Enanta Pharmaceuticals - Q2 2023
May 8, 2023
Transcript
Operator (participant)
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 prepared remarks. Please be advised that this call is being recorded. I would now like to turn the call over to Jennifer Viera, Investor Relations. Please go ahead.
Jennifer Viera (Executive Director of Investor Relations and Corporate Communications)
Thank you, operator. 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 Liu Lai, our President and Chief Executive Officer, Dr. Scott Rottinghaus, our Chief Medical Officer, Paul Mellett, our Chief Financial Officer, and Dr. Tara Keefer, 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. Enanta 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 Luly. Jay?
Jay Luly (President and CEO)
Thank you, Jennifer, and good afternoon, everyone. At Enanta, 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 2 SPRINT study of EDP-235, our 3CL 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?
Scott Rottinghaus (Chief Medical Officer)
Thank you, Jay. As Jay stated, EDP-235 met the primary endpoint and was generally safe and well-tolerated. We saw a dose-dependent symptom improvement with EDP-235 treatment compared to placebo. 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 2 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 5 days. We randomized 231 patients in a 1-to-1 to 1 fashion.
The safety population included all patients randomized. We followed the patients out to day 33, and as you can see, 95%-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 3 days of symptom onset. Baseline viral load was about 5 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 U.S. 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 1 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 call-outs. The patient I just mentioned, who is receiving EDP-235 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 6. His AST was 5 times the upper limit of normal. GGT was elevated at baseline and increased further to 4 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 EDP-235. Both total cholesterol and triglycerides 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, EDP-235 achieved target exposures, and the results were consistent with what we saw in phase 1. 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 EDP-235 on day five are shown in the table. 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-19. They're listed on the right-hand side of this slide. You can see here that there's a dose-dependent trend favoring EDP-235, 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 EDP-235 data that I just showed you next to data from another protease inhibitor, ensitrelvir. We chose ensitrelvir for contextualization because it's the only antiviral with a sufficiently robust symptom data set in the public domain. Our phase 2 study looked at the 14 symptoms I just discussed in 190 patients, and the change from baseline in total symptom score is graphed here out to 10 days. Ensitrelvir's phase 2B 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 2 groups, those with less than 3 days of symptoms and those with greater than 3 days of symptoms. We pre-specified an analysis of the patients who were randomized within 3 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 data set 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 5 symptoms from their phase 2b study, which were subsequently used as a primary endpoint in their phase 3. As shown here, we identified a subset of 6 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 6 symptoms in the pre-specified population of patients enrolled within 3 days of symptom onset. EDP-235 at the 400 milligram dose demonstrated an even greater improvement in symptom score at all time points. 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 6 symptoms from the last slide showed a statistically significant difference in the ITT population. As shown on this slide, this difference was even greater among patients who were enrolled within 3 days of symptom onset. You can see that the hazard ratio for the difference of EDP-235 at the 400 milligram dose versus placebo is 1.9, with a p-value of 0.006. Median time to improvement for these 6 symptoms was shortened by 2 days. Specifically, patients receiving placebo improved in 5 days, while patients receiving 400 milligrams of EDP-235 improved in 3 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 5 logs. 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 5 logs, and this represented about half of the study population. We saw a viral load decline of 0.4 logs at day 3 in both EDP-235 treatment groups compared to placebo. This 0.4 log decline was sustained at day 5 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 the 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 3 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 1 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 5 logs showed a viral RNA decline of 0.4 logs at day 3 in both EDP-235 treatment groups compared to placebo.
In conclusion, we're excited to see that EDP-235 at the 400 mg 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?
Jay Luly (President and CEO)
Based on the positive SPRINT data, we are focusing on partnership opportunities for phase 3 and on the potential for a phase 2 study in acute or long COVID that could further demonstrate the efficacy of EDP-235. 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 PLpro 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 EDP-938, the most advanced N-protein inhibitor in clinical development, as well as EDP-323, 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 2 studies of EDP-938. We expect enrollment to continue throughout 2023. Meanwhile, we are wrapping up our ongoing phase 1 study of EDP-323. 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 EDP-323, 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 EDP-323.
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 pre-clinical 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.
Paul Mellett (CFO)
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 MAVYRET beginning in July 2023 through June 2032, with total payments capped at 1.42x the purchase price. In exchange, the purchaser, OMERS, paid us $200 million upfront. We're 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 Enanta. 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 MAVYRET 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 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 MAVYRET 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?
