ENTA - NASDAQ

Good afternoon and welcome to the Enanta Pharmaceuticals Fiscal First Quarter 2022 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.

Thank you, operator and thanks to everyone for joining us this afternoon. The news release with our fiscal first quarter 2022 financial results was issued this afternoon and is available on our website. On the call today are Dr. Jay Luly, President and Chief Executive Officer; Paul Mellett, our Chief Financial Officer and other members of Enanta's Senior Management Team. Before we begin with our formal remarks, we 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-Q and other periodic reports filed with the SEC and 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, President and CEO. Jay?

Thank you, Jennifer, and good afternoon everyone. Enanta had a very productive fiscal first quarter of 2022, as we made significant progress in our RSV and COVID-19 programs, building a strong foundation for important inflection points to come this year. Today, I'll update you on our clinical development programs for respiratory syncytial virus. SARS-CoV-2 and hepatitis B virus, all of which have the goal of providing safe and effective oral antiviral treatment for viral diseases impacting broad patient population. I will additionally comment on our ongoing discovery efforts and progress in human metapneumovirus. Enanta has a successful and proven history of discovering and developing antiviral treatment as demonstrated by glecaprevir the HCV protease inhibitor component in Mavyret, a leading treatment for chronic hepatitis C virus. We have expanded and leveraged this long and deep experience in virology, we discovered small molecule therapeutics for multiple viruses, recently expanding our respiratory virology pipeline by developing a coronavirus protease inhibitor for SARS-CoV-2 and then L-inhibitor for RSV. The pandemic has made it clear the viruses can cause serious disease, which makes our work especially significant. With that backdrop, today, I will start by detailing progress in our respiratory virology programs, where we continue to build an industry-leading treatment portfolio. Our most advanced RSV program is our N-Protein inhibitor EDP-938, which has Fast Track designation and is currently in three Phase 2 studies in multiple patient populations. Additionally, we continue our leadership in RSV with the announcement of a clinical candidates in our RSV L-inhibitor program EDP-323. As a reminder, RSV is a severe respiratory infection associated with significant morbidity and mortality. The virus can cause serious disease in children, the elderly, and the immune compromised and there are no treatments or vaccines available for the virus, which was first characterized in 1956. We are excited by the potential of EDP-938, which is a potent inhibitor of the RSV N-protein that has shown robust clinical data in a Phase 2a challenge study, where it was not only safe and well tolerated, but also demonstrated significant effects on viral load and reduced symptoms of infection. In this human challenge study of EDP-938, we met the primary endpoint of viral load reduction and also a key secondary endpoint of total symptom score. In order to confirm our findings outside of a challenge study, we conducted the RSVP study to evaluate EDP-938 in an adult outpatient population infected with community-acquired RSV and to provide us additional information on symptom alleviation and viral load decline. Following a period of decreased RSV transmission, due to social distancing measures, late last year, there was an uptick in RSV activity in various regions of the world, including parts of the United States and Europe, which allowed us to complete enrollment beyond our initial target of 70 patients. We are on track to report top line data from RSVP next quarter. Our broad clinical development program includes two key Phase 2 studies of EDP-938, evaluating its safety and efficacy in young children and hematopoietic cell transplant recipients with RSV infections. Our clinical trial named RSVP in the Phase 2 study in pediatric RSV patients and the trial RSVTx is a Phase 2b study in adult hematopoietic cell transplant recipients with RSV. Data from these two studies will confirm the doses to be used in subsequent pivotal studies in this population. These studies, which were initiated after RSVP are expected to extend at least into 2023. We are monitoring RSV globally and we'll be providing further updates, as the incidence rates of all. This quarter we are pleased to announce that we broadened our footprint in RSV by introducing EDP-323, a potent RSV L-inhibitor. EDP-323 targets the RSV L-Protein, which is a viral polymerase that contains multiple enzyme activities, required for RSV replication. Preclinical data demonstrate nanomolar potency across the major RSV subtypes, RSV-A and RSV-B and good absorption and plasma exposure across multiple different species. We envision EDP-323 is a standalone treatment or for use in combination with other agents such as EDP-938 to potentially broaden the treatment window or expand the addressable RSV patient population. We expect to initiate a Phase 1 study of EDP-323 in the second half of this year. I'm proud of the work we have done thus far in RSV and I'm excited by the potential of our broad development program, allowing us to extend our leadership in the development of treatments for respiratory viruses. Turning to SARS-CoV-2, we're also excited by the promise of EDP-235, our oral coronavirus 3CL protease inhibitor, also known as a main a protease inhibitor, specifically designed for the treatment of COVID-19. EDP-235 is on track to begin dosing subjects in this month. This first in human, single on multiple ascending dose-ranging study will determine the safety, tolerability, and pharmacokinetics of EDP-235 in healthy participant. In preclinical studies, EDP-235 demonstrated highly potent antiviral activity against SARS-CoV-2 and pharmacokinetic properties, supporting a once-daily oral dosing regimen without the need for a boosting agent such as ritonavir, all which needs the potential of EDP-235 as a best-in-class compound. Specifically, EDP-235 potently block the replication of SARS-CoV-2 in multiple cellular models, including primary human airway epithelial cells with an EC90 of 33 nanomolar. Importantly, EDP-235 has shown potent antiviral activity in vitro across a range of currently circulating SARS-CoV-2 variants including Omicron and Delta, giving it pan-genotypic potential. Furthermore, EDP-235 has potent activity against other human coronaviruses, enabling the potential for a pan-coronavirus treatment including possibly coronaviruses that may infect human populations in the future. EDP-235 has also shown excellent exposure after oral administration without ritonavir boosting and favorable distribution in the key target tissues including lung in preclinical model. This positions EDP-235 among the most potent direct-acting antivirals, currently in development for SARS-CoV-2 infection, with the potential for convenient once daily dosing. With our Phase 1 study starting this month, assuming supportive data, we would advance EDP-235 to the next stage of clinical development in the second half of 2022. We also continue to pursue our respiratory virus discovery program in human metapneumovirus or hMPV, a virus that was first identified 20 years ago and now circulates worldwide with nearly universal infection by age 5. Like with RSV, there are a number of vulnerable populations, including children, the elderly, adults with underlying pulmonary disease and those who are immune compromised. We are nearing completion of lead optimization of potent nanomolar hMPV inhibitors and plan to select a clinical candidate in the second half of this year. Moving to Hepatitis B, we remain committed to our vision of developing a combination regimen to deliver a functional cure for chronic HBV patients. EDP-514, our HBV core inhibitor with Fast Track designation has been evaluated in two Phase 1b studies in different chronic HBV patient populations. Those who have a high viral load, whom you refer to as viremic patients and those who are on the treatment with a nucleoside reverse transcriptase inhibitor, whom we refer to as NUC-suppressed patients. Last year, we presented data demonstrating that EDP-514 has clear clinical evidence of a good safety profile alone and then in combination with NUC and displays significant antiviral activity over 28 days with a pharmacokinetic profile, consistently supportive of once daily dosing orally putting EDP-514 among the best core inhibitors currently in development. We remain focused on evaluating internal and external opportunities for additional compounds with alternative mechanisms to develop in combination with EDP-514, as we believe that a core inhibitor such as EDP-514 will ultimately be an important component of a successful combination regimen. Before moving to the financials, I'd like to wrap up by reiterating our upcoming milestones. We expect multiple catalysts, including the start of dosing in our Phase 1 study of our oral 3CL protease inhibitor, EDP-235 this month. If supported by Phase 1 results, we plan to advance EDP-235 to the next stage of clinical development for the treatment of COVID in the second half of this year. We plan to report top line data from the RSVP study of EDP-938 next quarter. Finally, we look forward to initiating a Phase 1 study for EDP-323, our RSV L-inhibitor and nominating a human metapneumovirus clinical candidate in the second half of this year. With that, I'll stop here and turn the call over to Paul to discuss the financials. Paul?

