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spk12: will begin momentarily. We thank you for your patience and ask that you please remain on the line. Once again, please stand by. The conference call will begin momentarily. Greetings and welcome to the Arcturus Therapeutics first quarter conference call. During the presentation, all participants will be in a listen-only mode. Afterwards, we will conduct a question and answer session. At that time, if you have a question, please press the 1 or by the 4 on your telephone. If at any time during the conference you need to reach an operator, please press star zero. As a reminder, this conference is being recorded today, Monday, May 10th, 2021. And now I'd like to turn the conference over to Neta Safarzadeh, Head of Investor Relations, Public Relations, and Marketing of Arcturus. Please go ahead.
spk01: Thank you, operator, and good afternoon, everyone. We are joined today by Joseph Payne, President and CEO of Andy Sassin, CFO, Dr. Pat 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 statements that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Secretary's 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 or 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 ARCTRES' most recent annual report on Form 10-K with the SEC and in other filings that ARCTRES makes with the SEC. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements which speak only as of the date they were made, whether as a result of new information, future events, or circumstances, or otherwise. Now it is my pleasure to pass the call to Joe Payne, President and CEO. Joe, please go ahead.
spk11: Hey, thank you, Netta. 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 ARCTO21, our vaccine candidate for COVID-19. I'll begin with an overview of our ARCTO21 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 two 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 variants circulating throughout the globe require vaccine modifications. Third, another important benefit of mRNA-based vaccines is their ability to be re-dosed if needed, potentially on a yearly basis. It is expected that long-term protection to COVID is likely to require periodic re-dosing. 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, ARCTO21 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 ARCTO21. Our phase two 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 2 study was to further evaluate the safety and immunogenicity of ARCT021. 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 seroconversion 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 two study, as well as from our prior phase one slash two trial, we have made the decision to advance a single shot, low five microgram dose regimen into phase three development. We are now in negotiations with multiple regulatory authorities regarding the specific design of this study. We are excited to move our ARCTO21 program into phase three, 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.
spk10: Thanks, Joe. I'll start with ARCT021, our COVID-19 vaccine. The phase one slash two 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 two 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 ARCT021 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 1 slash 2 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 ARCT021. 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 1 slash 2 study where 81% of participants seroconverted for anti-spike IgG by day 14 after a single 5-microgram dose, and 100% had seroconverted by 28 days post-single 5-microgram dose. Safety data to date continues to be favourable and is consistent with what we saw in the Phase 1-2 study. Phase 3 preparations are proceeding well, and we are in discussions with multiple regulatory authorities concerning the Phase 3 programme. I will turn now to ARCT810, our therapeutic candidate for ornithine transcarbamylase or OTC deficiency. ARCT810 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 nine-month chronic toxicology study in which 20 doses of ARCT810 were administered every two weeks in non-human primates. In this study, we observed no adverse histological findings, including at dose levels above those that we were evaluating in our Phase 1b and our Phase 2 clinical studies. These non-human primate data bolster the strong ARCT810 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 two 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 one healthy volunteer dose escalation study with ARCT810 the study demonstrated that administration of ARCT810 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 two weeks after dosing. Our phase 1b dose escalation study evaluating ARCT810 in patients with OTC deficiency remains ongoing, and we continue to open new sites to facilitate additional involvement in the coming quarter. Initial results from this study are anticipated later this year. I will finish with ARCT032, our therapeutic candidate for cystic fibrosis, or CF. ARCT032 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. ARCT032 utilizes Arcturus Lunar Lipid Aerosol Platform to deliver CFTR messenger RNA to the lungs. ARCT032 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 this year. I will now pass the call on to Andy, our CFO.
spk06: 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 partners. For the three months ended March 31st, 2021, the company reported revenues of $2.1 million compared with $2.6 million in the three months ended March 31st, 2020. Total operating expenses for the three months ended March 31st, 2021 were 59.8 million compared with 12.1 million for the three months ended March 31st, 2020 and 33.3 million for the three months ended December 31st, 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 three months ended March 31, 2020, and was primarily driven by an increase in clinical and manufacturing costs of $29.2 million for our ARCT21 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 Arctura 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 two years. We continue to plan for the potential that ARCT21 could receive emergency use authorization later this year in one or more countries. Along with our global manufacturing partners, We have laid the foundation to produce hundreds of millions of doses of ARCT21 annually. Additionally, we have secured manufacturing requirements to meet the clinical needs of all our pipeline programs. I'll now pass the call back to Joe.
spk11: Hey, thanks, Andy. This has been a production.
spk12: Ladies and gentlemen, please stand by. We appear to have lost the audio. We are going to try to establish the connection.
spk11: Hi. 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 three results. We believe that there is the potential for ARCT021 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 investigational vaccine with very low dose, ARCT021 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 two multiple dose study. For our ARCT 032 CF program, we're looking forward to a CTA filing later this year Our goal with ARCTO32 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.