Operator (participant)
Thank you. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw the question, simply press star 11 again. Please stand by while we compile the Q&A roster. One moment for our first question that comes from Yasmeen Rahimi with Piper Sandler. Please proceed.
Yasmeen Rahimi (Managing Director, Senior Research Analyst, Biotechnology)
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 3 design? 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? 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. Thank you for allowing me to ask my questions.
Jay Luly (President and CEO)
Sure. Hi, this is Jay. Maybe I'll let Scott fill in 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. At the end of the day, you know, the Agency doesn't approve any of the COVID drugs based on viral load. It's based on some other endpoint. 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. I think in particular, that's why we were really pleased to see the statistically significant improvements in the total symptom score and in the on the time to improvement. Those are both really important metrics that could be viewed as clinically, highly clinically relevant. Scott, anything to add on that or?
Scott Rottinghaus (Chief Medical Officer)
Yeah, Jasmine, thanks for that question. I mean, just to reiterate, we're so excited about the strong data in 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 3 design. While the virology data are mixed as you say, I do think we have an opportunity here given the symptom data. We're, you know, very excited and looking forward to moving this to next steps.
Jay Luly (President and CEO)
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. 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 has only built and built and built over time and in every sort of consecutive study population that people are looking at. You know, for that reason, as you saw the data, just even looking at the placebo curves in the slide deck, this slide deck will be posted at the end of the call.
When you, 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, you know, 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. 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.
I think that's, you know, an interesting next study. I think the question I think you asked, Yas, was, you know, next plans. I mean, we'll be thinking about other kinds of studies. You know, there's things you could think about, I'm talking about phase 2s now, that you could conduct in long COVID or in another patient population. I think we want to, you know, think about what any such study might look like. At the same time, obviously it's thinking about the future with phase 3. You know, 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. You know, really to 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. That's going to be our focus in terms of, phase 3. I don't know if you. I think you dropped off the call, Yes, but.
Yasmeen Rahimi (Managing Director, Senior Research Analyst, Biotechnology)
No, that was great. That was great. Thank you so much.
Jay Luly (President and CEO)
Okay. You're welcome.
Operator (participant)
One moment for our next question, please. It comes from the line of Brian Abrahams with RBC Capital Markets. Please proceed.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
Hey, good afternoon, guys. Thanks for taking my questions and thanks too for all the detailed SPRINT data. 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 and for the 400 milligram arm? I guess I'm curious, sort of at the end of day 5, 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?
Jay Luly (President and CEO)
Yeah, I think the go-forward dose is going to be 400. I mean, that stood out in so many, you know, 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 population. There's, you know, clear evidence that that 400 milligram moved very quickly and efficaciously in the right direction.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
Got it.
Scott Rottinghaus (Chief Medical Officer)
Yeah. 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. 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. Yeah, we feel quite confident in it.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
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 a, it's like 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?
Scott Rottinghaus (Chief Medical Officer)
Oh, yes. Key question, Brian. 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. We know that these patients have, you know, 95% seropositivity. 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, you know, 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.
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.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
That makes sense. If I could squeeze one more quick one in. Wondering if you could maybe talk a little bit more about the triglyceride and total cholesterol effects that you're seeing in terms of how long you followed those patients and how close to their baselines did they return? Does that imply anything in terms of how you might think about future studies in higher risk patients who may have concurrent hyperlipidemia at baseline? Thanks.
Scott Rottinghaus (Chief Medical Officer)
Absolutely. Obviously, we'll follow patients very closely in terms of lipids going forward. 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. We have every reason to believe that these cholesterol changes are mild and very manageable. Yeah, we think that we can monitor them and manage them pretty effectively, particularly given that, you know, this drug is for acute and not chronic use.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
Great. Thanks again.
Jay Luly (President and CEO)
I think the other thing that's interesting on that front is Shionogi saw some of these findings as well. I guess it begs and with a, you know, a very sort of a different chemical class. You know, it could beg the question, you know, is that some exposure is something that you will see with protease inhibitors? That's a, you know, that's an outstanding question. I think we're all, you know, finding this stuff out as more and more protease inhibitors, you know, gather clinical information.
Brian Abrahams (Managing Director, Head of Global Healthcare Research)
Got it. Thanks so much.