Thank you, Jay. I'd like to remind everyone the Enanta reports on a September 30th fiscal year schedule. Today, we are reporting results for our first fiscal quarter-ended December 31, 2021. For the quarter, total revenue was $27.6 million and consisted entirely of royalty revenue earned on AbbVie's global HCV product sales of $427 million. This compares to a total revenue of $31.7 million for the same period of 2020. As reported by AbbVie, treated patient volumes remain suppressed compared to pre-COVID levels. Royalty revenue was calculated on 50% of Mavyret sales at a blended royalty rate for the quarter of 13% and on approximately 30% of VIEKIRA sales at a royalty rate of 10% after adjustments for certain contractual discounts, rebates and set-offs, which are now approximately 2.7% of AbbVie's total reported HCV product sales. As a reminder, our royalties are calculated on a calendar year basis, therefore royalties for our fiscal first quarter ending December 31st are calculated at the highest royalty rate for the year. And royalties for our fiscal quarter ending March 31st will be calculated at 10%, our lowest royalty rate tier in our fiscal year. You can review our royalty tier schedule in our 2021 Form 10-K. Recently, AbbVie reported their global HCV sales were $1.7 billion in calendar 2021 and guided to $1.7 billion for Global HCV sales in calendar 2022. Moving on to our expenses, for the three months ended December 31, 2021, research and development expenses totaled $48.5 million compared to $36.7 million in the same period in 2020. The increase was primarily due to the timing of manufacturing in support of the company's clinical studies in our virology programs. General and administrative expense for the quarter was $9.5 million compared to $7.4 million for the same period in 2020. This increase was primarily due to increased headcount in compensation expense. Enanta recorded a minor income tax benefit related to the release of the state tax reserve for the three months ended December 31, 2021, compared to an income tax benefit of $3.3 million for the same period in 2020. Enanta recorded a larger income tax benefit in 2020 than in 2021, due to the provisions of the CARES Act of 2020, which enabled us to carry back our prior-year tax laws to offset taxable income in prior years. This provision does not apply to periods ending after September 30, 2021. Net loss for the three months ended December 31, 2021 was $30.1 million or a loss of $1.48 per diluted common share compared to a net loss of $8.3 million or a loss of $0.41 per diluted common share for the corresponding period in 2020. Enanta ended the quarter with $347.7 million in cash and marketable securities. Enanta expects that its current cash, cash equivalents, and marketable securities as well as continuing royalty revenue will be sufficient to meet the anticipated cash requirements for its existing business and development programs for at least the next two years. Further financial details are available in our press release and will be available in our quarterly 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 Instructions] Our first question comes from the line of Brian Abrahams of RBC Capital, I'm sorry, RBC Capital Markets. Your line is open.

