Q1 2021 Arcturus Therapeutics Holdings Inc Earnings Call

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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 the question and answer session at that time. If you have a question. Please press the one oh by the foreign your telephone.

And anytime during the conference you need to reach and operator, Please press star zero.

As a reminder of this conference is being recorded today Monday may 10th 2021 and.

And now I'd like to turn the conference over to net of so far is the day head of Investor Relations Public relations and marketing of Arcturus. Please go ahead.

Operator: Greetings and welcome to the Arcturus Therapeutics first quarter conference call. During the presentation, all participants will be in a listen-only mode. Afterward, we will conduct a question and answer session. At that time, if you have a question, please press the one, all by the four on your telephone. If at any time during the conference, you need to reach an operator, please press star zero as a reminder that this conference is being

Thank you operator, and good afternoon, everyone.

And today by Joseph Payne, President and CEO, Andy Sassine CFO, Dr. Apache of it because I see so LCL and Dr. Steve He was 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.

Operator: Monday, May 10th, 2021. I'd like to turn the conference over to Neta Safarzaday, head of investor relations, public relations, and marketing for Arc tourists. Please go ahead.

Neda Safarzadeh: Thank you, operator, and good afternoon, everyone. We are joined today by Joseph Payne, President and CEO, Andy Sassin, CFO, Dr. Pat Chivucola, CSO, and CEO, 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.

And of the form act of 1995.

Any statements other than the statements of historical Fox included and just kind of the indication, including those regarding the status of our results of clinical development programs. The planned initiation design of completion of clinical trials. The likelihood of success of the company's coronavirus, COVID-19 vaccine candidate or other products.

Neda Safarzadeh: 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 plan 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.

Candidates, the companys future manufacturing and other operations and the company's current and future cash and financial position our 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 and the ability to develop and market product candidates unexpected clinical results and general market conditions that may prevent such achievements or per for them.

Yes.

So I've talked to you of Mrs are based on management's current expectations.

Expectations and involve risks and uncertainties.

Including dose and discuss under the heading risk factor and Arcturus is most recent annual report on form 10-K with the S E T 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 day day ever made better as a result of the and information future events or circumstances or otherwise.

Neda Safarzadeh: Such statements are based on management's current expectations and involve risks and uncertainties, including those discussed under the heading risk factor in Artress's most recent annual report on Form 10K with the SEC and in other filings that ArtRES 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.

Now it is my pleasure to pass the call to Joe Payne, President and CEO Joe. Please go ahead.

Hey, Thank you Anita and good afternoon to all thank you for joining the Arcturus has corridor the call today.

And our tourist is developing and next generation class of mrna based medicines and vaccines. We believe that our platform has the 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 our CTO 'twenty one our vaccine candidate for COVID-19, and I'll begin with an overview of our CTO of 21 program.

Joseph E. Payne: Hey, thank you, Netta. Good afternoon to all.

Joseph E. Payne: Thank you for joining the Arc Turvices Quarterly call today. Arcturus is developing a next generation class of MRN-based medicines and vaccines. We believe that our platform has the potential 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 ARCTO 21 program.

Our CTO of 'twenty, one is the 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 for.

First by using self amplifying mrna technology a C. T. O 21 is designed to promote a strong immune response, followed by a single administration.

Joseph E. Payne: ARCTO 21 is a differentiated COVID-19 vaccine candidate based on 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-O21 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.

We believe the single shot dosing regimen would be highly favored compared to the two administration of approaches employed with currently authorized mrna vaccines for emergency use.

Second our 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 SAR C. O V. Two viral variance circulating throughout the globe require of vaccine modifications.

Third another important benefit of mrna based vaccines is their ability to be re dosed if needed potentially on a yearly basis.

Joseph E. Payne: 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 redosed, if needed, potentially on a yearly basis. It is expected that long-term protection against COVID is likely to require periodic redosers. And our approach, which utilizes lunar delivery technology and not a viral vector to deliver the vaccine, may be well suited to enable periodic or annual redosers.

It is expected that long term protection to COVID-19 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 or a.

Re dosing.

Our expectation is that the billions of individuals across the globe may require ongoing vaccination to protect against COVID-19 based on all of the favorable properties, we expect with our approach and believe that over the coming years a R. C. T O 21, as a low dose Lyophilize singles.

<unk> vaccine has the potential to become a favored or preferred vaccine option and many regions of the world.

We have continued to rapidly advance our clinical development program for <unk>, our CTO of 'twenty, one our phase II study is now fully enrolled with 580 participants were pleased to see the continued growth of our safety database and the consistency is reading through as we of clinically evaluated our VAT.

Joseph E. Payne: 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, ARCTO 21, 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 ARCTO 21.

Maxine and Singapore and now also with participants in the United States the.

The primary purpose of this phase two study was to further evaluate the safety and Immunogenicity of our CTO of 'twenty. One. The study remains ongoing we have had multiple interim analyses of the safety data that have been reviewed by the SMB and the study has been allowed to proceed with no changes to protocol.

Joseph E. Payne: Our phase two study is now fully enrolled with 580 participants. We're pleased to see the continued growth of our safety data and the consistency 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 two study was to further evaluate the safety and immunogenicity of ARCT-021. The study remains ongoing. We have had multiple in-term analyses of the safety data that have been reviewed by the DSMB, and the study has been allowed to proceed with no changes to the protocol.

As Steve will discuss shortly our in term of Immunogenicity data from the study demonstrate the high seroconversion rate.

Again in line with our expectations.

And given the 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 the single shot low five microgram dose regimen into phase III development.

Joseph E. Payne: As Steve will discuss shortly, our interim immunogenicity data from the study demonstrate a high serial 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 2 study, as well as from our prior Phase 1-2 trial, we have made the decision to advance a single shot, low 5-microgram dose regimen into Phase 3 development.

