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spk14: Good afternoon and welcome to Enanta Pharmaceuticals' first call. Second quarter ended March 31st, 2023 Financial Results Conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session at the end of the preparing marks. Please be advised that this call is being recorded. I would now like to turn the call over to Jennifer Vieira, Investor Relations. Please go ahead.
spk02: Thank you, Operator, and thanks to everyone for joining us this afternoon. The news release with our fiscal second quarter 2023 financial results was issued this afternoon and is available on our website. A news release with top line data from our SPRINT clinical trial was also issued this afternoon and can be found on our website as well. Slides from today's webcast will be available on our website after the call ends. On the call today are Dr. Jay Lulai, our President and Chief Executive Officer, Dr. Scott Rottinghaus, our Chief Medical Officer, Paul Mellett, our Chief Financial Officer, and Dr. Tara Kiefer, our Senior Vice President of New Product Strategy and Development. Before we begin with our formal remarks, we do want to remind you that we will be making forward-looking statements, which may include our plans and expectations with respect to our research and development pipeline and financial projections, all of which involve certain assumptions and risks beyond our control that could cause our actual developments and results to differ materially from those statements. A description of these risks is in our most recent form, 10-K, and other periodic reports filed with the SEC. Ananta does not undertake any obligation to update any forward-looking statements made during this call. I'd now like to turn the call over to Dr. Jay Lulli. Jay?
spk09: Thank you, Jennifer. And good afternoon, everyone. At Enanti, our goal has always been to develop curative therapies for patients in need. That effort continues today with our announcement of the top-line data from our Phase II Sprint Study of EDP-235, our 3-CL protease inhibitor, in development as an oral, once-daily treatment for COVID-19. I'll let Dr. Scott Rottinghaus, our Chief Medical Officer, present the data in a minute, but I will highlight a few key points which support our belief that EDP-235 could play an important role in the treatment of COVID-19. First, the trial met its primary endpoint, demonstrating a favorable safety and tolerability profile. In addition, we are excited that the SPRINT data show that EDP-235 had an impact on clinically meaningful endpoints. Scott's presentation will go through this in detail. With that, I'll turn the call over to Scott. Scott?
spk01: Thank you, Jay. As Jay stated, EDP235 met the primary endpoint and was generally safe and well-tolerated. We saw a dose-dependent symptom improvement with EDP235 treatment compared to placebo. However, we did not see an effect on virologic endpoints, likely because of the rapid viral decline in the placebo arm of this immunologically experienced standard risk population. As a reminder, This slide shows the study design of SPRINT, which was a randomized, double-blind, placebo-controlled Phase II clinical trial of EDP-235 in approximately 200 adults with mild or moderate COVID-19 who did not have risk factors for progression to severe disease. Patients were treated with EDP-235 at doses of 200 milligrams, 400 milligrams, or placebo, once daily for five days. We randomized 231 patients in a one-to-one-to-one fashion. The safety population included all patients randomized. We followed the patients out to day 33, and as you can see, 95 to 97% of the patients completed the study. The ITTC population of 190 patients is a modified intention to treat population that constitutes our primary efficacy analysis population. It includes all patients who were confirmed to have a positive PCR for SARS-CoV-2 at baseline. Demographics and baseline characteristics were well balanced between the arms. We had a young patient population with a median age of about 45 years. Most patients were white and Hispanic. Three-quarters were enrolled within three days of symptom onset. Baseline viral load was about five logs across arms. The majority of patients had been vaccinated against COVID, and about 95% were seropositive, indicating a high degree of baseline immunity against COVID. This is consistent with recent estimates from the CDC showing a high degree of seropositivity in the US population. The next slide summarizes the adverse events that we saw in the study. Among our 231 patients, only 10 adverse events were reported. While there were numerically more adverse events reported on 400 milligrams than on the other arms, the frequency was still low at 6.4% compared to placebo at 2.6%. There were no serious adverse events, or discontinuations due to adverse events. Most adverse events were mild in severity. The adverse event that was graded as severe in this table was a fall and resulting arthralgia that was judged by the investigator not to be related to study drug. This slide shows the specific adverse events. As you can see, no specific pattern of adverse events was identified. The two hepatotoxicities were asymptomatic transient elevations of transaminases, the one in 200 milligrams with a mild grade 1 elevation and the other in 400 milligrams. I'll discuss more on the next slide. Laboratory values were generally unremarkable, but there are two specific callouts. The patient I just mentioned who is receiving EDP235 at the 400 milligram dose reported concomitant use of alcohol and acetaminophen. He had ALT at the upper limit of normal at baseline and experienced asymptomatic ALT elevation up to 12 times the upper limit of normal on study day six. His AST was five times the upper limit of normal. GGT was elevated at baseline and increased further to four times the upper limit of normal. Bilirubin and alkaline phosphatase were normal. The patient remained asymptomatic, and all labs returned to normal in follow-up except for GGT, which remained mildly elevated but consistent with baseline. The second laboratory observation is a transient and dose-dependent elevation in total cholesterol and triglycerides with EDP235. Both total cholesterol and triglycerides then trended toward normal after treatment. Wrapping up safety. There was a low frequency of adverse events, and most were mild in severity. There were no serious adverse events or discontinuations due to adverse events. Laboratory values were generally unremarkable, apart from the patient with transaminase elevations and the lipid trends that I just discussed. Moving to PK, EDP235 