Thanks so much for taking my questions. I guess just a couple on 235, I'm curious with some of the latest developments on the progress with other protease inhibitors in the space. I'm wondering how you're thinking about the overall competitive opportunity for 235. Would you be thinking about maybe focusing initially on patients, who may not be able to take ritonavir, which packs over is boosted by, are there other sub-populations you might initially focus on? And then I'm just kind of curious, it sounds like the healthy volunteer study is on track to start this month, what are your plans for how you might reveal the safety and PK data, which of course given the in vitro potency is going to be very important in gauging, what the ultimate opportunity, probability of success of drug to be. Thanks so much.

Thanks, Brian. Hi, this is Jay. So yes, so the -- the Phase 1 in healthy is about to begin, be a standard SAD and MAD and we plan to harvest that data here in the first half and as with all of our other studies, once we've got that data in hand, we'll find the appropriate mechanism and then to put it out. Regarding the field in N-protease, I would describe it as very early yet. There are a few entrants in the space, but as we are not only in virals, but in lots of other disease areas, it's not necessarily the first one in, it's -- the high quality molecules that ultimately stand the test of time. So again, I think we've built some advantages and to EDP-235 from a positive standpoint, from a PK standpoint, from a tissue-targeting standpoint and overall, we think the profile is a strong one that you compete very well over the longer timeframe. Regarding trials beyond the Phase 1 healthy study of course, we'll be getting into key patient populations. There is standard risk, high risk, post-exposure prophylaxis et cetera and we would anticipate tapping into all of those opportunities. Thank you.

Thank you. Our next question comes from Eric Joseph of JPMorgan. Your question please.

Hi, good afternoon. This is Hannah on for Eric. Thanks for taking the questions. Just a few from us. So first, just wanted to get your thoughts on the severity of RSV symptoms in patients and how they're like compared this season versus prior season, given the loss in seasonal margins. Just wondering if there's any reason to think we might see more severe symptoms in patients this year and then also based on any unblinded looks at patient baselines entering the RSVP study. How should we be thinking about median age during the study, are there any pre-specified subgroup analysis by age or other risk factors? Thank you.

So I, maybe I'll let Nathalie comment on some of these, but again I don't think there's necessarily anything special about this RSV season versus prior ones, but I'll let Nathalie chime in.

