw the recent activity with respect to Pfizer and BioNTech. You understand that there's several vaccines on -- that are being tracked by the WHO. And the first significant deal, I would say, from the pharmaceutical industry was between Pfizer and BioNTech. And why this is important to understand is BioNTech is using a self-replicating messenger RNA concept delivered with a lipid nanoparticle, very similar to Arcturus' mechanism and approach. So we view this as validating and important. With respect to our business development discussions, we have ongoing conversations with Singapore, but you can understand that multiple pharmaceutical companies would be interested in the STARR technology, our LUNAR delivery capabilities and our manufacturing processes. So it bodes well for those type of conversations that are ongoing. And every time we have one of these calls, we reiterate the same message, right? That we're a platform. We have a platform of technologies that are very interested -- or very interesting to multiple pharmaceutical companies, and those conversations are always ongoing.

Our next question comes from Madhu Kumar with Baird.

So first one OTC deficiencies. So can you give us some sense of the target population you're looking at among the OTC patients to test 810? And will it be people who are currently on ammonia scavengers or people who aren't? And then similarly, are they allowed to stay on concomitant therapies in the trial? And then finally, on the OTC piece, do you expect to see changes in metabolic biomarkers and metabolic pathway changes in the healthy volunteer arm that will be predictive in the patient population?

Thanks Madhu for joining the call and the question. Steve, why don't you handle that one?

Okay. Thanks, Joe. So as I mentioned earlier, the first clinical trials that we do, in fact, the first clinical trials that any company would do, the primary endpoints are going to be focused very much on demonstrating the safety of the drug so that you can move forward into subsequent clinical trials and also enable you to select the optimal and the safest dose to take forward into subsequent development. So in the initial clinical trials, we're enrolling patients with stable OTC deficiency. And the reason for that is that including unstable patients in the initial studies could make it very difficult to get a clean read on the safety profile since unstable patients have a high risk of getting sick while they're on the study, and then it could be difficult to determine whether any sickness was due to the drug or due to the underlying disease. So that's the reason. As we move progressively further forward in clinical development and once we've established the safety profile, then that allows us to move into the rest of the sicker patients. And in fact, I think even it would be challenging to get a clinical trial approved in an unstable population, which is a very vulnerable patient group, ahead of getting data in a stable population. I don't -- I just don't think that the regulators would let you do that. Moving on to the next question, will the patients be allowed to stay on their scavenger therapy and their other medications? Yes, absolutely. Patients will stay on their background therapy as they progress within this clinical trial. The only caveat that I would make is that the regulators for these kind of diseases, where part of the disease management is actually diet control, these patients need to be on a low-protein diet and have a number of amino acid supplements that we're working with the dietitian at each site and actually with a central dietitian as well to optimize each patient's diet as they move into the studies so that we have the best chance of detecting changes on the biomarkers. Having said that, what we've seen in our animal studies is that the level of OTC protein within the liver actually increases as you give successive doses, up to the point where you reach a kind of plateau level. So it's possible that within our initial studies where we're only giving a single dose, but actually we don't get the OTC level up to where it needs to be to detect statistically significant changes in the biomarkers in what's a relatively small study. So as we dose in subsequent studies with multiple doses, obviously, the OTC levels will have the opportunity to accumulate to a higher level. And there, we have greater confidence that we would see statistically significant changes in the biomarkers. Did I cover the -- all of your questions?

And the last one is on the healthy volunteers, would you expect to see meaningful biomarker changes in a healthy volunteer population?

That's a good question. Maybe just to flip it around a bit. If we see biomarker changes in the healthy volunteer study and with all of the caveats that I've just mentioned in the response to the previous question, then we would definitely anticipate that, that would translate to a patient study. The flip side of that is that healthy volunteers obviously have a normal urea cycle, it's working completely normally. So whether giving additional messenger RNA and making additional OTC will result in detectable changes in any of the biomarkers, we actually don't know. But it would -- it's very easy to measure the biomarkers. So it certainly makes sense to include them in the clinical trial. But at this stage, because nobody has ever done this in a healthy volunteer patient, we really don't know whether those biomarkers are going to change in that study.