achieved target exposures, and the results were consistent with what we saw in Phase I. Plasma drug levels were 7 and 12 times higher than the EC90 of Omicron for the 200 milligram and 400 milligram dosing levels. Mean and median pre-dose concentrations of EDP235 on day five are shown in the table. Now for efficacy. Let's start with the total symptom score in the full efficacy analysis population, the ITTC. As a reminder, The total symptom score comprises all 14 symptoms as defined by the FDA for evaluating drugs to treat COVID. They're listed on the right-hand side of the slide. You can see here that there's a dose-dependent trend favoring EDP235 with statistical significance being achieved at multiple time points, as indicated by the asterisks, with a p-value of less than 0.05. Statistical significance was observed as early as the first time point evaluated, which was one day after the first dose. While the baseline total symptom score of the 400 milligram dose was slightly higher than the others, a rapid, early, and sustained improvement in symptoms was observed compared to placebo. For contextualization, this slide shows our EDP235 data that I just showed you next to data from another protease inhibitor, Incitrovir. We've chosen Citrovir for contextualization because it's the only antiviral with a sufficiently robust symptom data set in the public domain. Our phase two study looked at the 14 symptoms I just discussed in 190 patients, and the change from baseline and total symptom score is graphed here out to 10 days. And Citrovir's Phase IIb study of 341 patients looked at the same symptoms except for taste and smell, and these data are graphed out to Day 6. As you can see, dose-dependent trends and symptomatic improvement were observed for both antivirals. As you may remember, the protocol stratified patients at randomization into two groups, those with less than three days of symptoms, and those with greater than three days of symptoms. We pre-specified an analysis of the patients who were randomized within three days of symptom onset. You'll recall from the demographics slide that this population includes about three-quarters of the patients in the study. In this population, EDP-235 at 400 milligrams showed statistically significant reductions in total symptom score compared to baseline at all time points after treatment. We interrogated our dataset with the goal of identifying a subset of the FDA-specified 14 symptoms that better reflect the clinical manifestations of the current COVID-19 variants and the treatment effect on these symptoms. Shionogi performed a similar analysis, identifying five symptoms from their Phase IIb study, which were subsequently used as a primary endpoint in their Phase III. As shown here, we identified a subset of six symptoms, including shortness of breath, sore throat, stuffy or runny nose, chills or shivering, feeling hot or feverish, and headache. This figure shows an analysis of these six symptoms in the pre-specified population of patients enrolled within three days of symptom onset. EDP-235 at the 400 milligram dose demonstrated an even greater improvement in symptom score at all time points. Now, let's move to looking at time to symptom improvement. While our pre-specified endpoint of time to improvement for all 14 symptoms did not show a difference between the active and placebo arms, analysis of the six symptoms from the last slide showed a statistically significant difference in the ITT population. Furthermore, as shown on this slide, this difference was even greater among patients who were enrolled within three days of symptom onset. You can see that the hazard ratio for the difference of EDP235 at the 400 milligram dose versus placebo is 1.9, with a p-value of 0.006. Median time to improvement for these six symptoms was shortened by two days. Specifically, patients receiving placebo improved in five days, while patients receiving 400 milligrams of EDP-235 improved in three days. Moving to virologic endpoints, this graph shows change from baseline in viral RNA as measured by nasopharyngeal swabs. No difference was demonstrated between patients treated with EDP-235 and placebo, likely due to the rapid viral decline observed in the placebo arm. The mean baseline viral load in this study population was approximately five logs, and a precipitous decrease in viral RNA was observed in all study arms, indicating that this highly immune population rapidly cleared virus from the nose. To understand this further, we performed an additional analysis of patients with a baseline viral load greater than five logs, and this represented about half of the study population. we saw a viral load decline of 0.4 logs at day three in both EDP235 treatment groups compared to placebo. This 0.4 log decline was sustained at day five in the 400 milligram arm. For more contextualization, this slide compares the viral RNA change from baseline in the placebo arms of other direct acting antiviral COVID studies. You can see here that the decline seen in the placebo arm of the SPRINT study was more rapid than in any other study. This may not be surprising given the highly immune population in which this study was conducted, as evidenced by recent CDC data from a nationwide seroprevalence study showing a high prevalence of natural and hybrid immunity, which continues to grow over time. Details of these data can be found in the appendix of the slides posted to our website. In summary, EDP-235 was generally safe and well-tolerated. There was a low frequency of adverse events, and most were mild in severity. There were no serious adverse events or discontinuations due to adverse events. EDP-235 showed a dose-dependent improvement in total symptom score. Among patients enrolled within three days of symptom onset, there was a statistically significant improvement in the total symptom score for EDP-235 at 400 milligrams at all time points, starting at one day after dosing. there was no difference between treatment arms and placebo for viral RNA decline in this highly immune population that was able to rapidly clear SARS-CoV-2 from the nose. However, an additional analysis of patients with a baseline viral load greater than five logs showed a viral RNA decline of 0.4 logs at day three in both EDP235 treatment groups compared to placebo. In conclusion, We're excited to see that EDP235 at the 400 milligram dose had a significant effect on symptoms in this SPRINT study, suggesting that we have the potential to affect clinically meaningful endpoints moving forward in development. That concludes my presentation of the data. With that, I'll turn the call back to Jay. Jay?