Thank you, Jay. So your question I think was about the symptoms of the RSV infection was worse than before. We, I mean obviously even though we don't have access to unblinded data, but we can monitor our current ongoing study and even the study that just completed, we have not observed any worsening of the symptoms, patients present themselves in the clinic as far as and we concern.

All right. And so you don't have any data on median age entering the study at this current time?

Sorry, I'm not sure I understood your question, what age?

Median age.

Median age.

Median age. We haven't logged the database yet, they are being collecting, so I don't have the median age, but if you look at the criteria of eligibility, it's from 18 to 75 years old and so we would expect something I would say you know if I have to guess, I would say something along the line of 50.

Okay. And I'm just wondering based on or assuming success in RSVP trial, could you describe what next up would look like -- would look like toward a pivotal program, specifically how would a program in general adults be prioritized relative to pediatric and transplant population and would either of these trials be getting factors to and the Phase 2 discussions with the FDA.

So we're going to focus post RSVP on high-risk patient populations and they fall mainly into three buckets, the peds, transplant, and then other adult populations that are at higher risk. So those will be the basic patient populations that we'll be targeting, two of the three of which we've got ongoing now.

Thank you. Our next question comes from Yasmeen Rahimi of Piper Sandler. Please go ahead.

Hi team, thank you so much for the update. Two questions for you. A frequent question from a lot of our clients are just to understand how big the RSVP outpatient population is, adult population is, so can you maybe share with me some of the market research that Enanta has done, how big is this addressable market? And then the second question I have is in regards to the L-protein Inhibitor entering the clinic into the second half of 2022, what is the strategy there, like which patient population would you be prioritizing this. Are you going to go into the peds or immunocompromised or would you try it all population? So thanks for answering my questions.

You're welcome. So Yasmeen, again the RSVP so called the RSVP patient populations, otherwise healthy -- otherwise healthy adults, which is probably not where the -- it's a great sort of staging trial and it's a great bridge from our challenge study into other patient populations adult and peds, but it's not the main patient population that we would be focused on and instead going after the three high risk once that I had mentioned. It's not to say that of course, one is otherwise healthy adult that's presenting with RSV couldn't be addressed by our drug, it's just that on the route to approval and looking at the critical markets to address on the registration pathway. It's really going to be in the peds, transplant and higher risk adult populations. In terms of the L-protein, we just see -- we're going out and RSV, I think in a very significant way. As we know there aren't any approved therapeutics out there. We hope to be the first or certainly among a small number of drugs that could be approved in RSV over a reasonable timeframe and we just, as you know, we've been working on human respiratory viruses long before the pandemic, because we saw it is a major unmet medical need from a therapeutic standpoint. So when we size up a situation like that, we usually are doubling down on our strengths and so I think having an inhibitor like 938 is great, has high barrier, it's very potent, it's once daily dosing. We've already demonstrated strong antiviral effect. So it should be fine along the way as a single agent. But we also are looking at other direct-acting antiviral mechanisms too and L-protein. There is another very interesting target from a replication perspective. So, exactly how we took that in, could it be pursued principally as another single agent in say maybe a different patient population, perhaps you could -- you could think about different ways to position these things that you had multiple of them or might we put the two of them together in certain patient populations that might be very advanced in their infection. Otherwise, very hard to treat maybe severely immune-compromised patients that would just struggle with anything and/or might we use it to explore, could we widen the treatment window versus any single agent alone. We all know that and these -- and these infections, viral infection. There is a ticking clock, you have a defined window based on what virus it is and what mechanism you're pursuing and whatever that window is for one mechanism by putting two drugs together hitting it harder earlier might be able to -- or hitting it harder, you might be able to postpone treatment a little bit longer before therapy is administered and so doing, you would obviously be increasing the addressable patient population, which would grow the market opportunity significantly. So there's just various different ways, once you have a couple of tools that you could exploit them and we'll be looking into that as we evolve, but 323 is a very strong looking molecule, very potent, great PK. Again, we'll have it in the clinic in the second half and we'll be tracking hopefully a very successful other pathway using our N-protein and EDP-938.

Thank you, Jay and if I may ask a follow-up question to the remarks you had. So I think the question from a lot of investors will come in, how do we take the RSVP study and understand its translation in the more vulnerable populations. So have you been able to provide some clarity how this study could really de-risk RSVP and RSVTx.

