Arcturus Therapeutics Holdings Inc (ARCT) 2021 Q1 法說會逐字稿

Greetings, and welcome to the Arcturus Therapeutics first quarter conference call. (Operator Instructions) As a reminder, this conference is being recorded today, Monday, May 10, 2021.

I'd now like to turn the conference over to Neda Safarzadeh, Head of Investor Relations, Public Relations and Marketing of Arcturus. 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 Medical 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 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; the company's future manufacturing and other operations; 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 achievements are based on management's current expectations and involve risks and uncertainties, including those discussed under the heading Risk Factor in Arcturus' most recent annual report on Form 10-K with the SEC and in other filings that Arcturus 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 are made, whether as a result of 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.

Thank you, Neda. Good afternoon to all. Thank you for joining the Arcturus' quarterly call today.

Arcturus is developing a next-generation class of mRNA-based medicines and vaccines. We believe that our platform has potential promise to generate new vaccines and other transformative medicines that address the underlying molecular basis of many serious diseases. We have made tremendous progress advancing our pipeline, led by ARCT-021, our vaccine candidate for COVID-19.

I'll begin with an overview of our ARCT-021 program. ARCT-021 is a differentiated COVID-19 vaccine candidate based on a self-transcribing and replicating mRNA technology. We believe that our approach may provide meaningful advantages compared to currently available vaccines for COVID-19.

First, by using self-amplifying mRNA technology, ARCT-021 is designed to promote a strong immune response, followed by a single administration. We believe this single-shot dosing regimen would be highly favored compared to the 2 administration approaches employed with currently authorized mRNA vaccines for emergency use.

Second, a fundamental benefit of mRNA-based vaccines is that these vaccines may be readily modified and updated as needed. We expect that this could be an important benefit if the rapidly growing number of SARS-CoV-2 viral variance circulating throughout the globe require vaccine modifications.

Third, another important benefit of mRNA-based vaccines is their ability to be redosed if needed, potentially on a yearly basis. It is expected that long-term protection to COVID is likely to require periodic redosing. And our approach, which utilizes the LUNAR delivery technology and not a viral vector to deliver the vaccine, may be well suited to enable periodic or annual redosing.

Our expectation is that billions of individuals across the globe may require ongoing vaccination to protect against COVID-19. Based on all the favorable properties we expect with our approach, we believe that, over the coming years, ARCT-021 as a low-dose lyophilized single-shot vaccine has the potential to become a favored or preferred vaccine option in many regions of the world.

We have continued to rapidly advance our clinical development program for ARCT-021. Our Phase II study is now fully enrolled with 580 participants. We're pleased to see the continued growth of our safety database and the consistencies reading through as we have clinically evaluated our vaccine in Singapore and now also with participants in the United States.

The primary purpose of this Phase II study was to further evaluate the safety and immunogenicity of ARCT-021. The study remains ongoing. We have had multiple interim analyses of the safety data that have been reviewed by the DSMB, and the study has been allowed to proceed with no changes to protocol.

As Steve will discuss shortly, our interim immunogenicity data from the study demonstrate a high zero conversion rate, again, in line with our expectations. Given the study is ongoing, we remain blinded to full trial data, and we look forward to collecting additional endpoint measures from the study, including neutralizing antibody and T-cell data.

Based on the highly promising initial data that we've obtained from our Phase II study as well as from our prior Phase I/II trial, we have made the decision to advance a single-shot, low 5 microgram dose regimen into Phase III development. We are now in negotiations with multiple regulatory authorities regarding the specific design of this study.

We are excited to move our ARCT-021 program into Phase III, and we look forward to providing further updates on our progress in the near future. I'll now turn the time over to Dr. Steve Hughes, the Chief Medical Officer of Arcturus.

Thanks, Joe. I'll start with ARCT-021, our COVID-19 vaccine.