We are now and negotiations with multiple regulatory authorities regarding the specific design of this study.

We are excited to move our CTO of 'twenty, one program into phase III, and we look forward to providing further updates and our progress and the near future.

I'll now turn the time over the Doctor, Steve Hughes and the Chi.

<unk> medical officer of Arcturus.

Thanks Chuck.

I'll start with <unk> Xu of 'twenty one.

COVID-19 vaccine.

Joseph E. Payne: We are now in negotiations with multiple regulatory authorities regarding the specific design of this study. We are excited to move our ARCTO 21 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 our turn.

And one class II study conducted in Singapore completed and the first quarter and we anticipate submitting the full of adults to a peer reviewed journal later this quarter.

Our ongoing phase II study completed enrollment on the 13th of March with the 590 participants that were dosed and the pardon me vaccine and he's vaccination schedule is now complete.

Two interim analyses have been completed and reviewed by the data and safety monitoring board and they've recommended that the study can proceed with none of amendments required for the protocol.

Steve Hughes: I'll start with ARCT 021, our COVID-19 vaccine. The phase 1 slash 2 study conducted in Singapore was 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, I O T zero of 'twenty, one treated participants that have been followed up for at least 28 days after the first dose.

The emerging immuno day imaging and Immunogenicity data from this study is consistent with the results from our phase one and slash two study and showed greater than 90% of conversion the <unk> antibody binding to the full length of Spike protein at day 28, following a single dose of five micrograms of <unk>.

Steve Hughes: 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 1-2 study and shows greater than 90% zero conversion for IgG antibodies binding to the full-length spike protein at day 28 following a single dose of 5 micrograms of ARCT 021. Serra conversion is at the threshold of at least a fourfold increase from baseline values.

Zero of 'twenty one.

So of conversion is at the threshold of at least the four fold increase from baseline values. This is in line with all the expectations based upon what we saw and the phase one slash two study where 81% of participants who have converted for the anti Spike <unk> by day 14. After a single five microgram dose and 100 per se.

And I'd say of a converted by 28 days post the single five microgram dose.

Safety data to date continues to be favorable and is consistent with what we saw and the phase one the last two study.

Phase III preparations are proceeding well and we are in discussions with multiple regulatory authorities concerning the phase III program.

Steve Hughes: 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-micogram dose, and 100% had seroconverted by 28 days post-single 5-migram dose. Safety data to date continues to be favorable and is consistent with what we saw in the phase 1 slash 2 study. Phase 3 preparations are proceeding well, and we are in discussions with multiple regulatory authorities concerning the Phase 3 program. I will turn now to Art 810.

I'll turn now to out 810th.

Oh therapeutic candidate for ornithine trends called analyze for OTC deficiency.

And <unk> 10 utilizes two of us lunar lipid mediated delivery platform to deliver OTC messenger RNA to deliver the preliminary target tissue and OTC deficiency.

Expression of the normal one of the main trends Corp, analyze enzyme and the level of patients with OTC deficiency has the potential to the store U S Oracle activity, preventing neurological damage and the need for liver transplantation.

Steve Hughes: Our therapeutic candidate for or nathine transcarbales or OTC deficiency. ARCT810 utilizes Arcturus lunar lipid-mediated delivery platform to deliver OTC messenger RNA to the liver, the primary target tissue for OTC deficiency. Expression of the normal ornathine transcarbamalyze 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 the nine month, chronic toxicology study and which 20 doses of <unk>, a 10, well administered every two weeks and nonhuman primates and the study we observed no adverse histological findings, including at dose levels above those that we are evaluating and a phase one b and our phase II clinical study.

Yeah.

These non human primate data bolstered the strong IR Cta 10, preclinical data package that supported the advancement of the program into human studies and provide support for extended dosing in humans.

Steve Hughes: We recently completed a nine-month chronic toxicology study in which 20 doses of ARCT 810 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're 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 provides support for extended dosing in humans.

We remain on track to submit the Cta for a multiple dose phase two study and 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 the phase one healthy volunteer dose escalation study with iOS 10.

The study demonstrated that administration of <unk> 10 was associated with favorable Tolerability and then the attractive pharmacokinetic profile up to the top dose of north of four milligrams per kilogram, which is within the anticipated therapeutic range based upon data from our preclinical studies and.

Steve Hughes: 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 1 Healthy Volunteer dose escalation study with ARCT 810. The study demonstrated that the 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.

And that study, we were able to measure of messenger RNA and the last one was assessed which was two weeks after dosing.

Our phase <unk> dose escalation study evaluating <unk> 10, and patients with OTC deficiency remains ongoing and we continue to open new sites to facilitate additional enrollment in the coming quarter and initial results from this study of anticipated later this year.

And we'll finish with <unk> to the two <unk>.

RPT candidate for cystic fibrosis for CF.

Steve Hughes: In that study, we were able to measure messenger RNA at the last time point that was assessed, which was two weeks after the dose. Our Phase 1B dose escalation study evaluating ARCT 810 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.

<unk> two is designed to induce the expression of a fully functional transmembrane conductance regulator or the FTR and the lungs of CF patients C. F. T. O is the membrane protein and chloride channel that is deficient and CF patients, causing severe pathology, including lung dysfunction.

<unk> utilizes out too is the lunar lipid MSL platform to deliver CFT, our messenger RNA to the lungs <unk>.

Steve Hughes: I will finish with ARCT 032, 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. ARCT 032 utilizes the Arcturus Lunar Lipid aerosol platform to deliver CFTR messenger RNA to the lung. ARCT-032 preclinical studies have demonstrated the ability to efficiently deliver targeted MRNA to 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.

<unk> zero of 32 preclinical studies have demonstrated the ability to efficiently deliver targeted mrna to the airway epithelium cells following topical and aerosol administration and we believe that our approach has the potential to correct the underlying defect, causing the disease and CF patients. We remain on track to submit the Cta for the program and Q4.

