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spk08: Good afternoon, ladies and gentlemen. Welcome to the Atea Pharmaceuticals fourth quarter and full year 2022 financial results and business update conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we'll open the call up to your questions. To ask a question during the session, you need to press star 1-1 on your telephone. You'll then hear an automated message advising you that your hand is raised. To withdraw your question at any time, press star 1-1 again. Please be advised that today's conference is being recorded. I would now like to turn the call over to Joneigh Barnes, Senior Vice President of Investor Relations and Corporate Communications at Atea Pharmaceuticals. Ms. Barnes, please proceed.
spk11: Thank you, Operator. Good afternoon, everyone, and welcome to Atea Pharmaceuticals' fourth quarter and full year 2022 Financial Results and Business Update conference call. Earlier today, we issued a press release which outlines the topics we plan to discuss. You can access the press release as well as the slides that we'll be reviewing today by going to the investor section of our website at ir.ateafarma.com. With me from Atea are Chief Executive Officer and Founder, Dr. Jean-Pierre Samadosi, Chief Development Officer, Dr. Janet Hammons, Chief Medical Officer, Dr. Arantxa Horga, Chief Financial Officer and Executive Vice President of Legal, Andrea Corcoran, and our Chief Commercial Officer, John Bavrica. They will all be available for the Q&A portion of today's call. Before we begin the call, as outlined on slide two, I would like to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in today's press release and in the company's recent filings with the Securities and Exchange Commission, which we encourage you to read. Our actual results may differ materially from what is discussed on the call. With that, I'll now turn the call over to Jean-Pierre.
spk23: Thank you, Janae. Good afternoon, everyone, and thank you for joining us. As you will see on slide three, this year we are forced to continue the meaningful progress made across our advanced clinical development programs following strong execution in 2022. Clinical advocacy results from the Morning Sky trial informed our Phase III, Sunrise III trial of Beniposivir for the treatment of COVID-19, which was initiated in the first quarter of 2022. We anticipate an interim analysis from the Sunrise III trial in the second half of this year, followed by completion of enrollment by year end. We also made meaningful progress advancing our preclinical second-generation protease inhibitor program, and we anticipate finding an IND for a clinical candidate around the end of the year. With our HCV program, we completed preclinical and manufacturing work needed for the initiation of a phase two combination trial of benifosgravir and erizosvir in the second quarter. With our dengue program, we conducted two proof of concept studies for AT752, and the results will be shared with you today. Let's now move to CAVI-19. Turning to slide five, benifosbuvir is an oral nucleotide prodrug that targets viral RNA polymerase, a highly conserved enzyme critical to viral replication and transcription. We believe that benifosbuvir profile addresses the key limitations of current therapies. It has low risk of drug-drug interactions, and may be co-administered with commonly prescribed drugs for high-risk COVID-19 patients, a key limitation of PaxLogin. Scientific presentation demonstrating beneficiary lack of drug-drug interaction were presented last week at the Conference on Retroviruses and Opportunistic Infections, also called CORE. The U.S. COVID-19 public health emergency is set to expire on May 11, and the market dynamics for COVID continue to shift. Based on the current variants, there are very limited treatment tools available, with essentially only Paxlovid for outpatients or Vagluri or Remdesivir for hospitalized patients. The last thing of the public health emergency is going to make it even harder for this patient population to assess diagnostic and treatment. This is likely to lead to further mobility and mortality, particularly in the most vulnerable. Moving to slide six, we believe COVID-19 will continue to remain endemic throughout the world and particularly impact the patient population that we are studying in Sunrise Street. We believe that oral therapeutics will remain a multi-billion dollar opportunity for years to come, and projected annual COVID-19 oral antiviral U.S. demand using Acuvia retail prescriptions suggests the current estimated annual market opportunity over $10 billion. Beyond that, we believe that there is an opportunity to expand this market to patients where drug-drug interactions associated with Paxlovid are a concern, limiting and complicating prescribing. These include commonly prescribed drugs such as seizure medications, antipsychotics, anticoagulants, and more. Let me remind you that Paxlovid currently has 90% of the prescription market share, and there is still a significant unmet medical need as less than 30% of COVID-19 patients are being prescribed an oral antiviral. Turning to slide seven, as we are moving to a traditional payer market, it is clear that we will have to demonstrate a value proposition of the impact of Benipozivir against COVID. This will be achieved by using a primary endpoint of decrease in hospitalization and deaths. We believe that this will be the key consideration for drug reimbursement for COVID therapies in the future. This is why we are targeting the most vulnerable patient populations in Sunrise 3 who are the greatest risk for disease progression to severe COVID-19 or mortality and for whom there are limited treatment options. Let's keep in mind that CMS estimates an average cost approaching $22,000 per hospitalization. And approximately 70% of COVID-19-related hospitalizations of hospitalized patients were covered under Medicare. Moving to slide eight, let's now review our innovative Sunrise III trial, our Phase III registrational trial, which is evaluating Benifazovir as monotherapy and that's combination enteral terbine. Enrollment continues in this global phase three randomized double-blind placebo-controlled study, which will evaluate benifazovir or placebo administered at the same time as locally available standard of care. Patients will be randomized one-to-one to receive either benifazovir at 550 milligram twice daily or placebo. We expect to enroll at least 1,500 high-risk patients with mild or moderate COVID-19. Two study cohorts defined by the type of standard of care the patients receive would be studied. The first cohort is a monotherapy cohort that would be comprised of patients receiving supportive care, which represents the primary analysis population. The second cohort is a combination antiviral cohort that would be comprised of patients who are receiving a compatible antiviral against COVID-19 as part of the standalone care. The primary endpoint of the study is all-cause hospitalization of deaths through day 29 in at least 1,300 patients from the monotherapy cohort. You will recall that we have already evaluated hospitalization in the Morning Sky trial and been in foster care showed a 71% reduction in hospitalization versus placebo. And importantly, in addition, a