spk12: Thank you. If you'd like to register a question, please press the one followed by the four on your telephone. You will hear a three-tone prompt to acknowledge your request. If your question has been answered and you'd like to withdraw your registration, please press the one followed by the three. One moment, please, for the first question. Our first question comes from the line of Yasmine Rahimi with Piper Sandler. Please go ahead.
spk07: Hi, team. Thank you so much for taking my questions and all the great progress. A few questions for you. Maybe the first one is you mentioned on the call that you have had two data safety monitoring meetings with the FDA data safety monitoring committee meetings who cleared and said continue with the protocol. How many more are left to do for the phase two study And when should we, what's the rate-limiting step for the phase three 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.
spk10: There, 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 that they're reviewing. But at the front end of the study, we were doing dose selection for our Phase 3 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 two at least interim analyses planned. within the study, but they'll 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 three study. In terms of the total number of DSMB meetings, it's possible 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 COVID studies that you have a DSMB in place. And we'll have the same DSMB for our phase three study as well. And through phase three, they'll also be regularly reviewing the safety data. Although in phase three, 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 three, we're very pleased with the progress that we've made so far. We have a final protocol that's written and we're 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 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.
spk07: Thank you, Steve. And maybe you noted that we should be seeing neutralizing in T cell data in the second half of this year, in that so far, data based on the first 300 patients followed for 28 days. 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.
spk10: 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 six-month mark. And then within this study, at six months, people are randomized to either receive a placebo booster 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 one year. So there are a number of different data cuts that will be performing on the study, largely to inform our thinking of how we move the drug forward from the phase three study into the commercial setting and what additional data points we might want to collect in the post-market setting with the vaccine if approved.
spk07: Thank you, Steve. That was very helpful.
spk12: Thanks, Yas. Our next question comes from the line of Nick Abbott with Wells Fargo. Please go ahead.
spk14: Hi, guys. It's Joe on for Nick. Thanks for taking our questions and 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 three. 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?
spk11: Go ahead, Steve.
spk10: So first of all, talking to the T cell responses for the Phase 2 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 2 study will be any different to what we saw in the Phase 1 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 that maybe have lower seroconversion or non-seroconversion on antibodies, that means that they don't have a robust T cell response. The two things as we look at them are independent, and that's certainly what we saw in the Phase 1-2 study. I think the final piece is that we 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 will 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.
spk14: Did that answer your question? No, that's very helpful. Thank you, Steve. Thanks, Joe.
spk12: Our next question comes from the line of Seamus Fernandez with Guggenheim. Please go ahead.
spk03: Hi, guys. This is Adam Wang. I'm for Seamus. I have two questions, one on O2-1 and one on the OTC program. First, with the O2-1, is there any more data required for the Phase III, or is it simply operational in choosing the kind of countries, you know, where vaccines aren't broadly available? 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?
spk11: Well, we're definitely in the late stages. Yeah, sure. We're definitely in the late stages of operational planning for Phase 3. Anything else to add, Steve, on that?
spk10: 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 very swift 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.
spk11: 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, biophilized vaccine. And ARCTO21 has value to us, not only as a standalone asset, but it represents proof of concept for self-amplifying mRNA vaccine technology. And in addition to that, a safe, effective, and approved ARCTO21 can open the door or at least streamline the path to additional updated variant versions of ARCTO21. Got it.
spk03: That's helpful. And on OTC, you know, how is the program progressing and when will we see biomarker data from a single sending dose study? And are there any gating factors at the start of phase two?
spk10: Go ahead, Steve. So I heard the phase one data and I heard the gating factors for phase two. I think you broke up a little bit at the beginning of your question. So what was the first part?
spk03: It was regarding the phase 1B and when we'll see biomarker data from that study. Okay.
spk10: So the phase 1B study remains ongoing. We're anticipating that we'll see initial data later on in the year. So 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 two study, there's nothing 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 will get a timely review and be able to initiate that study a little bit later in the year as well.
spk03: Great. Thank you.
spk12: Thank you. As a reminder, to register for a question, please press the 1 followed by the 4 on your telephone. Our next question comes from the line of Yakal Nakomovitz with Citigroup. Please go ahead.
spk09: Hi. Great. Thank you very much for taking the questions. First of all, how quickly do you believe that you could submit the EUA after receiving positive Phase III data for ARC-021? Second, what other details do you believe need 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? Thanks.
spk11: 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 an additional color there. With respect to the trial design, we are conducting our phase three trials in areas where there's a high or an increased prevalence of COVID compared to six, nine 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?
spk10: Yeah, 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 to 45,000 participants. I guess the final question was the EUA.
spk11: Just the time between phase three data and EUA.
spk10: So that's something that we're not able to give clear guidance on at the moment. So we're in discussion with our CLO about how long it's going to take to clean that final data and lock the database and spit out the 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 central 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.
spk09: Great. Thank you very much.
spk10: I think maybe the last thing is that in terms of the guidance that we've previously given for EUA this year, that hasn't changed. That's still what we're targeting. Yeah.