The Phase I/II study conducted in Singapore completed in the first quarter, and we anticipate submitting the full results to a peer-reviewed journal later this quarter. Our ongoing Phase II study completed enrollment on the 13th of March with 580 participants that were dosed, and the primary vaccination schedule is now complete. Two interim analyses have been completed and reviewed by the Data and Safety Monitoring Board, and they have recommended that the study can proceed with no amendments required to the protocol.

The data includes over 300 ARCT-021-treated participants that have been followed up for at least 28 days after the first dose. Emerging immunogenicity data from this study is consistent with the results from our Phase I/II study and shows greater than 90% seroconversion for IgG antibodies binding to the full-length spike protein at day 28 following a single dose of 5 micrograms of ARCT-021.

Seroconversion is at the threshold of at least a fourfold increase from baseline values. This is in line with our expectations based upon what we saw in the Phase I/II study, where 81% of participants who are converted for anti-spike IgG by day 14 after a single 5 microgram dose and 100% of seroconverted by 28 days post single 5 microgram dose.

Safety data to-date continues to be favorable and is consistent with what we saw in the Phase I/II study. Phase III preparations are proceeding well, and we're in discussions with multiple regulatory authorities concerning the Phase III program.

I will turn now to ARCT-810, our therapeutic candidate for ornithine transcarbamylase, or OTC, deficiency. ARCT-810 utilizes Arcturus 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 urea cycle activity, preventing neurological damage and the need for liver transplantation.

We recently completed a 9-month chronic toxicology study in which 20 doses of ARCT-810 were administered every 2 weeks in nonhuman primates. In this study, we observed no adverse histological findings, including at dose levels above those that we're evaluating in our Phase Ib and our Phase II clinical studies. These nonhuman primate data bolstered the strong ARCT-810 preclinical data package that supported advancement of the program into human studies and provide support for extended dosing in humans. We remain on track to submit a CTA for a multiple-dose Phase II study in OTC-deficiency patients within the coming weeks, and we have already submitted the study protocol for ethics committee approval.

As a recap, to-date, we have completed a Phase I healthy volunteer dose-escalation study with ARCT-810. The study demonstrated that administration of ARCT-810 was associated with favorable tolerability and an attractive pharmacokinetic profile up to the top dose of 0.4 milligrams per kilogram, which is within the anticipated therapeutic range based upon data from our preclinical studies. In that study, we were able to measure messenger RNA at the last time point that was assessed, which was 2 weeks after dosing.

Our Phase Ib dose-escalation study evaluating ARCT-810 in patients with OTC deficiency remains ongoing, and we continue to open new sites to facilitate additional enrollment in the coming quarter. Initial results from this study are anticipated later this year.

We'll finish with ARCT-032, our therapeutic candidate for cystic fibrosis or CF. ARCT-032 is designed to induce the expression of a fully functional 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.

ARCT-032 utilizes Arcturus' LUNAR lipid aerosol platform to deliver CFTR messenger RNA to the lungs. ARCT-032 preclinical studies have demonstrated the ability to efficiently deliver targeted mRNA to the airway epithelial cells following topical and aerosol administration, and we believe that our approach has the potential to correct the underlying defect causing the disease in CF patients. We remain on track to submit a CTA for the program in Q4 of this year. I will now pass the call on to Andy, our CFO.

Thank you, Steve, and good afternoon, everyone. The press release issued earlier today includes financial statements for the first quarter of fiscal year 2021. Arcturus' primary sources of revenue is currently from licensing fee and collaboration payments received from research and development arrangements with our pharmaceutical and biotech partner.

For the 3 months ended March 31, 2021, the company reported revenues of $2.1 million compared with $2.6 million in the 3 months ended March 31, 2020. Total operating expenses for the 3 months ended March 31, 2021, were $59.8 million compared with $12.1 million for the 3 months ended March 31, 2020, and $33.3 million for the 3 months ended December 31, 2020.