Jay Luly (President and CEO)
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, you know, Gilead's drug, Remdesivir. You know, failed to demonstrate viral load changes in the nose. Other people have demonstrated viral changes in the nose, but not something else. Other. You know, this is why the FDA doesn't want to use viral loads as an approvable endpoint. You know, when we did look at a sub-patient population that had viral loads higher than the mean of 5, we did see, you know, about a half a log change in this, you know, still experienced patient population. It's just getting.
I think it's just getting harder and harder to find that in this otherwise healthy standard risk patient population with the current variants and the current state of immune education that patients have.
Operator (participant)
Thank you. One moment for our next question. It comes from the line of Roy Buchanan with JMP Securities. Please proceed.
Roy Buchanan (Director, Equity Research Analyst, Biotechnology)
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 EDP-235. 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. Just really quickly, EDP-514, just what's the status of searching for.
Jay Luly (President and CEO)
Maybe we'll.
Roy Buchanan (Director, Equity Research Analyst, Biotechnology)
Okay. Sure.
Jay Luly (President and CEO)
Sorry. Maybe we'll just focus on the first question, first. I think, in relation to. Well, first of all, 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. 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. It's fair to assume that we have nothing close to a ritonavir like profile when it comes to DDIs. We think it'll be a competitive profile going forward. I'm sorry.
You can go on to the next question if you have one, a brief one. I think you said EDP-514, if you're still on, Roy. If not, maybe you'll come back in the queue.
Operator (participant)
Roy?
Roy Buchanan (Director, Equity Research Analyst, Biotechnology)
Yeah. Sorry. 514, just the status on searching for additional candidates to combine with that. Have you considered out-licensing 514 in addition to in-licensing something else? Thanks.
Jay Luly (President and CEO)
I think we'd be open-minded in any way to bring together a marriage of the right combination. You know, to that end, I think, you know, there's more data readouts that are going to come out in the area of Hep B. It's still a little tricky to know exactly what that right combination might be for us or anybody else. You know, our plan is to, you know, continue to watch other datasets, think about other mechanisms, follow the literature closely, and looking at external assets that could be combined. 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.
Roy Buchanan (Director, Equity Research Analyst, Biotechnology)
Great. Thanks.
Operator (participant)
Thank you.
Jay Luly (President and CEO)
Welcome.
Operator (participant)
One moment for our next question. Again, it comes from the line of Akash Tewari with Jefferies. Please proceed.
Speaker 13
Hi, this is Amy on for Akash. Thanks so much for taking our question. Shionogi also had a high prior vaccinated/seropositive patients in their phase two trials in the range of mid to high 80% range, and 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?
Jay Luly (President and CEO)
I was going to say either one of us can take that. you know, the Shionogi study was run in Japanese patients, Asian patients, clearly with at a time that they had less exposure to natural infection. We would expect. 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. you know, we can see here in the year 2023 again, that populations have very high hybrid immunity. it's challenging to find, you know, any patients, much less a population, that has a baseline viral load of 7 logs like Shionogi did in order to show that big drop in viral load. I don't know if, Terry, you had anything to add to that.
Speaker 14
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. 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 2 studies. We know that that is a major factor in, you know, seeing these viral load declines. The Shionogi study had a baseline viral load of 7, which was 2 logs higher than what we had in SPRINT.
Jay Luly (President and CEO)
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 % of patients or % of the population that have been previously infected as measured by nucleocapsid antibodies. I think those trends are pretty interesting. 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.
Liisa Bayko (Managing Director, Senior Research Analyst)
Great. Thanks so much.
Jay Luly (President and CEO)
You're welcome.
Operator (participant)
One moment for our next question. It comes from the line of Liisa Bayko with Evercore ISI. Please proceed.
Liisa Bayko (Managing Director, Senior Research Analyst)
Hi there. How are you doing?
Jay Luly (President and CEO)
Good.
Liisa Bayko (Managing Director, Senior Research Analyst)
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, just wondering how much of a. How important that would be to potential partnering discussions?
Jay Luly (President and CEO)
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, I mean, again, it's the again, it was never powered on virology. 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 patient population or our treatment arm was in terms of demonstrating that.
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.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay. 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.
Jay Luly (President and CEO)
Yeah.
Liisa Bayko (Managing Director, Senior Research Analyst)
Make the linkage between like a change in symptoms and actual viral reduction, whether or not you can see it as a different.
Jay Luly (President and CEO)
Right.
Liisa Bayko (Managing Director, Senior Research Analyst)
You know, detect it as well as I understand is a different question.