For this year.

I will now pass the call onto Andy our CFO.

Thank you, Steve and good afternoon, everyone the per.

Press release issued earlier today includes financial statements for the first quarter of fiscal year 2021.

Our current as primary sources of revenue is currently from licensing fee and collaboration payments.

<unk> from research and development arrangement with our pharmaceutical and biotech partner.

For the three months ended March 31, 2021 of the company reported revenues of $2 1 million compared with $2 6 million and the three months ended March 31 2020.

Andrew H. Sassine: Thank you, Steve, and good afternoon, everyone. The press release issued earlier today includes financial statements for the first quarter of fiscal year 2021. Our TURIS's primary sources of revenues are currently licensing fees 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 31, 2021 for $59 8 million compared with $12 1 million for the three months ended March 31, 2020, and $33 3 million for the three months ended December 31 and 2020.

The increase of net expenditures were due primarily to the increased activity and clinical and manufacturing of expenditure.

Related to the company's COVID-19, and OTC program as well as increased personnel costs and other.

Andrew H. Sassine: 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 was due primarily to increased activity in clinical and manufacturing expenditures related to the company's COVID-19 and OTC programs, as well as increased personnel costs and other facility costs related to the organizational growth of the company.

Other facility costs related to the organization and 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 and clinical and manufacturing cost of $29 2 million for our <unk> 'twenty one program the <unk>.

The increase was primarily related to the acquisition of <unk>.

And the exclusive exclusive license from Alexia and pharmaceuticals to certain patent pending inventions related to nuclear assets purification technologies for approximately $5 million of Arcturus dock.

Andrew H. Sassine: Research and Development expenses increased by approximately $42.1 million compared to the three months ended March 31st, 2020, and this was primarily driven by an increase in clinical and manufacturing costs of $29.2 million for our ARCT-21 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 technologies for approximately $5 million of Arctura stock and an increase in personnel-related expenses. Our cash balance totaled approximately $467 million as of March 31st, 2020.

And an increase and personnel related expenses.

Our cash balance total approximately 467 million as of March.

March 31 2020.

Based on our current pipeline and the company's cash position.

Specced at the be sufficient to support operations for more than two years.

We continue to plan for the potential that <unk> 'twenty, one could we see the emergency use authorization later, this year and one or more countries.

Along with our global manufacturing partners, we have laid the foundation to produce hundreds of millions of doses of <unk> 21 annually.

Additionally, we have secured manufacturing requirement.

Andrew H. Sassine: 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 youth 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 ARCT 21 annually. Additionally, we have secured manufacturing requirements to meet the clinical needs of all our pipeline programs.

The clinical needs of all of our pipeline program.

I'll now pass the call back to Joe.

Hey, Thanks, Andy and this has been of product.

Joseph E. Payne: I'll now pass the call back to Joe. Hey, thanks, Andy. This has been a production.

Operator: Hey, thanks, Andy. This has been a production. Ladies and gentlemen, please stand by. We appear to have lost the audio.

Ladies and gentlemen, please standby we appear to have lost the audio we are going to try to establish the connection.

Okay.

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 III results. We believe that there is the potential for a RCT Oh 21 of the gain emergency use authorization and at least one country before year end.

Operator: We are going to try to establish the connection. Hi, I'll begin by saying thanks, Andy. I'll start after the transition.

Which would of course represent an enormous achievement for our company, we believe that as the single administration, Lyophilize, hence and investigational vaccine with very low dose.

Joseph E. Payne: This has been a productive quarter, and ArcTuris 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 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, liophilized investigational vaccine with a very low dose, ARCTO 21 could have a differentiated profile, positioning the product for potential benefits. We're also advancing our broader clinical and preclinical pipeline programs and anticipate reporting important milestones.

And our CTO of 'twenty, one could have a differentiated profile positioning the product for a 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 RCT 810 clinical study being conducted in patients with OTC and look and look forward to start.

The phase two multiple dose study.

For our <unk>, our CTO of 32 CF program, we're looking forward to of Cta filing later this year.

Our goal with our CTO of 32 is to utilize and easily administered aerosolized approach to correct. The underlying deficiency scene and cystic fibrosis, and the providing 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 apply.

Joseph E. Payne: Later this year, we expect to obtain initial safety and pharmacokinetic 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 ARCTO 32 CF program. We're looking forward to a CTA filing later this year. Our goal with ARCTO 32 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.

And our mrna technology to develop.

The novel vaccines and other medicines for many other life threatening diseases, we expect to have and 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.

Thank you.

If you'd like to register a question. Please press the one followed by the for on your telephone you will hear of three Tom prop technology request for 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.

Operator: 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. 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.

Our first question comes from the line of Yasmin Rahimi with Piper Sandler. Please go ahead.

Hi team. Thank you so much for taking my questions and all of the great progress for your question for you maybe the first one and you mentioned on the call that you of pad two data safety monitoring meetings with the FDA will look at.

Data safety monitoring committee meeting two cleared and that continuing 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 III to get kicked off and if you could provide some color in terms of debt.

Operator: followed by the three. One moment, please for the first question.

Yasmeen Rahimi: Our first question comes from the line of Yasmine Rahimi with Piper Sandler. Please go ahead. Hi Tim.

Yasmeen Rahimi: Hi Taine, thank you so much for taking my questions and all the great progress. I have 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, who have looked at data safety monitoring committee meetings and cleared them and said continue with the protocol. How many more are left to do for the state two study? And when should we, what's the rate-limiting step for 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.

Size of the study that would be helpful. And then I have a follow up.

Go ahead, Steve Okay.

So the for the question so.

The day of SMB will be reviewing the data regularly throughout the study is not just interim analysis and then.

Reviewing and at the front end of the study we were doing dose selection for phase III study. So we had a couple of very quick interim analysis, Bill and right at the front end of a day of SMB reviewed.