subgroup analysis showed an 82% reduction in patients over 40 years old. Sunrise 3 will focus on high risk patients that are the greatest risk for disease progression to severe COVID-19 or mortality. The study is expected to have a large global footprint with up to 300 clinical sites in 25 countries, including the United States, Europe, Japan, and the rest of the world. Moving now to our hepatitis C program, which we believe has the potential to become a best-in-class combination with the potential to improve upon the current standard of care by offering a shorter duration protease-inhibitor-free treatment for patients with HCV. Slide 10 outlines our Phase II open-labeled study of benifosvivir and risosvir in HCV patients. The study will enroll approximately 280 HCV-infected direct-acting antivalve naive patients across all genotype including a leading cohort of approximately 60 patients. Patients will be administered 550 mg benifosbuvir in combination with 180 mg risosvir once daily for eight weeks. The primary endpoints of the study are safety and sustained biological response, or SVR, at week 12 post-treatment. Other virologic endpoints include virologic failure, SVR at week 24 post-treatment, and resistance. Regulatory submissions for the initiation of the trial are ongoing, and dosing of patients in this clinical trial is expected to begin during the second quarter. Initial data from the leading cohort of approximately 60 patients is anticipated around the end of the year. Turning to slide 12, I will now provide an update on our program for AT752 intervention against dengue. We have been a pioneer in the development of our normal antiviral therapeutic for dengue. Our proof of concept study, DEFEN2, demonstrated that AT752 treatment led to a faster resolution of fever, which is the major clinical sign of dengue. However, the FEN-II also highlights the need for better diagnostics to identify patients earlier in the course of the disease and also the need for a large sample size to account for the high variability for treatment and for prophylaxis as well. To address these factors, robust Phase II studies would require long clinical timelines with major associated costs, which has led to the business decision to deprioritize the dengue program. Turning to slide 13, as you may recall, we have been conducting two studies to assess the efficacy of AT752 in the treatment and prevention of dengue fever. First, the different two phase two clinical trial was randomized placebo control and conducted in dengue endemic areas. It involved patients with dengue fever within 48 hours of the onset of fever and the diagnosis of dengue confirmed with a positive NS1 antigenemia test. The primary endpoint of this trial was changed in dengue viral load from baseline with exploratory analysis looking at the change in viremia, NS1 level, and fever. In the first cohort of the FEM2, we enrolled 21 patients in India, Thailand, and the Philippines. We have also been conducting a human infection challenge trial under a US IMD. The healthy subjects were treated on day one with AT752 placebo and then injected with a live attenuated strain of Dengue Type 1 on the following day. Subjects were dosed with AT752 or placebo for a total of 14 days. Subjects were then monitored for symptoms, viremia, NS1 level and safety. Let's move to slide 14. This schematic depicts our understanding of the time course of dengue illness. As you can see, there is a lag between infection and viremia, and viremia precedes the development of symptoms and sign. Our study was designed to enroll patients around day six of infection. Based on the data that we will now review, patients likely presented later in the course of the disease at enrollment. On slide 13, you can see that the viral load changes over time through day 7 as measured by PCR. Placebo patients are depicted in red and AT752 patients on the right in blue. Please notice that the study enrolled patients with all four serotypes of dengue, and it is well known that the viral kinetics of each serotype are quite different. At enrollment, patients presented late in the course of the disease with high variability and low viremia level at baseline, particularly in the placebo arm, which had three patients with viremia levels below the lower level of quantification. As a consequence, The primary endpoint of change in viral load decline, as you can appreciate from baseline, is unavoidable. Moving to slide 16. Platelets are a biomarker of dengue progression. You can see in this slide the trajectory of platelet counts from baseline to day seven for both the AT752 treatment arms and placebo. Consistent with the viremia data at baseline, platelets were already low or below the lower limit of normal in the majority of patients further demonstrating late presentation of disease at enrollment. Turning to slide 17, as I have mentioned, the fever is the major clinical sign of diabetes. This slide demonstrates the time to resolution of fever defined as a temperature of 37 degrees Celsius or less sustained for 24 hours and maintained through day five. In a pre-specified exploratory endpoint, in patients who presented with body temperature above 37 degrees Celsius, The median time to fever resolution was four days in the AT752 arm and greater than five days in the placebo arm. Slide 18 shows the change in body temperature for those patients who presented with a temperature of more than 37 degrees Celsius at baseline. In a post-hoc analysis, there was a difference in body temperature change from baseline of 0.9 degrees Celsius at day three in favor of the 87 as compared to the placebo. Also, at day three, 100% of patients who presented with baseline body temperature above 37 degrees Celsius at the reduction in body temperature below the baseline levels in the AT752 arm versus only 33% of patients in the placebo arm. Moving to slide 19, the safety profile of AT752 was favorable in the study, and there were no drug-related assays. An adverse event, were largely mild to moderate and occur at similar frequency with those in the placebo group. Two non-drug-related SAEs, which were hospitalization due to thrombocytopenia and disease progression to severe dengue, occurred. One out of seven in placebo and one out of 14 in the AT752R. Other non-serious adverse events were mostly mild and moderate, self-limiting, and occurred in comparable frequency in active and placebo. Turning to slide 20, the human interaction challenge study was also a randomized double-blind placebo control trying evaluating AT752 dose of 750 mg TID. where dosing was initiated prophylactically 24 hours ahead of subject receiving an injection of attenuated live dengue 1 virus. The available results in five healthy volunteers were uninterpretable due to the high variability observed in term of viremia, antigenemia, and the onset and severity of symptoms. there were much lower drug exposures than those observed in phase one with normal volunteers and in different two study with treatment patients, very likely due to a lack of dosing compliance. For this type of the study, it is clear that a much larger sample size of greater than 50 healthy volunteers would be needed to account for this high variability. I will now turn the call to Andrea Coccone, our CFO, to review our financial update.