spk09: Based on the positive SPRINT data, we are focusing on partnership opportunities for Phase III and on the potential for a Phase II study in acute or long COVID that could further demonstrate the efficacy of EDP235. We look forward to providing an update on our plans in the coming months. I also want to note we continue to progress our research program to develop SARS-CoV-2 papain-like protease or PL-pro inhibitors. Beyond COVID-19, our patient-centric approach continues with our industry-leading respiratory virology treatment portfolio. With RSV specifically, we are advancing a broad program, which includes EDP938, the most advanced end-protein inhibitor in clinical development, as well as EDP323, our novel oral therapeutic targeting RSV L-protein RNA polymerase. We are monitoring RSV epidemiology to evaluate the impact on trial enrollment and timing for data readouts in our ongoing Phase II studies of EDP 938, and we expect enrollment to continue throughout 2023. Meanwhile, we are wrapping up our ongoing Phase I study of EDP 323, and we look forward to reporting top-line data for EDP 323 next month. This quarter, we also announced that the FDA granted fast-track designation to ADP323, underscoring its potential as a once-daily oral therapeutic for the treatment of RSV. As a reminder, the Phase 1 study is a double-blind, placebo-controlled, first-in-human study that will enroll approximately 80 healthy subjects and is evaluating the safety, tolerability, and pharmacokinetics of orally administered single and multiple doses of EDP323. Beyond our clinical RSV programs, we are particularly excited by the potential of our novel, broader-spectrum antiviral research program targeting both RSV and human metapneumovirus, or HMPV, with a single agent. Both of these viruses have a severe impact on several vulnerable patient populations, such as children, the elderly, adults with underlying cardiopulmonary disease, and those who are immune compromised. Our preclinical data in support of this program show that our prototype dual inhibitor demonstrated potent nanomolar activity against multiple genotypes and strains of both viruses in a range of cell types. We're making progress in the optimization of our potent dual inhibitors and aim to select a clinical candidate in the fourth quarter of 2023. Before I turn the call over to Paul to provide an update on our financials, I want to comment on the $200 million royalty sale transaction we closed two weeks ago. The additional non-dilutive funding has increased our financial flexibility and extended our cash runway. With that, I'll turn the call over to Paul.
spk10: Thank you, Jay. Before I provide details on our second quarter financial results, I also want to take a moment to comment on our royalty sales transaction, which we announced in April. This transaction involved the sale of 54.5% of our future global royalties we earn on net sales of Maverick beginning in July 2023 through June 2032, with total payments capped at 1.42 times the purchase price. In exchange, the purchaser, OMERS, paid us $200 million up front. We are excited to partner with OMERS, which is one of Canada's largest defined benefit pension plans. This sale not only secures us additional non-dilutive funding, but also gives us increased financial flexibility and retained economics. Please note that Enanta retains 45.5% of all royalties until the cap is hit. at which point 100% of all further royalties revert to Inanta. Now let's turn to our quarterly results. For the quarter, total revenue was $17.8 million and consisted of royalty revenue earned on AbbVie's Global Maverick Net Product sales. This compares to total revenue of $18.7 million for the same period in 2022. The decrease was due to lower patient volumes in 2023 compared to 2022. Moving on to our expenses, for the three months ended March 31, 2023, research and development expenses totaled $43.5 million compared to $42.1 million for the same period in 2022. The slight increase was primarily due to the timing of clinical trial expenses in our virology programs. General and administrative expense for the quarter was $13.8 million compared to $10.5 million for the same period in 2022. The increase was due to increased stock-related compensation expense and legal fees associated with our patent infringement suit against Pfizer. Net loss for the three months ended March 31, 2023 was $37.7 million or a loss of $1.79 per diluted common share compared to a net loss of $33.6 million or a loss of $1.63 per diluted common share for the corresponding period in 2022. Enanta ended the quarter with approximately $225 million in cash and marketable securities before giving effect to the royalty sale transaction. We expect that our current cash, cash equivalents, and short-term and long-term marketable securities, along with the $200 million in cash we received on the sale of our portion of Maverick Royalties, as well as our retained portion of royalty revenue, will continue to be sufficient to meet the anticipated cash requirements of our existing business and development programs into calendar 2026. Further financial details are available in our press release and will be available in our report on Form 10-Q when filed. I'd now like to turn the call back to the operator and open up the lines for questions. Operator?