With the main part of the really big on the safety data.

And it just happened to coincide with when they would be doing the review.

Steve Hughes: Go ahead, Steve. Okay, thanks for the question. So, um, The DSMB will be reviewing the data regularly throughout the study. It's not just interim analyses at their review. At the front end of the study, we were doing dose selection for our phase three 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 focus 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 the interim analyses planned within the study, but that'll be a few months, Hawaii and as I said the the initial in terms of quite price together to allow us and confirm the dose selection for the phase III study.

In terms of the total number of the SMB meeting.

The possible to say for the entire study how many meetings now half because as the data matures for the SMB may decide that I would like to do meeting less frequently and are more frequently.

They will be and reviewing.

Steve Hughes: There are another two 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 three study. In terms of the total number of DSMB meetings, it's possible to say 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 plan 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.

All of the day data regularly to the study.

Which is really a requirement for these COVID-19 studies that you have of the SNB and place and we will have the same the SMB for a phase III study as well and through phase III that would also be regularly reviewing the safety data and are in phase III without having to them and out of season planned for that because we're not doing any further dose selection of it.

Sure.

In terms of the progress with phase three we're very pleased for the progress that we've made so far.

We have a final protocol, that's written and where and we've entered into discussions with the number of different regulatory authorities concerning.

That protocol and having the most efficiently move it forward in those countries.

So in terms of moving to the next that we need to conclude these discussions with the regulators and if the price goes acceptable and will and and or I should say once we get agreement on the on the study design.

And is the major elements of the study design and we'll complete the Cta process that will allow us to move forward to validate and and initiate sites and the different countries.

Steve Hughes: We have a final protocol that's written, and we've entered into discussions with a number of different regulatory authorities concerning that protocol and how we can 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, one. 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.

And.

Thank you David maybe.

And with you noted that we should be seeing neutralizing and T cell data and the.

The second half of this year in that so far data based on the first 300 patients followed for 28 days the immune.

And the profile of consistent with what we've seen so far but can you maybe help us understand.

And how much more we should be expecting to see other than all 580 patients until the second half.

But maybe we'll we have data on a longer longer and longer treatment beyond the 60, I think it would just be helpful to understand what we will be seeing and immunogenicity data and the second half of this year.

Yasmeen Rahimi: Thank you, Steve, and maybe it was, you noted that we should be seeing neutralizing effects in T-cell data and the 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 as we move into the second half of this year, we do have some additional interim analyses with wed later time points.

Yasmeen Rahimi: So can you maybe help us understand how much more we should be expecting to see other than all 580 patients in the second half? But maybe we will have data on a longer, longer, longer treatment beyond D60? I think it would just be helpful to understand what we will be seeing in immunogenicity data in the second half of this year.

And one.

One of those time points I believe is at around about the six month, Mark and then.

Within the study.

At six months people of randomized to either.

Receive of placebo boost or the receiver another boost the shops, so that we can evaluate.

And what the boost the sponsor is after after a long interval and so we'll be collecting them and the agenda study of data immediately prior to that boost and then again after the boost and then again at <unk> at one year.

Steve Hughes: As we move into the second half of this year, we do have some additional interim analyses with later time points. One of those time points, I believe, is at around the six month mark.

So there are a number of different data cuts that will be performing on the study.

Largely to inform.

Steve Hughes: 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 immunogenic 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 performed on the study.

Thinking of how we move the drug forward from the phase III study and to the commercial setting and what additional data points, we might want to collect and the post market setting with with the vaccine if approved.

Thank you Steve that was very helpful.

Thanks, guys.

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

Hi, guys, it's Joe on for Nick Thanks for taking our questions and congrats on the progress two questions from us.

Steve Hughes: 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 a postmarket setting with the vaccine, if approved.

The in terms of Immunogenicity do you expect the proportion of those patients who didnt zero convert the potentially still achieve some degree of T cell immunity and maybe how does the data presented today and provide you additional confidence and success.

Yasmeen Rahimi: Thank you, Steve. That was very helpful.

Nick Abbott: Our next question comes on the line from Nick Abbott with Wells Fargo. Please go ahead.

Success going forward and then secondly, maybe you focus more simply on timing around the phase III are you still.

Joe: Hi guys, it's Joe on for Nick. Thanks for taking our questions and congratulations on the progress. Two questions from us. Steve, you know, in terms of immunogenicity, do you expect a proportion of those patients who didn't zero convert?

Anticipate guiding towards the initiation in the second quarter or have you maybe experienced any delays.

Joe: 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 conversations with regulators that you could provide more color on.

Go ahead, Steve.

The first of all talking to the the T cell responses for the Phase II study, we we havent got the T cell data, yet and were expecting that to come and a little later.

Steve Hughes: And then secondly, maybe focused more simply on timing around phase three. Are you still guiding towards initiation in the second quarter, or have you maybe experienced any delays in conversations with regulators that you could provide more detail on?

And have no reason to believe that the T cell responses that we see and the phase II study will be any difference of what we saw and the phase one studies that were anticipating volume robust T cell responses and the participants the other pieces of that.

Eric: with regulators that you could provide more color on. Eric, go ahead.

We're not anticipating that people that.

That maybe have lower sale of conversion or non semi conversion.

Steve Hughes: Go ahead, Steve. So first of all, talking about 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 from what we saw in the Phase 1 study. So we're anticipating very robust T-cell responses in the participants.

On the antibodies that that means that I don't have a robust T cell response that the two things as we look at them are independent and.

And that certainly what we saw and the phase one two study.

And I think the final piece is that you have to remember that this data is day 28 data for first day of our conversion for the five microgram dose cohort and we do anticipate that because of the wrap the call mechanism with sustained antigen expression that will continue to say additional sale of conversions as we go out further in time so.