The increase in net expenditures were due primarily to the increased activity in clinical and manufacturing expenditures related to the company's COVID-19 and OTC program as well as increased personnel costs and other facility costs related to the organizational growth of the company. Research and development expenses increased by approximately $42.1 million compared to the 3 months ended March 31, 2020 and was primarily driven by an increase in clinical and manufacturing cost of $29.2 million for our ARCT-021 program.

The remaining increase was primarily related to the acquisition of an exclusive license from Alexion Pharmaceuticals to certain patent-pending inventions related to nucleic acid purification technology for approximately $5 million of Arcturus stock and an increase in personnel-related expenses.

Our cash balance totaled approximately $467 million as of March 31, 2020. Based on our current pipeline, the company's cash position is expected to be sufficient to support operations for more than 2 years. We continue to plan for the potential that ARCT-021 could receive emergency use authorization later this year in 1 or more countries. Along with our global manufacturing partners, we have laid the foundation to produce hundreds of millions of doses of ARCT-021 annually. Additionally, we have secured manufacturing requirements to meet the clinical needs of all our pipeline program. I'll now pass the call back to Joe.

Thanks, Andy. This has been

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I'll begin by saying thanks, Andy. I'll start after the transition. This has been a productive quarter, and Arcturus has made substantial progress advancing our mRNA-based therapeutic and vaccine platform with favorable Phase III results. We believe that there is the potential for ARCT-021 to gain emergency use authorization in at least one country before year-end, which would, of course, represent an enormous achievement for our company. We believe that as a single administration, lyophilized, hence investigational vaccine with very low dose, ARCT-021 could have a differentiated profile, positioning the product for potential broad uptake.

We're also advancing our broader clinical and preclinical pipeline programs and anticipate reporting important milestones. Later this year, we expect to obtain initial safety and pharmacokinetics data from our ARCT-810 clinical study being conducted in patients with OTC and look forward to starting a Phase II multiple-dose study.

For our ARCT-032 CF program, we're looking forward to a CTA filing later this year. Our goal with ARCT-032 is to utilize an easily administered aerosolized approach to correct the underlying deficiency seen in cystic fibrosis and to provide a meaningful new treatment option for the tens of thousands of individuals living with this disease.

In addition to these advanced programs, our team is also applying our mRNA technology to develop novel vaccines and other medicines for many other life-threatening diseases. We expect to have an exciting year ahead, and we look forward to keeping you informed of our progress. At this point, we can now go ahead and open the line for questions. Operator, please proceed.

Our first question comes from the line of Yasmeen Rahimi with Piper Sandler.

A few questions for you. Maybe the first one is, you mentioned on the call that you have had 2 data safety monitoring meetings so the FDA would look at -- Data Safety Monitoring Committee meetings who cleared and said continue with the protocol. How many more are left to do for the Phase II study? And when should we -- what's the rate-limiting step for the Phase III to get kicked off? And if you could provide some color in terms of the size of the study, that would be helpful. And then I have a follow-up.

Yes. Go ahead, Steve.

Okay. Thanks for the question. So the DSMB will be reviewing the data regularly throughout the study. It's not just interim analyses they're reviewing. But at the front end of the study, we were doing dose selection for our Phase III study. So we had a couple of very quick interim analyses built in right at the front end that the DSMB reviewed with the main purview really being on the safety data, and it just happened to coincide with when they would be doing the review. There are another 2 at least interim analyses planned within the study, but that will be a few months away yet. As I said, the initial interims are quite close together to allow us to confirm the dose selection for the Phase III study.

In terms of the total number of DSMB meetings, it's impossible to say, for the entire study, how many meetings they'll have because, as the data matures, the DSMB may decide that they would like to do meetings less frequently or more frequently. But they will be reviewing all of the data very regularly through the study, which is really a requirement for these coded studies that you have a DSMB in place. And we'll have the same DSMB for our Phase III study as well, and through Phase III, they'll also be regularly reviewing the safety data. When we're in Phase III, we don't have interim analysis planned for that because we're not doing any further dose selection.