Okay. And then moving over to the COVID vaccine drug. So can we just step back and look at it? As you've mentioned earlier, there are several messenger RNA vaccines in kind of preclinical or early clinical development. Can you kind of walk through briefly what about STARR, you think gives you all an edge in this COVID vaccine space?

That's a fair question. There's several different varieties of COVID-19 vaccines out there. How we differentiate is that, well, first, we're a messenger RNA vaccine, delivered with a lipid nanoparticle and instead of a conventional messenger RNA, we utilize self-replicating mRNA or our STARR mRNA technology. We also utilize what we believe is to be a very good delivery system, our LUNAR delivery technology is differentiating in terms of biodegradability and other features and benefits to that delivery technology. And when you combine those 2 together and the ability for us to manufacture both the drug substance and the drug product effectively with Arcturus' processes, that's differentiating as well. As you compare the field of messenger RNA COVID -- these vaccines to other types of vaccines, they may include viral vectors or viral components, it may be a dead virus or an attenuated virus or an attenuated live virus. Our vaccine, we remind people, is completely devoid of all viral materials, no viruses, no viral vectors and no adjuvants as well that you'll see -- commonly see in protein vaccines or -- and that's a unique advantage because it simplifies the therapeutic vaccine. And the simpler it is, the easier and more easily it is to evaluate the safety profile of the therapeutic. And Andy, any other comments?

Yes. I think what would be helpful is we gave you some dose range today. And I think another competitor, Moderna, provided their dose range, too. And so they mentioned that they'll be dosing at 100 micrograms, and it will be requiring 2 doses, including a booster. So as you can see, the dose range we gave you at 5 to 10 micrograms is substantially below what our competitors are. So hopefully, that helps in terms of understanding that our technology is pretty significant from an efficiency standpoint. And so hopefully, we'll give you more color as we collect more data. But hopefully, that will help differentiate our technology from our competitors.

[Operator Instructions] Our next question comes from Wangzhi Li with Ladenburg.

Congratulations on the progress. So the first question is, I understand that this is a single dose trial. But wanted to get some color in terms of the potential toxicity in terms of lipids -- toxicity in the liver. We now a key question is if the nanotechnology address the lipid accumulation toxicity faced with traditional lipid nanoparticle. I understand that it will not be easy to assess from a single dose study. But any color you think you will see potential liver toxicity single dose and how the nanoparticle may behave differently than what we expect for conventional lipid nanoparticle delivery for a single dose study, is there any possibility to get any insights from that?

Thanks, Wangzhi. This is Joe. We -- in contrast to the COVID-19 vaccine, which is an intramuscular very small dose injection, the LUNAR-OTC program is an intravenous messenger RNA therapeutic. And when you're injecting messenger RNA intravenously and on a regular basis, then it's extremely important to have a delivery technology that is nonaccumulating through these multiple injections. So you're spot on that the toxicity that people are looking for in our animal models prior to the clinic and neuro tox studies is often associated with lipid accumulation in the liver. And thankfully, our LUNAR technology is differentiated here from other competing lipid nanoparticle technologies. And that it readily clears, we have already shared data previously that it has a 20-hour half-life for these lipid excipients involved in the lipid nanoparticle rather than much, much longer than you may see in other technologies. This is important to maintain that level of safety. With respect to specific toxicity that you normally see, its elevations in ALT and AST enzymes that can be readily measured at high doses in our preclinical animal models. And did I address your question?

Yes, that's helpful. Maybe also additional question is, can you measure the half-life or the lipid nanoparticle from the Phase I study first in the healthy volunteer and the patient single dose, like how long they -- how fast they are degraded in the liver?

So yes, so maybe I'll try to take that question. So it's Steve here. So yes, we can measure the half-life, and that's part of our submission package to the regulators is to provide pharmacokinetic data including half-life from our animal studies. And then in the human studies for LUNAR-OTC, we'll be measuring a number of pharmacokinetic parameters, including the half-life. In terms of what -- in terms of the half-life that we saw in our animal studies, that isn't something that we're disclosing right now. And actually, the human data is going to be much, much more meaningful. And when we have that, we will disclose it pretty quickly. What I can say is that we've looked at the -- based upon the half-life and the persistence of the lipid within the system and the lipids are degraded very, very quickly. The lipids are gone after 1 dose before the next dose would be given in a multiple dose study. For the single dose study, it doesn't really matter because those patients aren't getting a subsequent dose or at least not getting a subsequent dose within this study. But the lipids are cleared out very quickly, certainly within a couple of weeks.