Steve Hughes: The other piece is that we're not anticipating that people that maybe have lower seroconversion or non-serro conversion on antibodies will mean that they don't have a robust T-cell response, and that's certainly what we saw in the phase one study. I think the final piece is that we have to remember that this data is day 28 data for zero conversion for the five microgram dose cohort, and we do anticipate that because of the Rappli So the 90% zero conversion rate at day 28 isn't the end of the story for zero conversions for these participants. Did that answer your question? No, that's very helpful. Thank you, Steve.

So the the.

The 90% sale of conversion rate at day 28, and at the end of the story for Sarah conversions for these participants.

Did the answer to your question.

No that's very helpful. Thank you Steve.

Yeah.

Thanks, Joe.

Our next question comes from the line of Seamus Fernandez Guggenheim. Please go ahead.

Hi, guys and Evan Wang on for Seamus.

Two questions one on.

And so you want on the one on.

The program first with the.

Q1, and is there any more data required for the phase III.

Or is it simply operational and choosing the kind of the countries now and we're back.

And very and probably 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 markets evolved over the last two months.

Seamus Christopher Fernandez: Our next question comes from the line of Seamus Fernandez. Guggenheim, please go ahead.

Edwin Zhang: Hi guys, this is Edwin-on-Fer Seamus. I have two questions, one on O21 and one on the OTC program. First, with the O2. Is there any more data required for phase three, or is it simply operational in choosing the kind of countries where vaccines aren't probably available? As a fallback to that, you know, how is the company thinking about the viability of moving forward with the product, given just how the markets have evolved over the last few months?

And we're definitely on the landscape of later.

Yes sure.

Definitely in the late stages of.

The operational planning for phase III.

And.

And anything else to add Steve on the us.

With that and don't anticipate any problems with with the regulators in terms of the data package that we have given them for discussion and it's always possible the regulators come back and ask for more data and.

And may not be clinical data and my ask for further clarification on the CMC side or the things like data as part of the normal regulatory review process and we get.

Joseph E. Payne: Well, we're definitely on the latest date. Yeah, sure. We're definitely in the late stages of operational planning for phase three. Anything else to add, Steve, on this?

And for advice Swift turnaround to address questions that they have when we receive them, but there's nothing at this point that we're thinking.

It's going to be a wrinkle that is kind of course significant issue.

Steve Hughes: So 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 will 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 relatively swift turnaround to address questions that they have when we receive them. But there's nothing at this point that we're thinking, you know, that it's going to be a real deal. wrinkle that's going to cause significant issues. And with respect, your

And with respect to your question about how the market continues to evolve and.

And our level of commitment of 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 lyophilize vaccine.

And our CTO of 'twenty, one has value to us not only as a standalone asset.

But it represents proof of concept for self amplifying mrna vaccine technology.

Joseph E. Payne: 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 moving forward at this time. We have contractual obligations to fulfill. Certain regions of the world may be more amenable to a single-shot, biofalyzed vaccine. And ARCTO 21 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 ARCTO 21 can open the door or at least streamline the path to additional updated variant versions of ARCTO 21.

And in addition to that of safe effective and approved a our CTO of 'twenty. One can open the door or at least streamline the path to additional updated variant versions of our CTO of 'twenty one.

Got it that's helpful and and OTC.

How does the current progressing and what and when we see biomarker data from our single ascending dose study.

And are there any gating factors for starting the phase III.

Go ahead, Steve.

So I had the phase one data and I heard the gating factors for phase two I think.

You broke up a little bit of at the beginning of your question. So what was the first part.

Regarding the phase one b and one and we'll see biomarker data from the study.

Joseph E. Payne: That's helpful. And on OTC, you know, how is the program progressing, and when will we feed biomarker data from a single-offending dose study? And are there any gating factors that start phase two?

Okay.

For the phase one B study have the amaze ongoing we're anticipating that we'll see initial data later on and the year. So.

And we really need to complete the carnival and the first cohort of moment and.

Steve Hughes: 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?

The follow up and then we'll have a look at the data at that point, and we will be able to.

Lack of disclosure in terms of the phase II study there is nothing that particularly the 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.

Steve Hughes: As regarding phase 1B and when we'll see biomarker data from that study, so the Phase 1B study

Steve Hughes: So the Phase 1B study remains ongoing, and we're anticipating that we'll see initial data later 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 2 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 and as I said earlier and that.

Again has the standard review time, so we're anticipating that we'll get the.

Tony review and be able to initiate that study a little bit lighter and the year as well.

Great. Thank you.

Thank you.

And.

As a reminder to register for a question. Please press the one followed by the four and your telephone.

Our next question comes from the line of you call. The <unk> with Citigroup. Please go ahead.

Steve Hughes: 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.

Alright, great. Thank you very much for taking the questions ahead of few first of all how quickly do you believe that you could submit the EUA aster and receiving positive phase III data for 'twenty one.

And second what other details of the leaves me to be hammered out with the regulatory agencies regarding the phase III trial design and will there be any notable differences and the way. The arcturus is conducting the phase III as compared with <unk> or of Pfizer.

Yikal Nakamovitz: As a reminder, to register for a question, please press the one, followed by the four on your telephone. Our next question comes from the line of Yikal Nakamovitz with Citigroup. Please go ahead.

Well, it's a good question.

Yikal Nakamovitz: Hi, great. Thank you very much for taking the questions. I had a few.

Does vary considerably depending on which regulatory agency, we talked to and which country with respect to timing of an emergency use approval request.

I'm sure, Steve can maybe provide us and them.

Yikal Nakamovitz: First of all, how quickly do you believe that you could submit the EUA after receiving positive phase three data for 2021? Second, what other details do you believe need to be hammered out with the regulatory agencies regarding the phase three trial design? And will there be any notable differences in the way that Arcturus is conducting the phase three trial as compared with Moderna or Pfizer? Thanks.