In terms of the progress with Phase III, we're very pleased with the progress that we've made so far. We have a final protocol that's written and where we've entered into discussions with a number of different regulatory authorities concerning that protocol and how we most efficiently move it forward in those countries. So in terms of moving to the next step, we need to conclude these discussions with the regulators. And if the protocol is acceptable, then we'll -- and/or I should say, once we get agreement on the study design or at least the major elements of the study design, then we'll complete the CTA process that will allow us to move forward to validate and initiate sites in the different countries.

Steven, maybe it was -- you noted that we should be seeing neutralizing in T-cell data on sort of second half of this year in that, so far, data based on the first 300 patients followed for 28 days, the immunogenicity profile is consistent with what we have seen so far. So can you maybe help us understand how much more we should be expecting to see other than all 580 patients into the second half? But maybe will we have data on a longer treatment beyond day 60? I think it would just be helpful to understand what we will be seeing in immunogenicity data in the second half of this year.

So as we move into the second half of this year, we do have some additional interim analyses with later time points. And one of those time points, I believe, is at around about the 6-month mark. And then, within this study, at 6 months, people are randomized to either receive a placebo boost or to receive another booster shot so that we can evaluate what the boost response is after a long interval. And so we'll be collecting immunogenicity data immediately prior to that boost. And then again, after the boost and then again at 1 year. So there are a number of different data cuts that we'll be performing on the study, largely to inform our thinking of how we move the drug forward from the Phase III study into the commercial setting and what additional data points we might want to collect in the postmarket setting with the vaccine, if approved.

Our next question comes from the line of Nick Abbott with Wells Fargo.

It's Joe on for Nick. Congrats on the progress. Two questions from us. Steve, in terms of immunogenicity, do you expect a proportion of those patients who didn't seroconvert to potentially still achieve some degree of T-cell immunity? And maybe how does this data presented today provide you additional confidence in success going forward?

And then secondly, maybe focus more simply on timing around the Phase III. Are you still anticipate guiding towards initiation in the second quarter? Or have you maybe experienced any delays in conversations with regulators that you could provide more color on?

Sure. Go ahead, Steve.

So first of all, talking to the T-cell responses. For the Phase II study, we haven't got the T-cell data yet. We're expecting that to come in a little later. But we have no reason to believe that the T-cell responses that we see in the Phase II study will be any different to what we saw in the Phase I study. So we're anticipating very robust T-cell responses in the participants.

The other piece is that we're not anticipating that people that maybe have lower seroconversion or non-seroconversion on antibodies, that means that they don't have a robust T-cell response. The 2 things as we look at them are independent. And that's certainly what we saw in the Phase I/II study.

I think the final piece is that you have to remember that this data is day 28 data for seroconversion for the 5 microgram dose cohort. And we do anticipate that, because of the replicon mechanism with sustained antigen expression that we'll continue to see additional seroconversions as we go out further in time. So the 90% seroconversion rate at day 28 isn't the end of the story for seroconversions for these participants. Did that answer your question?

No, that's very helpful.

Our next question comes from the line of Seamus Fernandez, Guggenheim.

This is Evan Wang on for Seamus. I have 2 questions. One on 021 and one on OTC program. First, with 021, is there any more data required for the Phase III? Or is it simply operational and choosing the kind of countries where vaccines aren't broadly available? And as a follow-up to that, how is the company thinking about the viability of moving forward with the product, given just how the market's evolved over the last few months?

(inaudible)

Yes, sure. We're definitely in the late stages of operational planning for Phase III. Anything else to add, Steve, on that?

We're certainly not anticipating problems with the regulators in terms of the data package that we've given them for discussion. It's always possible that regulators come back and ask for more data, and it may not be clinical data. They might ask for further clarification on the CMC side or other things. These are just part of the normal regulatory review process, and we just aim for a base with turnaround to address questions that they have when we receive them. But there's nothing at this point that we're thinking is going to be a wrinkle that's going to cause significant issues.