spk14: Thank you. And 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 the question, simply press star 1-1 again. Please stand by while we compile the Q&A roster. One moment for our first question that comes from Jasmine Rahimi with Piper Sandler. Please proceed.
spk06: Hi, team. Thank you so much for all the details from Sprint. I guess maybe now with this data on hand, like what are the next steps, right? Like how soon can you meet with the agency and get insight in regards to the phase three design? And maybe, you know, given that there was quite a bit of variability in the viral load and maybe not differences were depicted in the total symptom score, like do you think those data points could impact or may or may not impact the discussions with potential partners. So, if you could maybe highlight whether they have a deep appreciation of those variabilities and nuances, and then I'll jump back in the queue. And thank you for allowing me to ask my questions.
spk09: Sure. Hi. This is Jay. So, maybe I'll let Scott fill in some of the – a little bit of the details. You know, I think we'll be progressing our data set, taking it to the agency, you know, as a matter of course of finishing up the study. We'll be also, you know, in the context of the data, you know, the viral load bit, which, you know, we can talk a lot more about, but, you know, at the end of the day, The agency doesn't approve any of the COVID drugs based on viral load. It's based on some other endpoints. So if you're looking at a standard risk patient population, it's going to be based on symptoms. If you're going to be looking at a high-risk patient population, it's going to be on hospitalization and death. And so I think in particular, that's why we were really pleased to see the statistically significant increase improvements in the total symptom score and on the time to improvement. So those are both really important metrics that could be viewed as clinically, highly clinically relevant. So Scott, anything to add on that or?
spk01: Yeah, Jasmine, thanks for that question. I mean, just to reiterate, we're so excited about the strong data and symptoms, and we do expect that to form the basis of a discussion with regulators to look at, you know, next steps in terms of Phase III design. While the virology data are mixed, as you say, I do think we have an opportunity here, given the symptom data. you know, very excited and looking forward to moving this to next steps.
spk09: I think one of the other things that's clear is that, you know, the patient population over time since the beginning of the pandemic has changed dramatically, as has the virus. And so, you know, good for the humans. You know, the seropositivity that we're building up over time either through vaccination or through natural infection or both, you know, giving you hybrid immunity. This is only built and built and built over time and in every sort of consecutive study population that people are looking at. And, you know, for that reason, and as you saw the data, just even looking at the placebo curves in the slide deck. And again, this slide deck will be posted at the end of the call. But when you look at all those placebos from all the various studies, it becomes clear that over time, you know, the viral load drops have happened more quickly and more dramatically as time has gone on. at least as you can measure viral loads in the nose, which is obviously the compartment that can easily be interrogated. What's happening in the rest of the body and the rest of the tissues from a virologic standpoint, much more difficult to assess, but we know that our drug has great tissue penetration, high potency, good exposures, high multiples of EC90s, and has had a very significant effect on symptoms, which, again, we think compares very well to any other study that's been done in this patient population. So I think that's an interesting next study. I think the question I think you asked, Yaz, was next plans. I mean, we'll be thinking about Other kinds of studies, there's things you could think about, and I'm talking about phase twos now, that you could conduct in long COVID or in another patient population. I think we wanna think about what any such study might look like. And at the same time, obviously, it's thinking about the future with phase three. Our plan's always been to engage a partner for late-stage development, the commercialization strategy, and ultimately the launch. I think with this positive sprint data, we see a broad opportunity for 235 in multiple different treatment paradigms for COVID. You can think of standard risk, high risk, prophylaxis, long COVID. So, you know, really in order to realize this vision, we feel a pharma partnership would better enable us to get the best registration program and to achieve that optimal label. So that's going to be our focus in terms of phase three. I don't know if you, I think you dropped off the call.
spk06: No, that was great. That was great. Thank you so much. Okay.
spk15: You're welcome.
spk14: One moment for our next question, please. It comes from the line of Brian Abrahams with RBC Capital Markets. Please proceed.
spk12: Hey, good afternoon, guys. Thanks for taking my questions, and thanks, too, for all the detailed SPRINT data. Really, really helpful. I guess my first question is, when you think about a potential go-forward dose here, I guess how confident are you that some of the symptomatic benefits that you're seeing are indeed dose-dependent versus maybe related to a slightly higher baseline for the 400-milligram arm. I guess I'm curious sort of at the end of day five how 400 and 200-milligram patients compared in terms of where they got to on an absolute basis on symptom score and how you're thinking about the go-forward dose.
spk09: I think the go-forward dose is going to be 400. I mean, that stood out in so many ways. You know, there were slight differences in the baseline, but what happened there is that within the first, you know, really in the first 24 hours, the 400 milligram dose brought things down very quickly. and basically, you know, lined up with the other patient populations. So, there's, you know, clear evidence that that 400 milligram moved very quickly and efficaciously in the right direction.