No additional color there.

With respect to the trial design, we are conducting our phase III trials and areas, where theres a high for.

And increased prevalence of COVID-19 compared to six nine months ago, and some countries have much higher prevalence rates.

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

And it puts the.

The unique pressures on the regulatory agencies to transition the placebo group for example over too.

The vaccinated group sooner than previous trials, but.

Steve any additional color.

Yes.

And at a high level, that's the principle.

The thing that we need to build into our study as opposed to the Madonna and the size of the study is that the plan for the.

And how we transition placebo because it's not really.

Ethical to keep them of a wife and vaccine for long periods of time, particularly at the vaccine becomes available for that age group or the West group and that is one of the things that were in discussion with the regulators about at this time.

Steve Hughes: But Steve, any additional color? Yes, so I think

And I guess the other thing is that both Madonna and Pfizer did very very large clinical trials, we're doing a very large clinical trial dates and the order of 15000 participants.

Steve Hughes: 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 the vaccine for a long period 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 discussions with the regulators about at this time.

Not 30 to 45000 participants.

I guess the.

Final question of the EUA.

So it's just the time between Fei.

<unk> phase III data and the UAE.

And that's something that we're not able to give the.

Clear guidance on at the moment. So we're in discussion with our sellout of about how long it is kind of tight.

Steve Hughes: 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 parties, not 30 to 45,000 participants. I guess the final question was the EUA.

Between net final data and lock the database and.

And spit out the.

And the biostatistics outputs on the efficacy and safety that we made and also with the.

Medical lighting vendor as well, we're just in the process of going through the contracting process for the resources, we need to turn.

Steve Hughes: So the time between, you know, phase three data and the UA.

Steve Hughes: 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 biostatistical 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.

And the defense of the study of a pole and the.

<unk> CTD sections and of <unk>.

Yikal Nakamovitz: Great. Thank you very much.

The fashion that will be able to provide more color on that as we conclude.

Those discussions.

Great. Thank you very much.

Thank you.

And maybe the last thing is is that.

The.

The in terms of that with the guidance that replaces the previously given for EUA.

This year that Hasnt changed.

Still what we're targeting.

Yes.

Our next question comes from the line of Wang Z Li with Ladenburg. Please go ahead.

Alright, Thanks for taking my question maybe on.

The one person about of the imminent the nuclear profile of patient to fear of conversion rates of any further color on the corridor of the IGD antibody and it.

Joseph E. Payne: Thank you. 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. So it's still what we're targeting. Yeah.

And this moment and the Cologne.

And utilizing our T cell response.

And I understand you've made didn't have the data yet.

Boran Wang: Our next question comes on the line from Wang Z. Lee with Ladenberg. Please go ahead.

Yes, that's correct, we don't have data yet for neutralizing antibodies and T cells that is forthcoming.

Boran Wang: Hi, thanks for taking my question.

Boran Wang: Question, maybe on 21, first about the immunities profile, you know, efficient to zero.

And the blending and the binding and and the binding antibody data was it was.

Boran Wang: conversion rates, any further call on the Kite or the IgG antibody, and that this

Very in line with our expectations with respect of Seroconversion rates at day 28.

Steve Hughes: And at this moment, any colon neutralizing T-Cel response?

Oh, yes, sorry.

Yeah.

It's.

The studies because of the study is still blinded to a number to the investigator and all of the site staff of et cetera.

Steve Hughes: Yeah, that's correct. We don't have data yet for neutralizing antibodies and T-cells, but that is forthcoming. And the binding antibody data was very in line with our expectations with respect to serial conversion rates at day 28.

And where we're getting very high level data and not getting too granular on the data because the whole.

And blinded data that we get the more it could.

The compromise the integrity of the study in terms of assessments out of my study sites.

And so at this point, we're not disclosing the individual details of.

Steve Hughes: Yes, I believe where it's a, it's a, the study is still blinded to a number, to the investigator and all the site staff, etc. We're giving very high-level data and not getting too granular on the data because the more blinded 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 neutralizing, sorry, of the, sorry, are the antibody titus?

Of the neutralizing sorry of the.

Of the antibody titers.

Got it.

Okay.

And then for the OTC the program the <unk>.

Monkey study you determine the dose. The addition to safety and just wanted to do you have done any like PD marker or.

So of Immunogenicity on the target proofing.

Alright.

Maybe for US clarify the you see the human put in monkeys, and maybe not.

First for you mentioned instead of the task, but any color on that.

Yeah. This is the toxicology study designed to support of.

Boran Wang: Got it. Okay. And then for the OTCD program, the monkey study, you did 20 doses, in addition to safety,

Phase two multiple dose application.

The amount of any PD markers, you can do and a healthy monkey and got normal.

Boran Wang: I just wondered, do you have done any, like, a PD marker or something?

OTC enzyme activity. So the the PD studies really needs to be done and the mass model of disease, where the.

Boran Wang: Also, immunogenicity on the target protein.

Boran Wang: I should first clarify that this is a human pudding monkey, so maybe not the best for imagination testing, but any take on that?

Weather and.

And as the especially where the deficiency.

Most of have OTC deficiency.

And we can see PD and those studies have already been done for this very was to look at the the.

Steve Hughes: Yeah, this is a toxicology study designed to support, you know, a phase two multiple dose application.

Effects of long term dosing and to make sure that we didn't see any toxicities with long term dosing that would make and make us need to revise.

Steve Hughes: There aren't really any PD markers you can do in a healthy monkey because 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 immunogenicity, sorry, where they're deficient. But the mice that have OTC deficiency, and there 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 with long-term dosing that would make us need to revise our dose expectations. Thank you.

Those expectations.

Thank you, ladies and gentlemen, and for and for those familiar with lipid nanoparticle mrna therapeutics of 'twenty dose nine month, chronic Tox study and primates is of significant milestone.