And with respect to your question about how the market continues to evolve and our level of commitment to moving forward, I can assure you that we're committed to move forward at this time. We have contractual obligations to fulfill. Certain regions of the world may be more amenable to a single-shot lyophilized vaccine. And ARCT-021 has value to us, not only as a stand-alone asset, but it represents proof-of-concept for self-amplifying mRNA vaccine technology. And in addition to that, a safe, effective and approved ARCT-021 can open the door or at least streamline the path to additional updated variant versions of ARCT-021.

Got it. That's helpful. And on OTC, how is the burden progressing? And when will we see biomarker data from a single-ascending dose study? And are there any gating factors to the start of Phase II?

Go ahead, Steve.

So I heard the Phase I data, and I heard the gating factors for Phase 2. I think you broke up a little bit at the beginning of your question. So what was the first part?

As regarding the Phase Ib and when we'll see biomarker data from that study.

Okay. So the Phase Ib study remains ongoing. We're anticipating that we'll see initial data later on in the year. We really need to complete the cohort -- the first cohort enrollment and follow-up, and then we'll have a look at the data at that point, and we'll be able to make a disclosure.

In terms of the Phase II study, there's nothing that particularly that's gating on that. We're planning to submit the clinical trial application within the next couple of weeks. And then it will just follow the standard regulatory review cycle. It was already submitted to the Ethics Committee, as I said earlier. And that, again, has a standard review time. So we're anticipating that we'll get a timely review and be able to initiate that study a little bit later in the year as well.

(Operator Instructions) Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Thank you very much for taking the questions. I had a few. First of all, how quickly do you believe that you could submit the EUA after receiving positive Phase II data for 21? Second, what other details do you believe needs to be hammered out with the regulatory agencies regarding the Phase III trial design? And will there be any notable differences in the way that Arcturus is conducting the Phase III as compared with Moderna or Pfizer?

Well, it's a good question. It does vary considerably depending on which regulatory agency we talk to in which country. With respect to timing of an emergency use approval request, I'm sure Steve can maybe provide additional color there. With respect to the trial design, we are conducting our Phase III trials in areas where there's a high or an increased prevalence of COVID compared to 6, 9 months ago, and some countries have much higher prevalence rates, and it puts unique pressures on the regulatory agencies to transition the placebo group, for example, over to the vaccinated group sooner than previous trials. But Steve, any additional color?

Yes. So I think that's -- at a high level, that's the principal thing that we need to build into our study as opposed to the Moderna and Pfizer study is just a plan for how we transition placebos because it's not really ethical to keep them away from vaccine for long periods of time, particularly as the vaccine becomes available for their age group or their risk group. And that is one of the things that we're in discussion with the regulators about at this time. I guess the other thing is that both Moderna and Pfizer did very, very large clinical trials. We're doing a very large clinical trial, but it's in the order of 15,000 participants, not 30,000 to 45,000 participants.

I guess the final question was the EUA.

So the time between Phase III data and EUA.

So that's something that we're not able to give clear guidance on at the moment. So we're in discussion with our CRO about how long it's going to take to clean that final data and lock the database and spit out the biostatistics outputs on efficacy and safety that we need and also with our medical writing vendor as well. We're just in the process of going through the contracting process for the resources we need to turn around the clinical study report and the CTD sections in a timely fashion. So we'll be able to provide more color on that as we conclude those discussions.

So I think maybe the last thing is that the -- in terms of the guidance that we previously given for EUA this year, that hasn't changed. That's still what we're targeting.

Our next question comes from the line of Wangzhi Li with Ladenburg.

Maybe on 21. First, about the immunogenicity profile, in addition to seroconversion rates, any further color on the titer or the IgG antibody? And just any color on utilizing titer or T-cell response. If you -- I understand you really don't have data yet.