spk06: Thank you, Jean-Pierre. As Joneigh mentioned in her introductory remarks, earlier today we issued a press release containing our financial results for the fourth quarter and full year 2022. Those statements of operations and balance sheet can be found on slides 22 and 23. Our balance sheet remains strong with cash, cash equivalents, and marketable securities at $646.7 million at December 31-22 compared to $764.4 million at December 31-21. R&D expenses were $27.5 million and $81.9 million for the fourth quarter and full year 2022, respectively, compared to $57.8 million and $167.2 million for the corresponding period in 2021. The decrease in R&D expense was primarily due to the elimination of the cost share arrangement with Roche. In addition, in Q4 21, we recorded a $25 million expense due to the upfront payment related to our in-license of Rusevir from Merck. G&A expenses remained relatively consistent at $12.4 million and $48.7 million for the fourth quarter and full year 2022 compared to 13.2 million and 45.8 million for the corresponding period in 2021. Interest income and other was 5.6 million and 11.2 million for the fourth quarter and full year 2022 compared to less than 0.1 million and 0.2 million for the same period in 2021. The increase was primarily the result of investing in higher-yield marketable securities and higher interest rates. For 2023, our R&D spend will be driven principally by spending on clinical trials, including primarily our Sunrise Phase 3 clinical trial for COVID-19 and our Hepatitis C Phase 2 study of the combination of benifosavir and rusavir. In closing, due to the deprioritization of our program for dengue, we are extending our cash guidance into 2026. I'll now turn the call back over to Jean-Pierre for closing remarks.
spk23: Thank you, Andrea. In closing, on slide 25, we have a busy year ahead of us as we continue to advance our antiviral programs to fight serious viral diseases, especially for patients with limited treatment options. Importantly, We are well capitalized to fund our program through key inflection points and beyond to the finish line with an extended cash runway now until 2026 due to deprioritization of our Dengue program. With that operator, we will now open the call up to your questions.
spk08: Thank you. At this time, we'll conduct a question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, press star 1-1 again.
spk10: Please stand by while we compile the Q&A roster. Our first question comes from Matthew Harrison of Morgan Stanley.
spk08: Your line is open. Please go ahead.
spk12: Hi, this is Steve from Matthew. Thanks for taking my question. So I want to ask, would you consider to license out your Dengue program since you deprioritized this one? Thanks.
spk24: I'm sorry, can you repeat the question?
spk12: Oh, sure. Would you consider to license out your Dengue program?
spk23: Well, look, as you know, there is some nonprofit agency and government agency and other sub-parties as well. that have the potential to be interested in the collaboration, partnership. We are not giving our guidance on and when if this could happen, but certainly we are interested in discussing with third parties.
spk09: Thank you. One moment for our next question. Our next question comes from Tim Lugo of William Blair.
spk08: Your line is open.
spk19: Hi, this is John on for Tim. Thanks so much for taking our questions. So maybe two from us. So I'm wondering if you can maybe just give us some color commentary on your confidence in enrollment of the Sunrise Study. I mean, obviously, we're seeing a lot more apathy towards COVID, and there's less reporting that's going on. It's seeming to show, you know, that seems like trends are going in our favor, but sometimes it's a little hard to tell with the lower reporting. Maybe you could just tell us something about what you're seeing coming through, especially in the higher risk populations.
spk04: Yeah. Janet?
spk17: Thank you, John. Yes, so enrollment is continuing in Sunrise, and We're making good progress. We filed our clinical trial in all targeted countries for regulatory approval, and we are continuing to see enrollment, but we're not going to provide specific numbers at this point, but we will continue to report as the year goes through.
spk19: Maybe just one more from us. So I'm seeing some articles now coming out that viral rebound is more common than we initially might have thought, regardless of treatment with an antiviral such as Paxlovid. I'm wondering if you maybe have any updated thoughts about this, or the time course is just too short. Is this maybe fixed with a combination, and maybe how you're thinking about this longer term?
spk02: Janet, do you want to address the question?
spk17: Yes, thank you. Yes, we've been watching the reports also with some interest, and there seems to be a variety of theories, I think. So really, you'd have to call in as to what the cause for viral rebound may be. And it's something that we're certainly watching in our study. We're going to be collecting virological samples and also continuing to watch patients for viral symptoms of rebound as well as just plain viral rebound as we conduct the study. And so we hope to get some further clarity and information on that. But I think the jury is probably still out as to exactly what happens here, whether it's variant-specific, whether it's dependent on viral load and a much higher viral load and perhaps needing longer times to clear. It's still something that I don't think we fully understand. But thank you for the question.