Jay Luly (President and CEO)
Yeah. No, I mean, I suspect you would, but again, accessing those compartments, you know, whether it's.
Liisa Bayko (Managing Director, Senior Research Analyst)
Yeah.
Jay Luly (President and CEO)
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? I mean, there's all kinds of places you could go and look. 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. 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.
That's something we're thinking hard about. You know, are there interesting ways to go interrogate that and sort that out? Too early to call, you know, whether or not we would do, you know, sort of a smaller phase 2 study to explore and exploit some of those kinds of reservoirs of virus with 235.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay. 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?
Speaker 14
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, you know, could provide additional protection. you know, the nose is where the virus first enters and, you know, then continues to spread and replicate in other parts of the body, and that just appears to be
Thomas Yip (Equity Research Associate)
You know, where it's being cleared and, you know, patients have mucosal immunity built up that, you know, can contribute to the clearance, at least in the nasal compartment.
Liisa Bayko (Managing Director, Senior Research Analyst)
That makes sense in mucosal immunity.
Scott Rottinghaus (Chief Medical Officer)
Particularly.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay.
Scott Rottinghaus (Chief Medical Officer)
Yeah, I was just going to say, Liisa, particularly associated with natural infection, you get the mucosal immunity that you wouldn't.
Liisa Bayko (Managing Director, Senior Research Analyst)
Right.
Scott Rottinghaus (Chief Medical Officer)
Necessarily get to the same degree with vaccination.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay, that makes sense. Yeah, I get that. My associate, Seema, who's sitting with me here, raised a good point about rebounds. I think that was something that you were going to be exploring. Could you comment at all on, you know, if you've seen any difference in rebounds, if you checked for that, or if you will be checking or what's the plan there?
Scott Rottinghaus (Chief Medical Officer)
Yeah. Nothing yet, Lisa. We have looked grossly and haven't seen differences between arms, we're working on getting those analyses done properly.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay. Then just as we think about kinda 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, you know, the next steps?
Scott Rottinghaus (Chief Medical Officer)
I don't think that 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 2026. 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. I think that is going to be our current plan for progressing phase 3.
Liisa Bayko (Managing Director, Senior Research Analyst)
Okay, thanks a lot.
Scott Rottinghaus (Chief Medical Officer)
You're welcome.
Operator (participant)
Thank you. One moment for our next question, please. It comes from the line of Brian Skorney with Baird. Please proceed.
Brian Skorney (Senior Research Analyst, Biotechnology)
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 pre-specified protocol. You talked about total symptom score, and then you talked 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 3 and 4 are the ones that relate to symptoms when they say proportion of COVID-19 signs, symptoms, and change from baseline COVID-19 signs, symptoms. Is that the TSS or is that the 14 targeted COVID-19 symptoms?
Scott Rottinghaus (Chief Medical Officer)
It's the same. Yeah. The way we get it is we have the 14 symptoms, and each one is graded by the patient on a scale of 0, 1, 2, or 3, and then add up the score, and that's the score. Total Symptom Score and all 14 symptoms, we mean to be the same thing. Does that help?
Brian Skorney (Senior Research Analyst, Biotechnology)
I guess, 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 just I don't really understand the distinction between the two.
Scott Rottinghaus (Chief Medical Officer)
Oh, I see what you mean. We have a different evaluation for the time to improvement. For the time to improvement, you have to have all of your symptoms either absent or mild, anything that was present or anything that was absent at baseline needs to still be absent, that has to be the case for 2 days. That has to be the case with all 14 symptoms. All right? That's what I mean by time to improvement of all 14 symptoms. When I say to take a selected group of those symptoms, that's looking at just those symptoms specifically.
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.
Brian Skorney (Senior Research Analyst, Biotechnology)
Okay, thanks. That makes more sense.
Operator (participant)
Thank you. One moment for our next question, please. It comes from the line of Ed Arce with H.C. Wainwright. Please proceed.
Thomas Yip (Equity Research Associate)
Hi, good afternoon, everyone. It's Thomas Yip asking a couple of questions for Ed. Thank you for taking our questions. just trying to figure with COVID-19 entering a endemic phase, what do you estimate to be the market opportunity, both in US and ex-US markets and especially given how Pfizer met their latest performance with the inventory write-down that they just reported?
Jay Luly (President and CEO)
I'm sorry, could you repeat? I mean, you're asking what the market opportunity is for COVID therapeutics?