Got it. And a follow-up question is also, will you be able to measure the duration of the enzyme if you see a change in biomarker? Because that will also inform the -- into for -- between dosing when you started the multi dosing study, right? I know you expressed the enzymes in the half-life. But I know you see single dosing study. So -- but will you able to get when you start in terms of duration of the enzyme or on the messenger RNA expression? I mean, I guess that will depend on if you see biomarker changes, significant biomarker changes. Any color on that?

Go ahead, Steve.

Okay. So yes, definitely. We're measuring the biomarkers at multiple time points, both prior to dosing -- immediately prior to dosing and then measure them the day after dosing and then at subsequent intervals right the way out through the post dose follow-up period. So if we see changes in the biomarkers, we'd certainly be able to look at the duration of those changes. When we do a multiple dose study, we'll be doing exactly the same thing. We'll be looking at the levels of the biomarkers over successive time periods. So in that study, we'd be able to see those changes too. One thing to just bear in mind, though, is that it's entirely possible that if we see changes in the biomarkers in the single ascending dose study, because only a single dose is given and because with multiple doses, we would expect the OTC levels to build up very quickly, that any response that we see, if we see a response in the single dose study, doesn't persist for very long. And the reason for that could just be that the response is just above the threshold for detection at the early time point after dosing and then falls down below that limit of detection at subsequent time points. And so what we see in terms of duration of response from the single ascending dose study may not actually be that informative in terms of what we would see with multiple dosing.

Got it, makes sense. Maybe a quick question is, I think you received the FDA feedback. Last week you actually mentioned that. So just curious if you get any question for FDA during this IND period or it's just automatically after the 30 day?

Pad, why don't you address that?

No. I mean, of course, we've got some correspondents, but it was very minor, and there's not much to do -- there was not much changes we had to make.

Got it. Great. Last question on the COVID-19 vaccine. I know you already studied a mouse study, and you can also do a monkey study. The question is, I asked that because it's my knowledge the COVID-19 does not impact the mice well. Any color on that?

Here, Pad, why don't you address that?

Yes. For the preclinical studies that were intended to do for the COVID study, it's going to be rodent, mice, and we will do some work in rabbits and then anticipate getting into the clinic after that.

Our next question comes from Ed Arce with H.C. Wainwright.

Let me add my congrats on achieving this important milestone of getting into the clinic.

Thanks, Ed.

First question is I guess for Steve. In your prepared remarks, at some point, you had mentioned that with regards to the studies that you're planning to start, the single ascending dose study, that the levels of OTC could continue to rise even after the first, I think, couple doses you said. And I just wanted to clarify and maybe expand on that statement. If you could, please.

Okay. So within the single dose study, we're obviously not going to be testing multiple doses. So apologies if that caused some confusion. What I was trying to say was that when we move to multiple dose studies, multiple doses will be given. And therefore, because in the animal models, we see increases in OTC after each successive dose we would anticipate seeing increases in the OTC level with successive doses in the multiple dose study. In a single dose study, there wasn't the opportunity for that. So the change in OTC that occurs in a single dose study might not be sufficient to be detected as a statistically significant change in the biomarker. Whereas in a multiple dose study, because the OTC levels have a chance to build up to a higher level with successive dosing, those changes have a greater opportunity to be statistically significant.

Okay. Got it. And then with regards to your sort of preliminary time line as it were, you had mentioned as well, first data by year-end. Just wanted to clarify that as well, meaning most likely the primary data set for these -- for this study, meaning the safety and probably some PK and tolerability. But the question is, I guess this would necessarily mean the biomarker data is probably more like sometime in early 2021?

Thanks, Ed. So as you stated, the safety data is the initial readout. But the biomarker data, we're actually collecting in an ongoing fashion. And we would anticipate being in a position to process biomarker data at the end of each cohort because for the patients within that cohort, all of their biomarker data will be run on the assays at the same time. The limitation that we have is that the labs that we use -- central labs that we're using for the biomarker evaluations are all in the United States, and they might be affected by the COVID-19 slowdown. And so that might affect their timeliness within which they can process those samples. So at this point, we're not actually in a position to give guidance on when we would anticipate seeing that data. In the best-case scenario, that data is definitely in the 2021 -- sorry, for the 2020 time frame. But if there's a -- if the processing is slowed down by the COVID-19 restrictions, then it could be slightly later.