spk01: Yeah, and I would point out that, oh, sorry, Brian, I was just going to say I'd point out also that in addition to the decrease in total symptom score, If you look at those specific symptoms, you see an improvement in time to improvement. And so we have, you know, multiple different avenues of evidence that point to the fact that this is, you know, really a real dose-dependent improvement in efficacy. And, yeah, we feel quite confident in it.
spk12: Got it. To what do you attribute the TSS symptom signal that you're seeing here, given that there isn't a measurable antiviral effect? Is this related to maybe sort of an unmeasurable effect that's going on in terms of viral clearance in a different reservoir or some sort of additional benefit on anti-inflammatory benefit?
spk01: Oh, yes. Key, key question, Brian. So we think it's the compartment that we're measuring, right? Everybody looks at the nose. That's where we can, you know, easily access and check. But we know that these patients have, you know, 95% seropositivity. And you can look at some of the background information that we put in our decks as well. The whole population is becoming really strong in terms of hybrid immunity and ability to clear this virus. Now, that having been said, we do believe when you see these systemic symptoms in particular, there are clearly other reservoirs of virus throughout the body that we can't necessarily access to measure efficiently. But we do know that our drug has excellent tissue distribution, excellent tissue penetration, and we believe that that's what potentially sets it apart, and that's what's allowing us to get a therapeutic effect on symptoms, whereas we don't see so much on virus in the nasopharynx. That makes sense.
spk12: And if I could squeeze one more quick one in. I'm wondering if you could maybe talk a little bit more about the triglyceride and total cholesterol effects that you're seeing in terms of, I guess, how long you followed those patients and how close to their baselines did they return? And does that imply anything in terms of how you might think about future studies in higher risk patients who may have concurrent hyperlipidemia baseline? Thanks.
spk01: Yeah, absolutely. So obviously, we'll follow patients very closely in terms of lipids going forward. But we saw within 14 days, the triglycerides had returned entirely to normal. And within 14 days, the total cholesterol was well on its way. It's a little bit delayed from a metabolic perspective, of course. So we have every reason to believe that these cholesterol changes are mild and very manageable. So, yeah, we think that we can monitor them and manage them pretty effectively, particularly given that this drug is for acute and not chronic use.
spk12: Great. Thanks again.
spk09: I think the other thing that's interesting on that front is Shionogi saw some of these findings as well. And so I guess it begs, and with a very sort of a different chemical class. And so it could beg the question, is that some exposure is something that you will see with protease inhibitors? And that's an outstanding question. But I think we're all you know, finding the stuff out as more and more protease inhibitors, you know, gather clinical information. Got it. Also remind the folks that, you know, looking at other mechanisms even that measuring viral load changes in the nose has not always, you know, yielded findings. I mean, earlier in the pandemic, Gilead's drug, remdesivir, failed to demonstrate viral load changes in the nose. Other people have demonstrated viral changes in the nose, but not something else. So this is why the FDA doesn't want to use viral loads as a provable endpoint. When we did look at a subpatient population that had viral loads higher than the mean of five. We did see about a half a log change in this still experienced patient population. I think it's just getting harder and harder to find that in this otherwise healthy standard risk patient population with the current variance and the current state of immune education. that patients have.
spk15: Thank you. One moment for our next question.
spk14: And it comes from the line of Roy Buchanan with JMP Securities. Please proceed.
spk11: Hey, great. Thanks for taking the questions. Most have been answered. A couple quick ones. Just noticed that drug-drug interaction studies had completed. I know they're not the most exciting, but anything you can tell us about the drug-drug interaction profile of 235. And then just any, you know, potential alternative explanations for the lack of viral load effect. I guess maybe you guys have gone through it already, the tissue distribution of the virus and et cetera. Just anything else you guys can think of. And then just really quickly, EDP 514, what's the status of... Maybe we'll...
spk09: Okay, sure. Maybe we'll just focus on the first question first. So I think in relation to, well, first of all, there's, I think we've kind of explained what we can really tell you about, you know, viral load in the nose today. I think we've addressed that a couple different times. No further thoughts right now, certainly. And then with regards to the DDI studies that are ongoing, ritonavir has a very substantial load of baggage with it in terms of hitting all kinds of P450s and transporters and all kinds of stuff. So it's fair to assume that we have nothing close to a ritonavir-like profile when it comes to So we think it'll be a competitive profile going forward.
spk15: I'm sorry. You can go on to the next question if you have one, a brief one.
spk09: I think you said 514 if you're still on, Roy. If not, maybe you'll come back in the queue.
spk11: Roy? Yeah, sorry. Just the status of searching for additional candidates to combine with that. Have you considered out-licensing 514 in addition to in-licensing something else? Thanks.