It's a step-wise de-risking. I think actually one of the most significant de-risking events for EDP-938 happened in Phase 1 healthy, when we established that a really potent molecule with a high barrier to resistance could be administered safely and could deliver very nice drug exposures. So that gave us great confidence going into our first RSV infection study that's so-called challenge model, whereas you know it performed incredibly well. All of that said, that wasn't a virus that had been administered to patients, volunteers under a controlled setting, but it was still a real virus and real patient population. But, so to demonstrate good viral kinetics and good safety in that setting was further de-risking them, we're taking step further and doing it with real world virus, a real world infection I should say, so that people are catching the strain that's going around presenting in a very natural way to treater and then we treat them. So I think it's yet another de-risking step along an evolution rarely in clinical medicine or clinical investigations, do we have such checkpoints to be able to establish that new drug is actually doing what you had hoped for it to do, and granted that every patient population is slightly different and we'll explore those as we do. But again, I think the profile of the drug, the fact that it's a really potent antiviral and it appears to be working in every setting that we've put it in bodes well.

Thank you. Our next question comes from Roy Buchanan of JMP Securities. Please go ahead.

Hey, great, thanks for taking the questions. I guess start on EDP-235, it sounds like the next trial is going to be after the Phase 1 is going to be treating patients in the second half of the year, maybe a Phase 2, 3, just curious if you guys plan to run multiple Phase 1s in addition to the one that you're going to start this month and if so, what those might be.

Well, I mean you're always doing other kinds of ancillary studies along the way in development, such as DDI studies. Is that what you were thinking of?

Yes. Anything. Sure.

Those types of studies. Yes. No, I think those are the -- those are the main ones. Once you have SAD/MAD, understand your exposure and tolerability, you kind of know what your dosing parameters are for Phase 2. So you don't want to -- you don't want to be slowing that down Phase 2-3. And so, but there's always other studies that you're doing in parallel, in terms of DDIs et cetera, et cetera. Those will help down the road with special patient population.

Okay, great. And then I had one on 514, I guess, just curious maybe if you can speculate if that could be back into the clinic this year. And what about, I guess how are you guys thinking about the combos, maybe there are some less ideal agents out there that you could partner with just to get more data on the compound, what about running maybe a longer combination trial with just a NUC, some mentioned to us that might be something worth exploring, anything like that? Thanks.

No. Those are all good questions I think to answer your first direct question about, is it likely to be in the clinic this year, I won't say that it couldn't be under any circumstance. But what I would say is, we're really focused on, we have 514 plays well with NUC, we've done it on a one-month study with the two, making up a two-drug combo. We saw very nice behavior in terms of the two drugs playing well together, good safety profile and the combination, we have observed good antiviral effects, et cetera, et cetera. So it's the two-drug foundation now, it's just waiting for an ideal third ingredient to be added. And again, we thought we had that one lined up before, it turns out we don't know and so, again we're looking sort of both internally and externally for what I think will hopefully be a great next combo ingredient. I don't know -- I don't really necessarily want to be pursuing the lesser ideal ones, to me that's maybe just not a good use of capital. But as it pertains to more a longer NUC study, I think was your other question, could you do a core and a NUC for a really long time, I mean, that's probably not super high up on our list, but it is something that I know KOLs think could work over time, you just have to be patient enough to run those kinds of studies and sort of launch that satellite and then hope that it reports data back after a significant period of time. So those are -- those are interesting studies that maybe should be done in some fashion someday, but again our principal focus right now is looking through something that would make for a great third agent to add such that we could get to a functional cure and hopefully in a more reasonable amount of time.

Thank you. Our next question comes from

Good afternoon, thanks for taking my questions and really helpful updates. I think we just have a few, the first one is in the Phase 2a RSV study, you had symptom improvement that was being evaluated as a secondary endpoint, and you did show some impressive reduction in nasal mucus. But I think I was just kind of curious about symptom improvement being a primary endpoint for the Phase 2b study and if you're going to be looking at nasal mucus, how important is that endpoint to patients and is it likely that you'll be looking at some additional symptom measures for the Phase 2b study?