For the science.

Okay, great. Thanks for taking my question.

Okay. Thanks Lindsay.

Our next question comes from the line of <unk> Roy with Brookline. Please go ahead.

Hi, I'm sure window on behalf of Kumar from Brooklyn.

Joseph E. Payne: Thank you. Yeah, and for those familiar with lipid nanoparticle, MRNA therapeutics, a 20-dose, nine-month chronic oral study in primates is a significant milestone for the science.

I had a couple of questions. So one was so in terms of the size of the worldwide for the vaccine do we have molecules like the D and polysorbate back and they have you know allergic reactions of our other side effects.

Boran Wang: Okay, great. Thanks for already asking my question.

Now do we.

And as you can appreciate our the our CTO of 'twenty. One is of very low dose RNA vaccine. It's only five micrograms of its only a single administration.

Shubandu Senroy: Our next question comes in line with Shubandu Senroy with Brookline. Please go ahead.

Shavendu: Hi, I'm Shavendu on behalf of Kumar from Brooklyn.

And the.

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 and some talks discussions. So this could prove to be very fruitful, Steve with respect to providing color on.

Shavendu: I had a couple of questions. One was, so in terms of

Joseph E. Payne: side effect profile for the vaccine, do we have molecules like PEG and polysorbid that may have, you know, allergic reactions or other side effects?

Joseph E. Payne: No, we haven't. As you can appreciate, ARCTO 21 is a very low dose RNA vaccine. It's only five micrograms. It's only a single administration.

Have we observed any of these.

No serious adverse events that others have observed and their trials, maybe you can provide a little color there.

Joseph E. Payne: 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 on, you know, 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 all of.

The anaphylactic reactions.

Yeah that.

Have been some serious adverse events and the study of it at normal and in any study that you say and certainly nothing that has caused concern for us the orca.

Most concerned for the for the day of SMB.

Great.

Just one follow up question. So since this is the single dose of vaccine do you anticipate modifying the content with respect to wait and see every year annually.

Steve Hughes: So to my knowledge, we haven't seen any serious adverse events that are that are anaphylactic type reactions at all. Yeah. 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 DSI.

Yeah Yeah.

Definitely.

And are in the process of evaluating all of the major variance.

And were and are positioned to move very quickly to update our CTO of 'twenty one of if needed.

And.

I also point out that the our CTO of 'twenty one.

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

It is because of its robust cellular community or Immunogenicity profile.

Good as is with respect to variant coverage, but if we find some challenges for some challenging variance and our.

Joseph E. Payne: 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 ARCTO 21 if needed. But I also point out that ARCTO 21, as is, because of its robust cellular community 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 three studies, we'll be able to make it because of the efforts that have been ongoing pertaining to the present evaluation and synthesis of the variance.

And 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 variance.

And it sounds great. Thank you for taking my questions.

Thank you.

Our next question comes from the line of Stephens and seed House with Raymond James. Please go ahead.

Hi, Thank you first of all of the OTC program.

You mentioned no adverse histological findings and I'm, just curious and the histology data are you able to look at all of that OTC expression are you able to determine.

And you get per of portal delivery and OTC expression and the prime rate.

Lots of Great question, we've definitely shown.

Shavendu: Excellent. Sounds great. Thank you for taking my questions.

And.

Distribution to pair of portal hepatocytes and rodent models.

Stephen Seatheels: Our next question comes in line with Stephen Seatheels with Raymond James. Please go ahead.

Steve of pad have we seen any per of portal hepatocytes data and our primate studies.

Stephen Seatheels: First, on the OTC program, you mentioned no adverse histological findings. I'm just curious about 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 primary?

Nobody can just because of the high background level and non human primate, it's hard to distinguish the two between the human and nonhuman primate.

But what we do.

And in preclinical models previously we have looked at OTC expression and prime it and we do see of dose correlation for and pair of portal hepatocytes and generally in the liver, but not specifically and private portal.

Joseph E. Payne: That's a great question. We've definitely shown distribution to paraportal hepatocytes in rodent models. Steve or Pab, have we seen any periportal hepatocyte data in our primates yet?

Okay.

Okay and then.

And again understanding of the histological findings looked good just share on safety overall can you talk about if you saw any adverse events.

Steve Hughes: 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 primates. 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. Or in pariportal hepatocytes. In general, in the liver, but not specifically in pariportal.

And I.

And I guess, maybe the more specific question.

And he fold above your targeted clinical dose did you test and the prime minutes and did you determine the no observed adverse and that level.

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.

Stephen Seatheels: Okay, and then 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?

We didn't observe and allowance.

Yeah, we didn't observe and all.

Okay, that's very helpful. Thanks.

And then a positive outcome yes.

Okay.

And you foresee.

And I mean are you planning on filing and Indy and conducting a multi dose study at some point and the USB C. Any roadblocks there.

Joseph E. Payne: 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.

And maybe if I tie that question, yes. So the first port of call is true.

Joseph E. Payne: But we didn't observe a no-out. Yeah.

And Asia and start giving multiple doses with the current and planned Cta and then the way that we will definitely be evaluating whether we submit a protocol amendment and styles of the IMD for a multi dose study and the United States, but.

Joseph E. Payne: Yeah, we didn't.

Joseph E. Payne: Okay, that's very helpful, thank you. It was a positive outcome. Okay. Do you foresee, I mean, are you planning on filing an I and D and conducting a multi-dose study at some point in the U.S.? Do you see any roadblocks there?

In terms of facilities same thing in terms of facilitating that process I think it would be nice to get a.

A few doses and a couple of patients under the Cta. So that we can go and back to FDA and say look we've dosed X number of doses already and this is volume can be come the amend the protocol.

Steve Hughes: Maybe if I take that question. Yeah.