spk23: If I may just add, it sounds like in some post-hoc analysis or some trial, there is a rebound highly dependent on the age of the patients, and so we hope that with our high-risk patient population, actually mostly in the elderly, we are going to really evaluate, as Jared indicated, those potential rebounds and the impact of the combination.
spk20: Okay, thanks. Very helpful.
spk08: Thank you very much. As a reminder, to ask a question, you need to press star 11 on your telephone and wait for your name to be announced.
spk10: One moment for the next question. This question comes from Ruana Ruiz of SBB Securities.
spk08: Your line is open. Please go ahead.
spk14: Great. Thanks. Afternoon, everyone. I appreciate you walking us through the Dengue results. So I'll start there. I was curious if you could clarify which factors seem to contribute the most to the unavailable results for DEFEND-2. I started seeing different things like maybe possibly trial execution. Maybe there were some placebo arm trends that were difficult to interpret. Were you able to garner anything about the potency of 752 in this trial?
spk23: I'm going to let her answer, but in terms of potency, as I have indicated, I'm going to let her answer. Let's not forget that fever is the major clinical sign. Oh, thank you. So, Irenzo, why don't you address the question, please?
spk16: Yes, thank you. Thank you for the question. So, my contribution to the viral load to be unevaluable. I think the main reason is that the patients tend to come later in the course of the disease. And as you can see in the slide, a lot of them, particularly in the placebo group, have already either low or undetectable viral load by the time they come to you. And they come to you later. It's not unusual. We mandate a 48-hour fever criteria. But patients sometimes have a hard time identifying really when the fever started exactly. And so they probably came later, presented later by the time, you know, we were able to involve them. Another factor is that the test that we use for enrollment, the NS1 antigen, is an antigen test. And as you've seen with COVID, antigen tests are not often very sensitive. They're not as sensitive as PCR, but sites don't have PCRs available. So we will need to develop better, more sensitive diagnostic tests if we want to advance programs like this. So those are contributing factors. And with regards to the efficacy question, I think what we have seen in this data is a resolution of fever that is more rapid in the active. And as you know, fever is the main clinical sign for dengue. In fact, it's called dengue fever. And so we think that the faster resolution of fever, even considering such a small data set, is quite interesting and promising as a signal in this trial.
spk14: Got it. Thanks for clarifying. And another question on the COVID program. So could you remind us what you want to see in the Sunrise 3 interim to encourage you to move forward? And if we fast forward and get positive final results, do you still think EUA is on the table with the FDA?
spk03: Janet?
spk17: So we're planning to do an interim analysis when we achieve enrollment of 60% population in the study. And as you know, the primary endpoint is the proportion of patients who require hospitalization. So we're looking to see something which suggests that we're going to an overall hospitalization rate in the patient population of ideally 4% to 6% is what we're anticipating. And we still think that actually in the patient population that we're going after in the study, that this is not an unreasonable number. And there have actually been some recent articles coming out, I think, in support of that. So that's where we plan to be now.
spk15: Okay, great. Thanks a lot.
spk10: Thank you. One moment for our next question. This question comes from the line of Umar Rafat of Evercore ISI.
spk08: Your line is open.
spk18: Hi, this is Jessica Huayan for Umar. Just one question. We're trying to reconcile the Sunrise 3 study design with that of a competitor oral COVID antiviral, especially in light of the announcement last month that the COVID public health emergency will end in May. Specifically, the FDA took issue with a placebo-controlled study in the US. So I just want to confirm that in the Sunrise 3 trial, The randomized monotherapy population will still include U.S. patients, and you don't expect the FDA to want you to change your trial design.
spk23: The short answer is no, but Janet, what is the extent of my answer?
spk17: Sure. So, yes, the answer is no. The FDA has endorsed and reviewed our phase 3 clinical trials. And I think as we described, patients are being randomized to drug or placebo on top of what is the available standard of care for the patient where they are. And actually, I think as Jean-Pierre mentioned in his remarks, there actually are a significant number of people and actually particularly unfortunately in the most vulnerable patient population, people who are unable to take Paxlovid because of drug interactions. And so for patients such as these, Our drug is administered on standard of care, which would not include a direct-acting antiviral. We do allow patients to have access to direct-acting antivirals, monoclonal antibodies, if those were to be considered to be effective, and patients are allowed to be vaccinated also. But many patients, we believe, will actually not be taking anything other than our drug or placebo because of these circumstances.
spk01: Okay, thank you.
spk10: One moment for another question. We have another question from Ron Ruiz of SVB Securities.
spk08: Your line is open.
spk14: Hey, thanks for taking that extra question. I just want to circle back about the possibility of an EUA for Bendifosavir. Do you have any updated thoughts on that?
spk05: Janet?
spk17: I'm so sorry. I realized as soon as I finished that I hadn't answered your question completely. Yes. So we believe that emergency use authorization is still possible. I think it's at the discretion of the Health and Human Services to allow for EUAs even with the passing of the or the lapsing of the pandemic health emergency. So we believe it will be data driven and depending on what we see as to whether such a thing might be possible. But we believe it is still possible should we have good results, even at the interim analysis.
spk13: Okay, great. Thanks.
spk08: Thank you. That concludes our Q&A segment. I'll now turn it back over to the Atea Pharmaceuticals team for any closing remarks.
spk22: Again, thank you all for joining us today.
spk08: And thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
spk07: The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1 1. The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1 1. Music playing Thank you. Thank you Thank you. Thank you. you you Thank you.