Yes, so good question,

Thanks. And then, I'm sure you get this one a lot, but just kind of curious about the five-day treatment period for the RSVP study. I know you use the same, the treatment period in the prior study, but we're just wondering is that really long enough or based on the MOA of an inhibitor, it's likely that no additional benefits could be gain from treating longer?

Well, I guess you could never really know the answer to that without doing the study, but what we did find in this patient population that -- in RSVP, we think it will substantially mirror the challenge setting that's -- that should be -- we think that should be adequate, when you get into the immune compromised setting, RSVTX, the hematopoietic cell transplant recipients are highly I mean suppressed in the first year close transplant and for these individuals, who don't have confident full immune system helping them, we are dosing longer 21 days in fact in that study. So there may be certain pockets or patient populations, where you want to have the latitude to be able to dose longer, but ultimately the goal is to try to find a convenient dosing regimen, that's -- that is adequate and quite attractive. And generally speaking, the shorter you can make that, the higher you're going to have compliance and the better the product profile is overall.

Got it. Was thinking that, yes, I was partly related to also being cautious of the burden to patients and then the last one here is just about the combo strategy, so if you were to do a combo with the N and L, do you start with the N-inhibitor and then follow with the L or do you just on-board both of them at the same time. And then I'm just going to squeeze in a question here for Paul, regarding Mavyret revenues, 2021 revenues came in lower than what AbbVie guided to at the beginning of the year, which was $2 billion and I think it came in at $1.7 billion and they've guided modestly for 2022 at about that $1.7 billion and so I was just wondering how should we be thinking about the cadence of revenues beyond 2022 and how that has factored into your projections, but I think you said a runway for the next two years.

Well, regarding what happens after 2022, it's -- it's really all up to the COVID pandemic situation. You're correct AbbVie has guided again for fiscal -- for calendar 2022 at $1.7 billion, so they're expecting a flat year 2021 with no relief I guess from the COVID suppression impact, what happens after that is really going to be up to with variance, is there going to be a follow on Omicron, it's unknown at this point in time. And I would say that the two-year guidance we gave on cash was based upon our existing cash balances, our R&D and G&A guidance for fiscal '22 and obviously our AbbVie HCV royalties for the next fiscal year. So we look at that whole picture and we feel comfortable that we've got at least a two-year run rate on cash.

And to answer your other question,

Thank you. Our next question comes from Jay Olson of Oppenheimer. Your line is open.

Thank you for the update and congrats on the progress. I think there has been some discussion about using Merck's Molnupiravir together with other anti-virals in a combination approach to treat COVID. Is that something you would consider with EDP-235 and if so which drugs would you consider combining it with? And then if I could ask a financial question, assuming AbbVie's guidance of $1.7 billion in 2022 sales indicates that Mavyret is stabilizing, would that support a level of royalties that could continue to support Enanta's operating expenses for the foreseeable future?

I think as Paul sort of just outlined the $1.7 billion that they're guiding for the year is pretty much, where they came in now and that's what's built into our forecasts, we model based on their guidance and we do see that as propelling the cash runway for that two-year, at least the two-year period based on current cash and anticipated royalty revenue. Regarding your question about combos, there is no indication right now that you need combos. It is an acute viral infection, we have potent antivirals that appear to be from what we can see with antiviral drugs going after COVID that five-day treatments are sort of the norm, much like we had already established in our RSV study. So I would say that there could be the need for combinations down the road, but we don't see that need yet, but nonetheless, we're anticipating that having more mechanisms rather than fewer down the road can be a valuable thing. So we're not just working on protease in-house here and when the pandemic started, we started multiple different programs and we're hoping to harvest other agents of other mechanisms over time. So stay tuned on that front. But in any event, to your direct question, I don't see the need at this time to be doing those combination studies, I'm not sure what you'd be trying to establish.

Thank you. Our next question comes from Brian Skorney of Baird. Please go ahead.

This is Luke Herrmann on for Brian. Thanks for taking my question. And thinking about RSV development strategy from earlier questions, it seems like you're leaning towards the higher-risk RSV populations for the initial registrational path. In a situation that RSVP readout positively, do you think the RSVP then RSVTx studies might serve as pivotal for those indications and otherwise, what can we expect a pivotal program to look like and would you choose to move it forward yourself? Thank you.