Thomas Yip (Equity Research Associate)
Yes, because, as COVID-19 has hit a transition from a pandemic and a pandemic phase and also demand for treatment as well, how do you look at the COVID-19 treatment market going forward?
Speaker 14
Sure. 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. 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. You know, we do believe that there's a good market and still a lot of use for antivirals in this, in this indication.
Thomas Yip (Equity Research Associate)
I see. Thanks. 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 optimally compare to COVID? Are there any endpoints in the phase study that you glanced that could suggest potential in long COVID?
Jay Luly (President and CEO)
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. 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 were we to do one in long COVID, you know, we'll design or give further details around the design, you know, at that, at that point. It's premature for us to comment on that today.
Thomas Yip (Equity Research Associate)
Got it. just one last one from us. with 323, switching gears to 323, with the phase 1 data expected next month, can you remind us what would be the next step? Is it a challenge study? If so, can you give us some preliminary thoughts on what that study will look like?
Jay Luly (President and CEO)
Yeah. EDP-323, again, our polymerase inhibitor, super potent, great preclinical PK and safety. Took it into 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, and PK. From that, it will allow us to derive, you know, what sorts of multiples we have of a, you know, protein-adjusted EC90, which are the hallmarks of efficacy surrogates that you can measure in a phase 1 study, even in healthy patient population. I think the logical next step, assuming positive data there, would be a challenge study. From that standpoint, you know, we've had a very successful challenge study for EDP-938 in the past.
Again, one could look at that to get insights as to how we might be thinking about progressing EDP-323, assuming positive data. We'll have, you know, more details on data and next steps when we release it next month.
Thomas Yip (Equity Research Associate)
Understood. Thank you so much again for taking our questions.
Jay Luly (President and CEO)
You're welcome.
Operator (participant)
Thank you. One moment for our next question, please. It comes from the line of Roanna Ruiz with SVB Securities. Please proceed.
Roanna Ruiz (Senior Research Analyst)
Great, thanks. Some of my questions were already asked, but maybe a quick one on EDP-235. I was curious if your outlook on time to possible approval for that asset has changed at all, and especially considering, the phase 3 and possibly an additional phase 2, that you might run.
Jay Luly (President and CEO)
Again, a phase 2 would be supportive perhaps of a different indication. You know, 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 you know, the potentially the time to approval could be accelerated by the strength and resource of a global pharma partner helping us to execute. 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.
Roanna Ruiz (Senior Research Analyst)
Yep. Understood. Last one from me. I was curious, in those 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?
Jay Luly (President and CEO)
Thanks, Ramah. 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. We haven't detected anything specific or any patterns in terms of outliers. It was just kind of a general population trend.
Roanna Ruiz (Senior Research Analyst)
Got it. Helpful. Thanks again.
Jay Luly (President and CEO)
Thank you.
Operator (participant)
Thanks. One moment for our next question, please. It comes from the line of Hannah Adeoye with J.P. Morgan. Please proceed.
Hannah Adeoye (Equity Research Associate)
Hi, this is Hannah on for Eric Joseph. Thanks for taking the question. 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-19 patients, how are you thinking about the target patient population for the therapy? Just secondly, with Pfizer announcing plans to develop a next-gen COVID-19 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.
Jay Luly (President and CEO)
Yeah. No, I mean, we've always assumed there are going to be multiple players in the COVID space. I mean, that's not different than, you know. 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 Shionogi has. Apart from, you know, apart from Pfizer and Shionogi, I would say we've got the other ones. 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. I'm sorry, what was the other part of your question?
Hannah Adeoye (Equity Research Associate)
Just your thoughts on, targeted patient populations for the therapy since this phase 2.
Jay Luly (President and CEO)
Oh, I.
Hannah Adeoye (Equity Research Associate)
Study enrolled in high-risk.
Jay Luly (President and CEO)
Yeah. Yeah. The patient population. I mean, I, 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.
Hannah Adeoye (Equity Research Associate)
Okay. Thanks for taking the questions.
Jay Luly (President and CEO)
You're welcome.
Operator (participant)
Thank you. With that, I'll turn the call back to Jennifer Viera for final comments.
Jennifer Viera (Executive Director of Investor Relations and Corporate Communications)
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. Have a great night.
Operator (participant)
Thank you, ladies and gentlemen, for participating in today's conference. You may now disconnect.