spk12: Our next question comes from the line of Wang Zili with Ladenburg. Please go ahead.
spk02: Hi. Thanks for taking my question. Maybe on 21, first about the immunogenicity profile, in addition to zero conversion rates, any further call on the titer or the IgG antibody? And at this moment, any call on neutralizing titer or T cell response? I understand you may don't have data yet.
spk11: Yeah, 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.
spk10: Because the study is still blinded to the investigator and all the site staff, et cetera, 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. So at this point, we're not disclosing the individual details of the antibody titers. Got it.
spk02: 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 monkey, so maybe not the best for immunogenicity testing, but any comment on that?
spk11: Yeah, this is a toxicology study designed to support a phase two multiple dose application.
spk10: There aren't 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 they're immunogenicities, sorry, where they're deficient. The mice that have OTC deficiency. We can see PD, but 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.
spk11: Yeah, and for those familiar with lipid nanoparticle mRNA therapeutics, a 20-dose, nine-month chronic tox study in primates is a significant milestone in for the science.
spk02: Okay, great. Thanks for taking my question.
spk11: Okay, thanks, Wangzi.
spk12: Our next question comes in line of Shubendu Senroy with Brookline. Please go ahead.
spk04: Hi, I'm Shubendu 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?
spk11: No, we haven't. As you can appreciate, the ARCTO21 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 talks, discussions. So this could prove to be very fruitful. Steve, with respect to providing color, have we observed any of these serious adverse events that others have observed in their trials? Maybe you can provide a little color there.
spk10: 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.
spk04: 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?
spk11: Yeah, yeah. We definitely are in the process of evaluating all the major variants and we're in a position to move very quickly to update ARCTO21 if needed. You know, I also point out that ARCTO21 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.
spk04: Excellent. Sounds great. Thank you for taking my questions.
spk12: Thank you. Our next question comes from the line of Stephen Seathouse with Raymond James. Please go ahead.
spk13: I thank you. 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 that OTC expression? Are you able to determine if you get paraportal delivery and OTC expression in the primates?
spk11: That's a great question. We've definitely shown distribution to paraportal hepatocytes in rodent models. Steve or Pat, have we seen any paraportal hepatocyte data in our primate studies?
spk05: No, just because of the high background level in non-human primates, it's hard to distinguish the two between the human and non-human primate. But what we do, you know, at least in preclinical models previously, we have looked at OTC expression in primates, and we do see a dose correlation there.
spk11: Or in paraportal hepatocytes.
spk05: In general, in the liver, but not specifically in paraportal.
spk13: Okay, and then with Again, understanding that the histological findings looked 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?
spk11: Yeah, 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.
spk10: But we didn't observe an LL.
spk11: Yeah. Yeah, we didn't observe an all.
spk13: Okay. That's very helpful. Thank you.
spk11: It was a positive outcome, yes.
spk13: Okay. 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?
spk10: Maybe if I take that question? Yeah. So the first port of 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 multi-dose study in the United States. But in terms of facilitating that process, I think it would 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, you know, we've dosed X number of doses already and this is fine. Can we amend the protocol? So that's definitely under discussion at the moment.
spk13: Terrific. Thanks. 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 three studies, the Valneva study. They're using an immunogenicity primary on point testing neutralizing antibodies versus a comparator vaccine. 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 3 by any U.S. or European regulator, or specific in those geographies, are they still good with the event-driven studies? Thank you.
spk11: No, it'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, you know, to these early vaccines as others. And there's a higher sense of urgency and are more open to a placebo-controlled trial. Makes sense. Anything to add? Okay. Great. Thanks, Steve.
spk12: Our next question comes from the line of Yale Jen from Laidlaw and Company. Please go ahead.
spk08: Good afternoon. Thanks for taking questions and congrats on the data so far. Just two quick ones. The first one is in terms of starting the phase three study. You have two additional internal analysis. Is that the outcome from those internal analysis be a gating factor to starting the phase three or that's not relevant?
spk10: So it is relevant because normally to go into a phase three study, you would have some phase two data that showed that, you know, in moving from tens of patients in phase one to tens of thousands of patients in phase three, that, you know, a stepwise approach where you expose 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 for 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.
spk08: That's very helpful. Maybe the follow-up question here is that in terms of the Phase 2 study so far, have you guys measuring whether there's patients infected by variants or mostly by wild type, quote unquote wild type, the original strain in those patients?
spk11: Yeah, our Phase 2 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?
spk10: Yeah, so the phase two study is only about 600 people, so that's not enough to be looking at COVID cases. We're just not anticipating 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 three study, we're definitely going to be archiving samples from infected participants so that we can have a look at that.
spk08: Yeah. Okay, great. And thanks a lot and congrats for the progress.
spk11: Hey, thanks, Gilles. Okay.
spk12: I'll turn the call back over to you, Gilles.
spk11: All right, well, thanks, everyone. 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.
spk12: That does conclude the conference call for today. We thank you for your participation and ask that you please disconnect your line.
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