spk09: I think we'd be open-minded in any way to bring together a marriage of the right combination. And, you know, to that end, I think, you know, there's more data readouts that are going to come out in the area of HEPB. It's still a little tricky to know exactly what that right combination is. might be for us or anybody else. So our plan is to continue to watch other data sets, think about other mechanisms, follow the literature closely, and looking at external assets that could be combined. And we're agnostic as to whether we export our asset or import another, but we just want to make sure it's the right combination.
spk11: Great, thanks.
spk14: Thank you. One moment for our next question. Again, it comes from the line of Akash Tiwari with Jefferies. Please proceed.
spk16: Hi, this is Amy on for Akash. Thanks so much for taking our question. So, Shinogi also had a high prior vaccinated slash zero positive patients in their phase two trials in the range of mid to high 80% range. I believe they showed a half a log to one log benefit over on viral load over placebo. What are the major differences between your phase two and prior COVID antivirals that would attribute to a potentially more aggressive placebo?
spk01: I was going to say either one of us can take that. You know, the Shinogi study was run in Japanese patients, Asian patients, clearly at a time that they had less exposure to natural infection. So we would expect a much, and I don't have these data for either population yet, but we'd expect a much lower rate of nucleocapsid positivity among that population than among our population. So, you know, we can see here in the year 2023, again, that populations have very high hybrid immunity. So it's challenging to find, you know, any patients, much less a population that has a baseline viral load of seven logs like Shionogi did in order to show that big drop in viral load. I don't know if, Tara, you had anything to add to that.
spk04: Yeah, I think, you know, the terminology of seropositivity is somewhat heterogeneous, you know, in terms of what provides that seropositivity, whether it's through vaccination or natural infection. And we're seeing data coming out of the CDC now that in the U.S., the percentage of people with hybrid immunity, meaning they have had it through both vaccination and or natural infection, is increasing, probably provides somewhat better immunity. And that's probably borne out in the difference in baseline viral load between the two studies. We know that that is a major factor in seeing these viral load declines. So yeah, the Shinobi study had a baseline viral load of seven, which was two logs higher than what we had in SPRINT.
spk09: And we've got, just as an appendix to the slide deck that we presented today, which again should be on our website soon if it's not already there, has a little bit of supplemental information about seropositivity and also percent of patients or percent of the population that have been previously infected as measured by nucleocapsid antibodies. So I think those trends are pretty interesting. So if you extrapolate them backward into Japan at that time and place, I think you would get a sense that you know, it likely was a bit of a different patient population.
spk14: Great. Thanks so much.
spk15: You're welcome.
spk14: One moment for our next question. It comes from the line of Lisa Baker with Evercore ISI. Please proceed.
spk05: Hi there. How are you doing? Good. I guess first question. Do you think showing an RNA change is important in terms of partnering discussions? Like, how important is that? I know you've got symptoms and that's going to be important for phase three, but just wondering how much of a, how important that would be to potential partnering discussions.
spk09: Well, I mean, again, you have to look at the totality of any data set. I think at the end of the day, people want to make sure you have sort of signs of a registration path forward, and symptoms certainly help to provide that. You know, the viral load data or the viral load data, I mean, again, it's the, again, it was never powered on virology. And, you know, it was surprising to us, you know, when we saw the placebo, especially when we laid our placebo against every other placebo that's been done in a comparable study, just how disadvantaged our treatment arm was in terms of demonstrating that. But I think it's a sign of the times in terms of, again, sort of immune training of patients as well as the evolution of the virus.
spk05: Okay. Um, do you think if you were able to tap into some of these other viral reservoirs, and I know that's not possible to do, but just theoretically, you would see a change or. I guess I'm trying to make the linkage between, like. A change in symptoms and actual viral viral reduction, whether or not you can. See, it as a different question, you know, detectives I understand is a different question.
spk09: Yeah, no, I mean, I, I suspect you would, but again. accessing those compartments, you know, whether it's, you know, the heart, the liver, lungs, you know, other tissues, these are reservoirs. I mean, the virus has been found in the brain, right? So, I mean, there's all kinds of places you could go and look, but I think that that's a, it becomes a challenge. Obviously, you know, sort of in long COVID, for example, I mean, long COVID, there's probably a subset, maybe even a good subset of patients out there that still have, you know, virus fermenting in various other tissues. It might not be the nose. The folks continue to, you know, swab negatively. But when you look at some of the symptoms and the drivers of some of the symptoms that are exhibited in long COVID, there are very likely patient populations that could have reservoirs of that. And that's something we're thinking hard about. You know, are there interesting ways to go interrogate that and sort that out? But too early to call, you know, whether or not we would do, you know, sort of a smaller phase two study to explore and exploit some of those kinds of reservoirs of virus with 235.
spk05: Okay. And does, I guess, natural immunity or vaccination disproportionately reduce virus in the nasal passage? Or why would it be different, I guess, than other reservoirs?