spk08: Good afternoon, ladies and gentlemen. Welcome to the Atea Pharmaceuticals fourth quarter and full year 2022 financial results and business update conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we'll open the call up to your questions. To ask a question during the session, you need to press star 1-1 on your telephone. You'll then hear an automated message advising you that your hand is raised. To withdraw your question at any time, press star 1-1 again. Please be advised that today's conference is being recorded. I would now like to turn the call over to Joneigh Barnes, Senior Vice President of Investor Relations and Corporate Communications at Atea Pharmaceuticals. Ms. Barnes, please proceed.
spk11: Thank you, Operator. Good afternoon, everyone, and welcome to Atea Pharmaceuticals' fourth quarter and full year 2022 Financial Results and Business Update conference call. Earlier today, we issued a press release which outlines the topics we plan to discuss. You can access the press release as well as the slides that we'll be reviewing today by going to the investor section of our website at ir.ateafarma.com. With me from Atea, our Chief Executive Officer and Founder, Dr. Jean-Pierre Semedosi, Chief Development Officer, Dr. Janet Hammond, Chief Medical Officer, Dr. Arantxa Horga, Chief Financial Officer and Executive Vice President of Legal, Andrea Corcoran, and our Chief Commercial Officer, John Bavrica. They will all be available for the Q&A portion of today's call. Before we begin the call, as outlined on slide two, I would like to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in today's press release and in the company's recent filings with the Securities and Exchange Commission, which we encourage you to read. Our actual results may differ materially from what is discussed on the call. With that, I'll now turn the call over to Jean-Pierre.
spk23: Thank you, Janae. Good afternoon, everyone, and thank you for joining us. As you will see on slide three, this year we are poised to continue the meaningful progress made across our advanced clinical development programs following strong execution in 2022. Clinical efficacy results from the Morning Sky trial informed our Phase III, Sunrise III trial of Beniposivir for the treatment of COVID-19, which was initiated in the first quarter of 2022. We anticipate an interim analysis from the Sunrise 3 trial in the second half of this year, followed by completion of enrollment by year end. We also made meaningful progress advancing our preclinical second-generation protease inhibitor program, and we anticipate finding an IND for a clinical candidate around the end of the year. With our HCV program, we completed preclinical and manufacturing work needed for the initiation of a phase two combination trial of benifosgravir and erizosvir in the second quarter. With our dengue program, we conducted two proof of concept studies for AT752, and the results will be shared with you today. Let's now move to COVID-19. Turning to slide five, benifosbuvir is an oral nucleotide for a drug that targets viral RNA polymerase, a highly conserved enzyme critical to viral replication and transcription. We believe that benifosbuvir profile addresses the key limitations of current therapies. It has low risk of drug-drug interactions, and may be co-administered with commonly prescribed drugs for high-risk COVID-19 patients, a key limitation of PaxLogin. Scientific presentation demonstrating beneficiary lack of drug-drug interaction were presented last week at the Conference on Retroviruses and Opportunistic Infections, also called CORE. The U.S. COVID-19 public health emergency is set to expire on May 11, and the market dynamics for COVID continue to shift. Based on the current variants, there are very limited treatment tools available, with essentially only Paxlovid for outpatients or Vagluri or Remdesivir for hospitalized patients. The last thing of the public health emergency is going to make it even harder for this patient population to assess diagnostic and treatment. This is likely to lead to further mobility and mortality, particularly in the most vulnerable. Moving to slide six, we believe COVID-19 will continue to remain endemic throughout the world and particularly impact the patient population that we are studying in Sunrise 3. We believe that oral therapeutics will remain a multi-billion dollar opportunity for years to come, and projected annual COVID-19 oral antiviral U.S. demand using Acuvia retail prescriptions suggests the current estimated annual market opportunity over $10 billion. Beyond that, we believe that there is an opportunity to expand this market to patients where drug-drug interactions associated with Paxlovid are a concern, limiting and complicating prescribing. These include commonly prescribed drugs, such as seizure medications, antipsychotics, anticoagulants, and more. Let me remind you that Paxlovid currently has 90% of the prescription market share, and there is still a significant unmet medical need as less than 30% of COVID-19 patients are being prescribed an oral antiviral. Turning to slide 7, as we are moving to a traditional payer market, it is clear that we will have to demonstrate a value proposition of the impact of Benipozivir against COVID. This will be achieved by using a primary endpoint of decrease in hospitalization and deaths. We believe that this will be the key consideration for drug reimbursement for COVID therapies in the future. This is why we are targeting the most vulnerable patient populations in Sunrise 3 who are the greatest risk for disease progression to severe COVID-19 or mortality and for whom there are limited treatment options. Let's keep in mind that CMS estimates an average cost approaching $22,000 per hospitalization. And approximately 70% of COVID-19 related hospitalizations of hospitalized patients were covered under Medicare. Moving to slide eight, let's now review our innovative Sunrise III trial. Our Phase III registration trial, which is evaluating Benifazovir as monotherapy and that's combination enteral terbine. Enrollment continues in this global phase three randomized double-blind placebo-controlled study, which will evaluate benifazovir or placebo administered at the same time as locally available standard of care. Patients will be randomized one-to-one to receive either benifazovir at 550 milligram twice daily or placebo. We expect to enroll at least 1,500 high-risk patients with mild or moderate COVID-19. Two study cohorts defined by the type of standard of care the patients receive would be studied. The first cohort is a monotherapy cohort that would be comprised of patients receiving supportive care, which represents the primary analysis population. The second cohort is a combination antiviral cohort that would be comprised of patients who are receiving a compatible antiviral against COVID-19 as part of the steno care. The primary endpoint of the study is all-cause hospitalization of deaths through day 29 in at least 1,300 patients from the monotherapy cohort. You will recall that we have already evaluated hospitalization in the Morning Sky trial and been in foster care showed a 71% reduction in hospitalization versus placebo. And importantly, in addition, a subgroup analysis showed