Yes. So again, I think once you have the data for RSVP, we'll have that information and of course we'll have that discussion with the agency that could inform how you know the future of the development program looks like on the path to registration. But at this time, we are not currently expecting that those two studies are necessarily registration studies. Is that helpful?

Yes. Thank you.

Yes. I'm sorry, did you have another question?

It was just other, if those -- if those weren't registrational, what would pivotal development look like, if you could speculate at all?

Yes, I think the FDA, I mean I think the FDA and EMA, both want to I think focus on high risk, as they expedient path to approval, so I think that's what we need to do.

Thank you. Our next question comes from Roanna Ruiz of SVB Leerink. Your line is open.

Great. Thanks. So I wanted to circle back to your COVID asset, so for 235, do you have any thoughts on what percentage of patients, out of the total eligible patient pool for antivirals might be really fully unable to take an antiviral that has ritonavir boosting, maybe possibly due to drug-drug interactions or things like that?

Yes, it's hard to get your hands on that exact number now, maybe that is -- that's more of a Pfizer question, I think the -- but what I will say is there is a very substantial amount of the pharmacopoeia that is influenced by ritonavir dosing. So you just need to understand what other concomitant meds patients are on and understand what potential impact ritonavir would have, do you need to take people off certain meds, do you need to dial them down or dose adjust, in some instances ritonavir can reduce exposure of other medicines, you need to dose elevate other drugs to compensate for that. So there is just different things going on that you need to be able to understand and I think any time a patient's on concomitant meds, it's a -- the question that physicians will need to understand and explain to patients and then set up whatever plan of attack that you would need to set up to make sure everyone is safely medicated. Our hope is to just sidestep that issue entirely.

Yes. Makes sense. And then a quick one for your RSV programs, I was curious for the Phase 2 studies in pediatric and transplant patients, are there any other strategies or levers that you can pull to further accelerate enrollment of those trials and what are you tracking to help you make that kind of decision, if you want to apply those additional strategies?

Yes. So we're looking at new strategies all the time, the other thing you do is improve your catchment in terms of trial sites et cetera, et cetera. I think it's just a question of how you adapt protocols to make it friendly for -- not friendly, it's maybe the wrong word, but make it convenient for parents of peds to enhance enrollment, not having extensive barriers, there are extensive blood draws, other kinds of things that might slow things down a little bit or put people on the fence in terms of coming in and participating in the trial. Like one of the other things, just during the pandemic, the transplant recipients are probably among the most cautious people, right, because they're immune suppressed, they have to be incredibly careful post-transplant because of COVID and so that raises other special challenges during the pandemic, but we're just going to have to, just like with RSVP we had to -- as you know was compromised by the pandemic for a while and we just needed to be ready with sites and all the appropriate spots for when things opened up a little bit and then take advantage of harvesting the trial enrollment. So I don't know that there is any special tricks, we're just always trying to optimize enrollment in which way we can without jeopardizing the study of course.

[Operator Instructions] Our next question comes from Liisa Bayko of Evercore ISI. Your line is open.

Hi, thanks for taking my question. Just wanted to get a sense, you all have Phase 1 data for the COVID program, looks like in the second quarter, that's kind of come before or after, do you think the RSV data and then how quickly would you be able and prepared to go into Phase 2/3 with your COVID program from wrapping up the Phase 1?

Yes. So I can't really, I guess speak to which data would come first, we haven't -- we're going to begin dosing 235 soon and we'll get into that study and get the various cohorts progressed, so depending upon how many doses we have et cetera, et cetera, it's safe to say they're -- they're probably both Q2, but exactly which one's first, I can't really speak to today. And then your other question, obviously we'll be preparing for the steps, Phase 2, 3, after the Phase 1 to get into that as quickly as we can, making sure drug supply and sites et cetera, et cetera are lined up. And so we'll be doing it as quickly as possible and starting in the second half, so stay tuned on that front.

Okay. And is that part of your assumption in your guidance and I'm just looking at R&D, because you came in at around $49 million this year, I feel like you have a lot going on in your pipeline, you're guiding to $168 million, sorry $150 million to $170 million, where -- like how do we kind of make the math work with all these studies going on, is there something, I know a couple of things probably wrapped up in the fourth quarter, maybe a wrapping up in the first quarter, but given the --

Sure. Now, there is wind-down cost and so forth associated with some of the NASH studies, et cetera, et cetera, they won't be obviously carried through for the rest of the year, but I think the plan is still intact and encompasses what we're aiming to do with these various programs.