spk04: Lisa, I think that's a good question. You know, certainly hybrid immunity, we think from at least some of the data that's out there could provide additional protection. The nose is where the virus first enters and then continues to spread and replicate in other parts of the body, and that just appears to be where it's being cleared. And patients have mucosal immunity built up that can contribute to the clearance, at least in the nasal compartment.
spk05: That makes sense, the mucosal immunity.
spk01: Yeah, I was just going to say, Lisa, particularly associated with natural infection, you get the mucosal immunity that you wouldn't necessarily get to the same degree with vaccination.
spk05: Okay, that makes sense. Yeah, I get that. And then my associate, Tima, who's sitting with me here, raised a good point about rebounds. I think that was something that you were going to be Could you comment at all on, you know, if you've seen any difference in rebounds, if you've checked for that or if you will be checking or what's the plan there?
spk01: Yeah, nothing yet, Lisa. We have looked grossly and haven't seen differences between arms, and we're working on getting those analyses done properly.
spk05: Okay. And then just as we think about kind of next steps, are those predicated on finding a partnership, or is that something you'd be willing to take on yourself? Like, how are we thinking about the gating factors for developing, you know, the next?
spk09: I don't think any phase two study would be gating, you know, in a different population, like long COVID or something like that. That's not gated, and in fact, it's built into the financial guidance that Paul talked about. You know, we would be able to do that and still have cash into calendar 26. But I do believe that as it relates to phase three, you know, these are bigger, much more expensive trials that ultimately I think you do want to have a partner engaging on, you know, the trial design, how you would set those up and then, you know, push them forward with dispatch and Importantly, gaining a launch partner. You know, we're not – we've never, you know, planned on commercializing in COVID, but rather to do – you know, we've said this since the beginning of time. Our plan has always been to find a late-stage partner and commercialization launch partner for this. So I think that is going to be our current plan for progressing Phase 3.
spk05: Okay. Thanks a lot.
spk09: You're welcome.
spk14: Thank you. One moment for our next question, please. And it comes from the line of Brian Scorney with Baird. Please proceed.
spk13: Hey, good afternoon, everyone. Thanks for taking my question. Question on just the wording in the press release as it relates to sort of the specified protocol. You talk about total symptom score, and then you talk about 14 targeted COVID-19 symptoms. Can you just help me understand, are these different arrays of symptoms that you're evaluating here? And when I pull up the protocol that's posted on clinicaltrials.gov, number three and four are the ones that relate to symptoms, and they say proportion of COVID-19-signed symptoms and change from baseline COVID-19-signed symptoms. Is that the TSS, or is that the 14 targeted COVID-19 symptoms?
spk01: It's the same. Yeah, so the way we get it is we have the 14 symptoms, and each one is graded by the patient on a scale of zero, one, two, or three, and then add up the score, and that's the score. So total symptom score and all 14 symptoms, we mean to be the same thing. Does that help?
spk13: I guess I'm having trouble understanding the line where you say, well, no difference was observed in time to improvement of 14 targeted COVID-19 symptoms. Is that basically there was no difference in observed time to improvement in the TSS? I don't really understand the distinction between the two.
spk01: Oh, I see what you mean. So we have a different... A different evaluation for the time to improvement. So for the time to improvement, you have to have all of your symptoms either absent or mild. And anything that was present or anything that was absent at baseline needs to still be absent. And that has to be the case for two days. And that has to be the case with all 14 symptoms. All right, so that's what I mean by time to improvement of all 14 symptoms. And then when I say to take a selected group of those symptoms, then that's looking at just those symptoms specifically. And, you know, the selected symptoms have given us a greater degree of power to detect a difference with placebo because those symptoms seem to persist more in placebo and go away more quickly with EDP-235. Okay. Thanks. That makes sense.
spk14: Thank you. One moment for our next question, please. And it comes from the line of Ed Arce with HC Wainwright. Please proceed.
spk08: Hi. Good afternoon, everyone. Thomas here asking a couple questions for Ed. Thank you for taking our questions. So just trying to figure with COVID-19 entering a pandemic phase, what do you estimate could be the market opportunity both in U.S. and ex-U.S. markets, and especially given how Pfizer and Moderna latest performance with the inventory right now that they just reported?
spk15: Sorry, could you repeat?
spk09: I mean, you're asking what the market opportunity is for COVID therapeutics?
spk08: Yes, because as COVID-19 has transitioned from a pandemic into an endemic phase and also demand for treatment as well, how do you look at the COVID-19 treatment market going forward?
spk04: Sure. So I think what we can look at is what the guidance has been provided in terms of revenue from the drugs that are currently available. You know, looking at remdesivir, molnupiravir, and Paxlovid, I think combined it's around 10 billion market size. And so if you look at Pfizer's information that they just released on their quarterly revenue, They were guiding to $8 billion revenue 2023, and they actually reported $4 billion just in Q1. So, you know, we do believe that there's a good market and still a lot of use for antivirals in this syndication.