Yes, that's correct. We don't have data yet for neutralizing antibodies and T-cells. That is forthcoming. And the binding antibody data was very in line with our expectations with respect to seroconversion rates at day 28.

Yes. We're -- it's because the study is still blinded to a number -- to the investigator and all of the site staff, et cetera, there's -- we're giving very high-level data and not getting too granular on the data because the more unblinded data we give, the more it could compromise the integrity of the study in terms of assessments that are made by study sites op. So at this point, we're not disclosing the individual details of the neutralizing -- sorry, of the antibody titers.

Got it. Okay. And then for the OTCD program, the monkey study, you did 20 doses. In addition to safety, I just wondered do you have done any like PD marker or also immunogenicity on the target protein? Maybe first clarify this is a human protein in monkey, so maybe not the best for immunogenicity testing. But any color on that.

Yes, this is a toxicology study designed to support a Phase II multiple-dose application.

There are not really any PD markers you can do in a healthy monkey. They've got normal OTC enzyme activity. So the PD studies really need to be done in the mouse model of disease, where the immunogenicities -- sorry, where the deficiency -- mice that have OTC deficiency. And we can see PD. Those studies have already been done. So this really was to look at the effects of long-term dosing and to make sure that we didn't see any toxicities with long-term dosing that would make us need to revise our dose expectations.

Yes. And for those familiar with lipid nanoparticle mRNA therapeutics, a 20-dose, 9-month chronic tox study in primates is a significant milestone for the science.

Our next question comes from the line of [Shubhendu Sen Roy] with Brookline.

I'm Shubhendu on behalf of Kumar from Brookline. I had a couple of questions. So one was -- so in terms of the side effect profile for the vaccine, do we have molecules like PEG and polysorbate that may have allergic reactions or other side effects?

No. We haven't. As you can appreciate, our -- the ARCT-021 is a very low-dose RNA vaccine. It's only 5 micrograms. It's only a single administration. And the theoretical benefits of that are attributed to less stuff being injected, less RNA and less LUNAR ingredients or lipid ingredients, including the PEG lipid that's been implicated in some tox discussions. So this could prove to be very fruitful. Steve, with respect to providing color on -- have we observed any of these serious adverse events that others have observed in their trials. Maybe you can provide a little color there?

So to my knowledge, we haven't seen any serious adverse events that are anaphylactic type reactions at all. There have been some serious adverse events in the study, but that's normal in any study that you see and certainly nothing that's caused concern for us or caused concern for the DSMB.

Great. Just one follow-up question. So since this is a single-dose vaccine, do you anticipate modifying the content with respect to variants, say, every year annually?

Yes. Yes. We definitely are in the process of evaluating all the major variants, and we're in a position to move very quickly to update ARCT-021, if needed. I also point out that ARCT-021 as is, because of its robust cellular immunity or immunogenicity profile, may be good as is with respect to variant coverage. But if we find some challenges -- or some challenging variants in our Phase III studies, we'll be able to move quickly because of the efforts that have been ongoing pertaining to present evaluation and synthesis of the variants.

Our next question comes from the line of Steven Seedhouse with Raymond James.

First on the OTC program. You mentioned no adverse histological findings. I'm just curious in the histology data, are you able to look at all at OTC expression? Are you able to determine if you get periportal delivery and OTC expression in the primates?

It's a great question. We've definitely shown distribution to periportal hepatocytes in rodent models. Steve or Pad, have we seen any periportal hepatocyte data in our primate studies.

No, just because of the high background level in nonhuman primate, it's hard to distinguish the two between the human and nonhuman primate. But what we do, at least in preclinical models previously, we have looked at OTC expression in primates, and we do see a dose correlation there.

Or in periportal hepatocytes.

In general, in the liver, but not specifically in periportal.