Okay. And then just one or two questions on RSVP. The strain that you used in the challenge study, is that like pretty representative of kind of how the different -- because virus out there, it just came to my attention because you talked about the strains going around right now, how similar or divergent can strains be for RSV from and compared to what you looked down the challenge study, because as I recall, yours was one of the more it seems like, I don't know if the right word, is virulent or whatever but you had one of the higher viral loads, as I was kind of looking at across other challenge studies. So, it looked like you had a pretty serious virus that you were using for the challenge study --

Yes. And I'm sorry to -- sorry to interrupt Liisa, but I think it's a standard virus that has been used to cement the strains and used in multiple challenge studies, I think, yes, you know, it may differ, a little bit in terms of when people elected to dose, we waited to dose once the viral load had reached a certain threshold, not a certain number of days post inoculation. So we inoculated people in that challenge study with the virus, waited for the viral load, we checked people twice a day by RT-PCR, waited for the viral loads to start to climb up and waited until they got up to about three logs if I recall and then we started dosing. So obviously, if you dose sooner than that, you'll be dosing with a lower viral load. So that's probably the variable there. I think ultimately it's a real virus and we -- but you need -- you do need to ultimately get out in the real world, where you're going to run into different, slightly different strains, you might have RSV-A, you might have RSV-B, might be various subtypes along the way. But this is why we did a lot of work on clinical isolates before embarking on the study, we weren't using just lab strains and things, et cetera, et cetera. We got geographically dispersed by virus samples from different patients in different seasons, et cetera. And we tested our drug against them and the drug performed uniformly very well against the clinical output, so it is a variable, but that's the real world, right. Real world infection and that's among the things that RSVP will be looking at, but I think we've tried to fence and as much as we could possibly fence in from a de-risking prior to doing this.

Okay. And then just a final question from me. So, you mentioned you dosed around three logs and I see from your graph, your trials, so that makes sense, it's when you started dosing. How does it relate to like symptoms among patients start feeling symptoms and present, because I think that's what we're -- a lot of people are trying to figure out is like that window of opportunity, you have, I know it has to be within two days of symptoms, but you started dosing on Day-3 here, how does -- sorry, not on Day-3, at three logs of viral loads, so how does that relate to kind of the onset of symptoms and that kind of stuff?

Well, if you and we've got these sites in our corporate deck on our website, it's probably what you're looking at, but if you look at the symptoms by the time, people were three logs in the challenge study, and this is the trial, we're talking about, it's a challenge study, by the time people were three logs, they were also starting to express at least one symptom. And so they were becoming symptomatic, so then if you translate that into the real world study now and say in RSVP, what is the window, what is the window that we could possibly be dosing patients in? You're not going to get people to come into your study or into the doctor's office period within 24 hours of symptoms, right. Nobody sort of dose that they languish a little bit before they pick up the phone and so the earliest you might reasonably expect to catch a patient in a real-world setting is within 48 hours. And that's obviously what we were able to do in RSVP that was in fact was one of the parts of the study we're just doing, just to make sure we could catch RSV patients within 48 hours of symptom onset and that indeed was the case. That's the requirement for flu, if you want a flu drug to work, you've got to catch people in the first 48 hours or maybe 72 hours of symptoms if you want that drug to work. We don't know what the window is for RSV, it's probably more forgivable -- forgiving I should say than flu, where it's a real tight window. We're starting to get experience now in the community with regards to COVID, right. It appears that you can maybe there is a 5-day treatment window for COVID, where does RSV lie, these are among the things that will ultimately be sorting out in various studies. But just for the very specific RSVP trial, we did put that 48-hour constraint on there, just because we didn't have a basis to necessarily make it much longer. We've just said, well, let's assume it's like flu and then we can always go longer, you don't want to -- you don't want to make the wrong guess at the beginning of your development life. So I think that's where it is, you can't practically do it shorter than 48 hours and we saw no reason necessarily to go longer than 48 hours. So I think it's a good sweet spot.

Thank you. At this time, I'd like to turn the call back over to Jennifer Viera for any closing remarks. Ma'am?

Thank you to everyone for joining us today. If you have additional questions, feel free to reach out and contact us by email or give us a call at the office. Thanks so much. Have a good night. Bye-bye.