spk08: I see. Thank you for the additional information. Perhaps two more questions from us. You mentioned in the press release that a long COVID could be a possibility. How does that actually compare to COVID, and are there any endpoints in the FACES study that you glance that could suggest potential long COVID?
spk09: Yeah, well, long COVID is very different than acute COVID. It has different clinical manifestations and a diverse patient population. That said, there may be common elements in a subset that could be a patient population that could benefit from an antiviral. And so, again, as I mentioned a minute ago, we're going to look and think about that. And, you know, any plans for any next study where we to do one in long COVID, you know, design or give further details around the design, you know, at that point. So it's premature for us to comment on that today.
spk08: Got it. Just one last one from us with 323, switching gears to 323. With the phase 1 theta expected next month, can you remind us what would be the next step? Is it a challenge study? And if so, can you give us some preliminary thoughts on what that study will look like?
spk09: Yeah, so 323, again, our polymerase inhibitor, super potent, great preclinical PK and safety. Phase 1 study in healthies, MAD-SAD study, that's the data that we'll report out next month. Top line would have safety, tolerability, NPK. From that, it will allow us to derive, you know, what sorts of multiples we have of, you know, protein-adjusted EC90, which are the hallmarks of efficacy surrogates that you can measure in a Phase I study, even in healthy patient populations. So I think the logical next step, assuming positive data there, would be a challenge study. And from that standpoint, you know, we've had a very successful challenge study for EDP938 in the past. Again, one could look at that to get insights as to how we might be thinking about progressing 323, assuming positive data. And we'll have, you know, more details on data and next steps when we release it next month.
spk08: Understood. Thank you so much again for taking our questions.
spk14: You're welcome. Thank you. One moment for our next question, please. Any calls from the line of Roana Ruiz with SBB Securities? Please proceed.
spk07: Great, thanks. Some of my questions were already asked, but maybe a quick one on 235. I was curious if your outlook on time to possible approval for that asset has changed at all, especially considering the Phase 3 and possibly an additional Phase 2 that you might run.
spk09: Again, a phase two would be supportive, perhaps, of a different indication. I think the wild card there is in the context of a partner. I mean, obviously, one of the reasons we're seeking a partner would be potentially the time to approval could be accelerated by the strength and resource of a global pharma partner helping us to execute So, yeah, I think right now I would assume that it's going to be a lot driven by a partner in terms of moving that time either forward or backward, I would say.
spk07: Yep, understood. And then last one from me. I was curious. individuals where you saw elevated cholesterol or triglycerides, was there any trends or commonalities among them that could help you identify them proactively in some of the data that you've seen so far?
spk01: Thanks, Rana. So, nothing specifically, you know, we've gone through at a population basis. There weren't any substantial outliers who didn't already have really high lipids at baseline. So we haven't detected anything specific or any patterns in terms of outliers. It was just kind of a general population trend.
spk07: Got it.
spk14: Helpful. Thanks again.
spk01: Thank you.
spk14: Thanks. One moment for our next question, please. And it comes from the line of Hannah Adeoye with JP Morgan. Please proceed. Hi.
spk03: This is Hannah on for Eric Joseph. Thanks for taking the question. So just acknowledging that there are a number of details left to be finalized as it relates to a pivotal study design. Given the fact that you have observed treatment benefit in non-high risk mild to moderate COVID patients, how are you thinking about the target patient population for the therapy? And then just secondly, with Pfizer announcing plans to develop a next-gen COVID antiviral to Paxlovid that won't be using ritonavir boosting, just wanted to get your sense of how you're thinking about the impact that might have and if it might have any bearing on potential partnership discussions for EDP-235.
spk09: Yeah. Now, I mean, we've always assumed there are going to be multiple players in the COVID space. I mean, that's not different than So I think with regards to Pfizer's next molecule, we'll see what data they can achieve with that one. I mean, we know what they have with Paxlovid. I think we know what Shinogi has. And apart from Pfizer and Shinogi, I would say we've got the other ones. So at least right now, the space, I think, is still favorable given the size of the market and what a protease can add to the overall treatment landscape in COVID. So, I'm sorry, what was the other part of your question?
spk03: Just your thoughts on targeted patient populations for the therapy since this study .
spk09: Yeah, no, the patient population, I mean, again, I think we're thinking broadly about it. Standard risk, the high-risk patient population, which fits a, you know, sort of a different risk profile. Prophylaxis, long COVID, I mean, there's nothing that I would see that would necessarily be not to be considered in a broad development program.
spk03: Okay, thanks for taking the questions.
spk09: You're welcome.
spk14: Thank you. And with that, I'll turn the call back to Jennifer Vieira for final comments.
spk02: Thank you, everyone, for joining us today. Please note that we will have these slides on our website as well as our updated corporate presentation. If you have any additional questions, feel free to contact us by email or call the office. Thanks and have a great night.
spk14: Thank you. Ladies and gentlemen, for participating in today's conference you may now disconnect.
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