an 82% reduction in patients over 40 years old. Sunrise 3 will focus on high risk patients that are the greatest risk for disease progression to severe COVID-19 or mortality. The study is expected to have a large global footprint with up to 300 clinical sites in 25 countries, including the United States, Europe, Japan, and the rest of the world. Moving now to our hepatitis C program, which we believe has the potential to become a best-in-class combination with the potential to improve upon the current standard of care by offering a shorter duration protease-inhibitor-free treatment for patients with HCV. Slide 10 outlines our Phase II open-label study of benifosvivir and risosvir in HCV patients. The study will enroll approximately 280 HCV-infected direct-acting antivalve naive patients across all genotype including a leading cohort of approximately 60 patients. Patients will be administered 550 mg benifosbuvir in combination with 180 mg risosvir once daily for eight weeks. The primary endpoints of the study are safety and sustained biological response, or SVR, at week 12 post-treatment. Other virologic endpoints include virologic failure, SVR at week 24 post-treatment, and resistance. Regulatory submissions for the initiation of the trial are ongoing, and dosing of patients in this clinical trial is expected to begin during the second quarter. Initial data from the leading cohort of approximately 60 patients is anticipated around the end of the year. Turning to slide 12, I will now provide an update on our program for AT752 intervention against dengue. We have been a pioneer in the development of our normal antiviral therapeutic for dengue. Our proof of concept study, DEFEN2, demonstrated that AT752 treatment led to a faster resolution of fever, which is the major clinical sign of dengue. However, the phase II also highlights the need for better diagnostics to identify patients earlier in the course of the disease and also the need for a large sample size to account for the high variability for treatment and for prophylaxis as well. To address these factors, robust phase II studies would require long clinical timelines with major associated costs, which has led to the business decision to deprioritize the dengue program. Turning to slide 13, as you may recall, we have been conducting two studies to assess the efficacy of AT752 in the treatment and prevention of dengue fever. First, the different two phase two clinical trial was randomized placebo control and conducted in dengue endemic areas. It involved patients with dengue fever within 48 hours of the onset of fever and the diagnosis of dengue confirmed with a positive NS1 antigenemia test. The primary endpoint of this trial was changed in dengue viral load from baseline with exploratory analysis looking at the change in viremia, NS1 level, and fever. In the first cohort of the FEM2, we enrolled 21 patients in India, Thailand, and the Philippines. We have also been conducting a human infection challenge trial under a US IMD. The healthy subjects were treated on day one with AT752 placebo and then injected with a live attenuated strain of Dengue type 1 on the following day. Subjects were dosed with AT752 or placebo for a total of 14 days. Subjects were then monitored for symptoms, viremia, NS1 level and safety. Let's move to slide 14. This schematic depicts our understanding of the time course of dengue illness. As you can see, there is a lag between infection and viremia, and viremia precedes the development of symptoms and time. Our study was designed to enroll patients around day six of infection. Based on the data that we will now review, patients likely presented later in the course of the disease at enrollment. On slide 13, you can see that the viral load changes over time through day 7 as measured by PCR. Placebo patients are depicted in red and AT752 patients on the right in blue. Please notice that the study enrolled patients with all four serotypes of dengue, and it is well known that the viral kinetics of each serotype are quite different. At enrollment, patients presented late in the course of the disease with high variability and low viremia level at baseline, particularly in the placebo arm, which had three patients with viremia levels below the lower level of quantification. As a consequence, The primary endpoint of change in viral load decline, as you can appreciate from baseline, is unavoidable. Moving to slide 16. Platelets are a biomarker of dengue progression. You can see in this slide the trajectory of platelet counts from baseline to day seven for both the AT752 treatment and placebo. Consistent with the viremia data at baseline, platelets were already low or below the lower limit of normal in the majority of patients further demonstrating late presentation of disease at enrollment. Turning to slide 17, as I have mentioned, the fever is the major clinical sign of diabetes. This slide demonstrates the time to resolution of fever defined as a temperature of 37 degrees Celsius or less sustained for 24 hours and maintained through day five. In a pre-specified exploratory endpoint, in patients who presented with body temperature above 37 degrees Celsius, The median time to fever resolution was four days in the AT752R and greater than five days in the placebo R. Slide 18 shows the change in body temperature for those patients who presented with a temperature of more than 37 degrees Celsius at baseline. In a post-hoc analysis, there was a difference in body temperature change from baseline of 0.9 degrees Celsius at day three in favor of the 87 as compared to the placebo. Also, at day three, 100% of patients who presented with baseline body temperature of 37 degrees Celsius at the reduction in body temperature below the baseline levels in the AT752 arm versus only 33% of patients in the placebo arm. Moving to slide 19, the safety profile of AT752 was favorable in the study, and there were no drug-related assays. An adverse event, were largely mild to moderate and occur at similar frequency with those in the placebo group. Two non-drug-related SAEs, which were hospitalization due to thrombocytopenia and disease progression to severe dengue, occurred. One out of seven in placebo and one out of 14 in the AT752R. Other non-serious adverse events were mostly mild and moderate, self-limiting, and occurred in comparable frequency in active and placebo. Turning to slide 20, the human interaction challenge study was also a randomized double-blind placebo control trying evaluating AT752 dose of 750 mg TID. where dosing was initiated prophylactically 24 hours ahead of subject receiving an injection of attenuated live dengue 1 virus. The available results in five healthy volunteers were uninterpretable due to the high variability observed in term of viremia, antigenemia, and the onset and severity of symptoms. there were much lower drug exposures than those observed in phase one with normal volunteers and in defend two study with treatment patients, very likely due to a lack of dosing compliance. For this type of the study, it is clear that a much larger sample size of greater than 50 healthy volunteers would be needed to account for this high variability. I will now turn the call to Andrea Coccone, our CFO, to review our financial update.