Fair enough. And then one final question, if I may, on your COVID-19 vaccine program. Just a few days ago, you've announced the first human dosing expected in the summer. And you had mentioned as well some other mRNA vaccines that are being tracked by the WHO and some deals. My question is, given the rather unique profile of your vaccine, how do you see it progressing in the time line from the first human testing into later testing relative to others that are already starting human trials?

Yes. Right. Well, the COVID-19 vaccine development path is very unique because of the pandemic background authorization for emergency use could always accelerate any program in this sort of environment. So all the standard rules are kind of being set aside at this point. We are working with the HSA, this is a regulatory agency that knows which corners to cut and which corners not to cut, this is not their first epidemic. And so we're fortunate to be working with a regulatory agency that understands the urgency of the matter. At the same time, they're very professional. And then with respect to your question as to where do we fit in terms of the time line, there's approximately 10 vaccines that are entering the clinic in the next couple of months. We aim to be one of them. And it looks like approximately half of those are messenger RNA vaccines. And so they're gaining traction as a field, and we're differentiated again from -- within this niche area of messenger RNA vaccines by being self-replicating, a potential single dose, a very low dose. And we look forward to seeing how this plays out together.

Our next question comes from Yale Jen with Laidlaw & Company.

As well as add my congrats to the -- this milestone for your lead product. Press release as well as your script statement earlier, that you have 30 individuals in New Zealand and up to 12 in the United States. Are they all healthy volunteers? What might be the number of patients and OTC patients you may contemplate for the study later on?

Yes. The number 30 references the healthy volunteer trial in New Zealand and the number 12 or the up to 12 is OTC deficient patients here in the U.S.

Okay. So they probably will -- in terms of U.S. patients that at least they will get into the study potentially with maybe the first few single ascending dose has been done in the New Zealand and maybe even some multiple dosing has been done in New Zealand as well, is that right?

I believe you're asking this -- I may need you to restate the question.

In terms of in the U.S. for the OTC patients, their study, I know it started in the third or fourth quarter, which, by that time, some of the single ascending dosing as well as some potentially multiple ascending dosing study has been done. Will that be the case?

I'll just correct you. Yes, this is Pad. That's partially correct. So yes, we are conducting a single ascending dose in healthy volunteers, and that data should come in before we start the -- some of the patient studies. But we're not doing any multi-dose studies in volunteers, we're just doing single dose.

Okay, great. That's clear. That's useful. And maybe a question about the COVID-19 vaccine. 2 questions here. Number one, given that you mentioned that you could generate up to, I guess, 20 grams of vaccine, which could be useful up to a million patients, would that be the case that you guys could continue to have this production capacity that any potential partners you need outside of Singapore will be purely for marketing and sales, and you guys can control the manufacturer side of the operation?

Yes. Obviously, this gives us a wonderful opportunity to be able to participate. As we announced earlier in all the stockpiling situation, we can't give you any confirmation that we will be involved. But there are numerous companies that are participating in the stockpiling. But at least share with you that we had some doses that we can participate in the stockpiling if the opportunity presents itself. Hopefully, that will help. You'll appreciate the situation, it's very fluid. But we're certainly doing anything we can to help governments and various foundations that are trying to be proactive in this pandemic and certainly understand the situation. So hopefully, that helps. And we'll give you more detail with respect to our dosing in the coming months, and that will hopefully give you a chance to crystallize what hopefully we can do for various countries.

And to address the second part of the question, is that the manufacturing process is very scalable for both the drug substance mRNA molecule and the drug product formulation, that process, right? So it's a very scalable process as well.

That's all the time we have for questions today. I will now turn the call back to Joseph Payne for closing remarks.

Hey, thank you, everyone, for listening in, and it was a very active Q&A session afterwards. We appreciate the time. At this point, we're going to close the call. As always, please feel free to reach out for any follow-up questions. Thanks, everyone.

Thank you. This concludes today's call. All parties may disconnect. Have a good day.