Okay. And then with -- again, understanding that the histological findings look good. Just on safety overall, can you talk about if you saw any adverse events? And I guess, maybe a more specific question. How many fold above your targeted clinical dose did you test in the primates? And did you determine the no-observed-adverse-event-level?

Yes. We carefully worded our press release to capture that we evaluated doses above our maximum targeted clinical dose, but we haven't disclosed the specifics.

But we didn't observe a NOAEL.

Yes. Yes, we didn't observe a NOAEL.

It was a positive outcome.

Okay. And do you foresee -- I mean, are you planning on filing an IND and conducting a multidose study at some point in the U.S.? Do you see any roadblocks there?

So maybe if I take that question?

Yes.

So the first call is to initiate and start giving multiple doses with the currently planned CTA . And then we will definitely be evaluating whether we submit a protocol amendment and file to the IND for a multidose study in the United States. But in terms of facilitating that process, I think it will be nice to get a few doses in a couple of patients under the CTA so that we can go back to FDA and say, look, we dosed x number of doses already, and this is fine, can we amend the protocol? So that's definitely under discussion at the moment.

Terrific. And last question for me. I appreciate you taking all the questions. At least one, this is on the COVID vaccine. There's one recent Phase III study -- this is the Valneva study. They're using an immunogenicity primary endpoint testing neutralizing antibodies versus a comparator vaccine. I'm -- that's the first I've seen of that design. And obviously, you're still speaking about an event-driven study. So I'm curious if you've been asked at all to run a similar type of immunogenicity study for Phase III by any U.S. or European regulator or specific in those geographies, are they still good with the event-driven studies?

No, that's a great question. And you're right, there's considerable variability depending on which country and which regulatory agency we're in conversations with, but some regulatory agencies in countries that have early access to the vaccines are definitely requesting more information about the potential of doing a comparison study. But that's not in all of our conversations. Some countries are -- do not have the same access to these early vaccines as others. And there's a higher sense of urgency and are more open to a placebo-controlled trial. Anything to add?

Our next question comes from the line of Yale Jen from Laidlaw & Company.

Congrats on the data so far. Just 2 quick ones. The first one is in terms of starting the Phase III study. You have 2 additional internal analyses. Is that the outcome from those internal analysis, be a gating factor to starting the Phase III? Or that's not relevant?

So it is relevant because, normally, to go into a Phase III study, you would have some Phase II data that showed that moving from tens of patients in Phase I to tens of thousands of patients in Phase III, that is a step-wise approach where you expose it -- several hundred patients first. The question is how long you follow those several hundred patients up for. And traditionally, for vaccines, 28 days after the dose is the time point at which you determine safety, certainly from moving to the next phase of development, which is exactly what we've done.

We've gone to 28 days after the first dose. We've established that the 5 microgram dose is behaving very nicely. Actually, the 7.5 microgram dose is behaving very nicely as well. But the 5 microgram dose in terms of immunogenicity, we think, is the sweet spot. And now we have sufficient data to put together a compelling regulatory package to submit CTAs.

Okay. Great. That's very helpful. Maybe the follow-up question here is that in terms of the Phase II study so far, have you guys been measuring whether there's patient infected by variants or mostly by wild card or original strain in those patients?

Yes. Our Phase II is conducted primarily in the U.S. with some of the patients being in Singapore. With respect to the variant profile in these areas is well understood. But Steve, anything to add?

Yes. So the Phase II study is only about 600 people. So that's not enough to be looking at COVID cases. We did not anticipate enough COVID cases in the study of that size to be able to make a reasonable assessment of whether there's any particular bias towards one variant or another. In our Phase III study, we're definitely going to be archiving samples from infected participants so that we can have a look at that.

Congrats to progress.

I'll turn the call back over to you, Joe.

All right. Well, thanks, everyone. It looks like our time's up, and we're going to be closing the call. 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.

That does conclude the conference call for today. We thank you for your participation and ask for you, please, disconnect your line.