spk06: Thank you, Jean-Pierre. As Joneigh mentioned in her introductory remarks, earlier today we issued a press release containing our financial results for the fourth quarter and full year 2022. Those statements of operations and balance sheet can be found on slides 22 and 23. Our balance sheet remains strong, with cash, cash equivalents, and marketable securities at $646.7 million at December 31, 2022, compared to $764.4 million at December 31, 2021. R&D expenses were $27.5 million and $81.9 million for the fourth quarter and full year 2022, respectively, compared to $57.8 million and $167.2 million for the corresponding period in 2021. The decrease in R&D expense was primarily due to the elimination of the cost share arrangement with Roche. In addition, in Q4 21, we recorded a $25 million expense due to the upfront payment related to our in-license of Rusevir from Merck. G&A expenses remained relatively consistent at $12.4 million and $48.7 million for the fourth quarter and full year 2022 compared to 13.2 million and 45.8 million for the corresponding period in 2021. Interest income and other was 5.6 million and 11.2 million for the fourth quarter and full year 2022 compared to less than 0.1 million and 0.2 million for the same period in 2021. The increase was primarily the result of investing in higher-yield marketable securities and higher interest rates. For 2023, our R&D spend will be driven principally by spending on clinical trials, including primarily our Sunrise Phase 3 clinical trial for COVID-19 and our Hepatitis C Phase 2 study of the combination of feniphosphere and lucifer. In closing, due to the deprioritization of our program for dengue, we are extending our cash guidance into 2026. I'll now turn the call back over to Jean-Pierre for closing remarks.
spk23: Thank you, Andrea. In closing on slide 25, we have a busy year ahead of us as we continue to advance our antiviral programs to fight serious viral diseases, especially for patients with limited treatment options. Importantly, We are well capitalized to fund our program through key inflection points and beyond to the finish line with an extended cash runway now until 2026 due to deprioritization of our Dengue program. With that operator, we will now open the call up to your questions.
spk08: Thank you. At this time, we'll conduct the question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, press star 1-1 again.
spk10: Please stand by while we compile the Q&A roster. Our first question comes from Matthew Harrison of Morgan Stanley.
spk08: Your line is open. Please go ahead.
spk12: Hi, this is Steve from Matthew. Thanks for taking my question. So I want to ask, would you consider to license out your Dengue program since you did prioritize this one? Thanks.
spk24: I'm sorry, can you repeat the question?
spk12: Oh, sure. Would you consider to license out your Dengue program?
spk23: Well, look, as you know, there is some nonprofit agency and government agency and other sub-parties as well. that have the potential to be interested in the collaboration, partnership. We are not giving our guidance on and when if this could happen, but certainly we are interested in discussing with third parties.
spk09: Thank you. One moment for our next question. Our next question comes from Tim Lugo of William Blair.
spk08: Your line is open.
spk19: Hi, this is John on for Tim. Thanks so much for taking our questions. So maybe two from us. So I'm wondering if you can maybe just give us some color commentary on your confidence in enrollment of the Sunrise Study. I mean, obviously, we're seeing a lot more apathy towards COVID, and there's less reporting that's going on. It's seeming to show, you know, that It seems like trends are going in our favor, but sometimes it's a little hard to tell with the lower reporting. Maybe you could just tell us something about what you're seeing coming through, especially in the higher risk populations.
spk04: Yeah. Janet?
spk17: Thank you, John. Yes, so enrollment is continuing in Sunrise. We're making good progress. We filed our clinical trial in all targeted countries for regulatory approval, and we are continuing to see enrollment, but we're not going to provide specific numbers at this point, but we will continue to report as the year goes through.
spk19: Maybe just one more from us. So I'm seeing some articles now coming out that viral rebound is more common than we initially might have thought, regardless of treatment with an antiviral such as Paxlovid. I'm wondering if you maybe have any updated thoughts about this, or the time course is just too short. Is this maybe fixed with a combination, and maybe how you're thinking about this longer term?
spk02: Janet, do you want to address the question?
spk17: Yes, thank you. Yes, we've been watching the report also with some interest, and there seems to be a variety of theories, I think, so really you'd have to call them as to what the cause for viral rebound may be. And it's something that we're certainly watching in our study. We're going to be collecting virological samples and also continuing to watch patients for viral symptoms of rebound as well as just plain viral rebound as we conduct the study. And so we hope to get some further clarity and information on that. But I think the jury is probably still out as to exactly what happens here, whether it's variant-specific, whether it's dependent on viral load and a much higher viral load, perhaps needing longer times to clear. It's still something I don't think we fully understand. But thank you for the question.