Steve Hughes: So the first port of call is to initiate and start giving multiple doses with the currently planned CTA. And then, with it, we will definitely be evaluating whether we submit a protocol amendment and file for the I&D 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 at the CTA so that we can come back to FDA and say, look, you know, we've given X number of doses already, and this is fine, can we go on the protocol. So that's definitely under discussion at the moment.

And at the end of the discussion of the amendment.

Terrific. Thanks, and last question for me I. Appreciate you taking all of the questions at least one this is on the COVID-19 vaccine and Theres. One recent phase III studies development of the study they are using.

And the Immunogenicity primary endpoint and testing neutralizing antibodies versus the comparator vaccine.

For the first I've seen of that design and obviously, you're still speaking about and event driven studies and I'm curious if you've been asked at all of the run.

Similar.

And April of Immunogenicity study for phase III by any of you.

The us or European regulator or.

Stephen Seatheels: Terrific, thanks. And last question for me: I appreciate you taking all the questions.

Specific in those geographies of Theres still good with the event driven studies. Thank you.

No that's of Great question, and you're right there is.

The considerable variability, depending on which country and which regulatory agency and conversations with.

But some regulatory agencies and countries that have early access to the vaccines.

Are definitely are requesting.

Requesting more information and about the potential of doing the comparison study.

But that's not in all of our conversations some some countries are.

Stephen Seatheels: At least one, this is on the COVID vaccine. There's one recent phase three study, the Valneva study. They're using an immunogenicity primary on point testing, neutralizing antibodies versus a comparator vaccine. I'm curious; it'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 three by any U.S. or European regulator, or specific in those geographies, are they still OK with event-driven studies? Thank you.

And do not have the same access.

Joseph E. Payne: 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 the case in all of our conversations. Some countries 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.

These early vaccines as others and there is of higher sense of urgency.

And are more open to a placebo controlled trial.

Makes sense of anything to add.

Okay great.

Great.

Thanks, Steve.

Our next question comes from the line of Yale Jen.

From Laidlaw and company. Please go ahead.

Okay.

Good afternoon, and thanks for taking the questions and congrats on all of the data so far.

Just two quick ones. The first one is in terms of the starting the phase III study you will have two additional internal analysis.

Steve Hughes: Makes us. Anything to add? Okay. Great. Thanks, Steve. Our next question comes from the line of Yale Jen, from Laidlaw and Company.

Is that the.

The outcome of from those and tunnel knowledge, the gating factor to starting the phase III or that are not relevant.

And.

So it is relevant because normally to go into the phase III study you would have some phase II data that showed debt and moving from tens of patients in phase one to tens of thousands of patients in phase III debt.

Yale Jen: Good afternoon, thanks for taking questions and congrats on the data so far. Just two quick ones.

Yale Jen: The first one is in terms of starting the phase three study. You have two additional internal analyses. Is the outcome from those internal analyses a gating factor to starting phase three, or that's not relevant?

Yeah.

And so stepwise approach, where your exposure of 100 patients first.

The question is how long you've followed by several hundred patients optical and and.

And traditionally for vaccines 28 days after the doses at the time point of which you determine safety and.

Steve Hughes: 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's a stepwise approach where you expose a hundred patients first. The question is how long you follow those several hundred patients up for.

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 five microgram doses behaving very nicely actually of the seven five microgram dose is behaving very nicely as well by the five microgram dose in terms of Immunogenicity. We think is the sweet spot and now we have sufficient data.

Put together.

Steve Hughes: 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 five microgram dose is behaving very nicely. Actually, the 7.5 microgram dose is behaving very nicely as well. But the five 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 to CISO, TAs.

Okay.

Impelling regulatory package to submit and C C.

Yes.

Okay, Great that's very helpful and maybe the follow up question here.

In terms of the phase two study so far.

Have you got.

Magazine with the patients.

In fact, it by Varian of mostly by the wildcard Couldnt go wild type of the hour relative strength.

And those patients.

Yeah, our phase II is conducted primarily in the U S with some of the patients being in Singapore.

With respect to the the.

Yale Jen: Okay, great, that's very helpful. Maybe the follow-up question here is that, in terms of the phase two study,

<unk> profile and in these areas.

And.

Yes.

Well understood but.

Yale Jen: So far, have you got measuring whether this page is?

Steve anything to add the <unk>.

Phase II study.

Yale Jen: are infected by variants or mostly by wild type, called called wild type, the original strain at the

And the.

And at 600 people, so thats not enough to be looking at COVID-19 cases, we did not anticipating and up COVID-19 cases, and the study of that size to be able to make.

Joseph E. Payne: in those patients. Yeah, our phase two is conducted primarily in the US, with some of the patients being in Singapore. With respect to the variant profile in these areas, it is, you know, well understood, but Steve, anything to add?

Ladies and Bill assessment of whether Theres any particular bias towards 1 billion of another phase III study.

And are you going to be archiving samples.

Some of them and from infected participants so that we can have a look at that yes.

Okay, great and thanks, and congrats on the progress.

Steve Hughes: Yeah, so the phase two study is only, you know, about 600 people. So that's not enough to be looking at COVID cases. We did not anticipate enough COVID cases in a 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. Yeah. Okay, great, and thanks a lot and congratulations.

Hey, Thanks, Joe.

Okay.

Okay.

I will turn the call back over to you Joe.

Alright, 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 and our responses and bye for now.

Yes.

Yale Jen: Okay, great, and thanks a lot and congratulations on the progress. Okay, thank you.

That does conclude the conference call for today, we thank you for your participation and ask that you. Please disconnect your lines.

Joseph E. Payne: I'll turn the call back over to you, Joe. All right, well, thanks, everyone.

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Joseph E. Payne: 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.

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

Operator: Thank you for your participation and ask you please to disconnect your line.

Operator: Thank you. Thank you. Thank you. Thank you. Thank you. Thank you.

And then.

Alright.

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