spk23: If I may just add, it sounds like in some post-hoc analysis or some trial, there is a rebound, highly dependent on the age of the patients, and so we hope that with our high-risk patient population, actually mostly in the elderly, we are going to really evaluate, as Janet indicated, those potential rebounds and the impact of the combination.
spk20: Okay, thanks. Very helpful.
spk08: Thank you very much. As a reminder, to ask a question, you need to press star 11 on your telephone and wait for your name to be announced.
spk10: One moment for the next question. This question comes from Ruana Ruiz of SBB Securities.
spk08: Your line is open. Please go ahead.
spk14: Great. Thanks. Afternoon, everyone. I appreciate you walking us through the Dengue results. So I'll start there. I was curious if you could clarify which factors seem to contribute the most to the unavailable results for DEFEND2. I started seeing different things like maybe possibly trial execution. Maybe there was some placebo arm trends that were difficult to interpret. And were you able to garner anything about the potency of 752 in this trial?
spk23: I'm going to let her answer. But in terms of potency, as I have indicated, and I'm going to let her answer, let's not forget that fever is the major clinical sign. Oh, thank you. So, Irenzo, why don't you address the question, please?
spk16: Yes, thank you. Thank you for the question. So, my contribution to the viral load to be unevaluable. I think the main reason is that the patients tend to come later in the course of the disease. And as you can see in the slide, a lot of them, particularly in the placebo group, have already either low or undetectable viral load by the time they come to you. And they come to you later. It's not unusual. We mandate a 48-hour fever criteria. But patients sometimes have a hard time identifying really when the fever started exactly. And so they probably came later, presented later by the time, you know, we were able to involve them. Another factor is that the test that we use for enrollment, the NS1 antigen, is an antigen test. And as you've seen with COVID, antigen tests are not often very sensitive. They're not as sensitive as PCR, but sites don't have PCRs available. So we will need to develop better, more sensitive diagnostic tests if we want to advance programs like this. So those are contributing factors. And with regards to the efficacy question, I think what we have seen in this data is a resolution of fever that is factored more rapidly in the active. And as you know, fever is the main clinical sign for dengue. In fact, it's called dengue fever. And so we think that the faster resolution of fever, even considering such a small data set, is quite interesting and promising as a signal in this trial.
spk14: Got it. Thanks for clarifying. And another question on the COVID program. So could you remind us what you want to see in the Sunrise 3 interim to encourage you to move forward? And if we fast forward and get positive final results, do you still think EUA is on the table with the FDA?
spk03: Janet?
spk17: So we're planning to do an interim analysis when we achieve enrollment of 60% population in the study. And as you know, the primary endpoint is the proportion of patients who require hospitalization. So we're looking to see something which suggests that we're going to an overall hospitalization rate in the patient population of ideally 4% to 6% is what we're anticipating. And we still think that actually in the patient population that we're going after in the study, that this is not an unreasonable number. And there have actually been some recent articles coming out, I think, in support of that. So that's where we plan to be.
spk15: Okay, great. Thanks a lot.
spk10: Thank you. One moment for our next question. This question comes from the line of Umar Rafat of Evercore ISI.
spk08: Your line is open.
spk18: Hi, this is Jessica Huayan for Umar. Just one question. We're trying to reconcile the Sunrise 3 study design with that of a competitor oral COVID antiviral, especially in light of the announcement last month that the COVID public health emergency will end in May. Specifically, the FDA took issue with a placebo-controlled study in the US. So I just want to confirm that in the Sunrise 3 trial, The randomized monotherapy population will still include U.S. patients, and you don't expect the FDA to want you to change your trial design.
spk23: The short answer is no, but Janet, what is the extent of my answer?
spk17: Sure. Yes, the answer is no. The FDA has endorsed and reviewed our phase 3 clinical trials, And I think as we described, patients are being randomized to drug or placebo on top of what is the available standard of care for the patient where they are. And actually, I think as Jean-Pierre mentioned in his remarks, there actually are a significant number of people and actually particularly unfortunately in the most vulnerable patient population, people who are unable to take Paxlovid because of drug interaction. And so for patients such as these, Our drug is administered on standard of care, which would not include a direct-acting antiviral. We do allow patients to have access to direct-acting antivirals, monoclonal antibodies, if those were to be considered to be effective, and patients are allowed to be vaccinated also. But many patients, we believe, will actually not be taking anything other than our drug or placebo because of these circumstances.
spk01: Okay, thank you.
spk10: One moment for another question. We have another question from Ron Ruiz of SVB Securities.
spk08: Your line is open.
spk14: Hey, thanks for taking that extra question. I just want to circle back about the possibility of an EUA for Bendifosavir. Do you have any updated thoughts on that?
spk05: Janet?
spk17: I'm so sorry. I realized as soon as I finished that I hadn't answered your question completely. Yes. So we believe that emergency use authorization is still possible. I think that's the discretion of the Health and Human Services to allow for EUAs even with the passing of the or the lapsing of the pandemic health emergency. So we believe it will be data driven and depending on what we see as to whether such a thing might be possible. But we believe it is still possible should we have good results, even at the interim analysis.
spk13: Okay, great. Thanks.
spk08: Thank you. That concludes our Q&A segment. I'll now turn it back over to the ATEA Pharmaceuticals team for any closing remarks.
spk22: Again, thank you all for joining us today.
spk08: And thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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