SCYNEXIS, Inc. (SCYX) Earnings Call Transcript & Summary

Good morning, and welcome to the SCYNEXIS Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Troy Neubecker of Investor Relations. You may begin.

Good morning, and thank you for joining us as we report positive results from the second interim analysis of our ongoing Phase III open-label FURI of -- study -- FURI study of oral Ibrexafungerp as a salvage treatment for difficult-to-treat invasive fungal infections. Joining me today are Dr. Marco Taglietti, President and Chief Executive Officer; Dr. David Angulo, Chief Medical Officer; and Eric Francois, Chief Financial Officer. During this call, please note we will be making forward-looking statements. These statements are subject to factors, risks and uncertainties, including those that are detailed in today's presentation and our Form 10-K for the year ended December 31, 2018, as well as our subsequent SEC filings that may cause actual results to differ materially from those results expressed or advised by such statements. Please also note that this call is being webcast and accompanying slides are available on the Investor page of the SCYNEXIS website at www.scynexis.com. With that, I would like to turn the call over to Marco for his opening remarks. Marco?

Thank you, Troy. Happy New Year, [Foreign Language] to everyone, and thank you all for joining us this morning. We are excited to share with you the positive results from the second interim analysis of our ongoing Phase III FURI study in patients with difficult-to-treat mucocutaneous and invasive fungal infections. But before Dr. David Angulo, our Chief Medical Officer, dives into the results of the FURI study, let me spend a couple of minutes on why we believe that these additional FURI results, combined with the recent positive Phase III data from our vulvovaginal candidiasis program, further confirm our vision for Ibrexafungerp to be a transformative antifungal agent, both in the hospital and in the community setting. Fungal infection remain a major and sadly, a growing public health threat. In the hospital setting, the interaction of new therapies for cancer, transplantation and other medical conditions has resulted in a rising number of severely immunocompromised patients susceptible to invasive fungal infections, often causing mortality sometime in excess of 50%. Additionally, the development of fungal strain resistant to or refractory to currently available antifungals is making treatment of patients with fungal infection progressively more difficult because the currently available treatment are becoming less and less effective. Unfortunately, the same issues are also present in the community setting, such as in patients with vulvovaginal candidiasis. These challenges are compounded by the fact that there are so few available systemic antifungals, less than 10, and even fewer orally bioavailable antifungals. For example, for vulvovaginal candidiasis, there is only 1 systemic treatment available on the market, fluconazole, which was approved more than 25 years ago. Finally, fungal pathogens are evolving. A new threat are emerging. Most recently, in the last 10 years, a new Candida species, Candida auris, has been appearing on the world scene. And as many of you know, it is a very scary pathogen, multidrug-resistant, associated with biomortality up to 60%, and it has the ability to be transmitted from patient to patient and contaminate surfaces. In fact, given the severity of this new strain, Candida auris is now included in the short list of urgent public health threat by the CDC. Now let me quickly remind you of our current focus and ongoing programs for our lead agent, Ibrexafungerp. Ibrexafungerp, the first representative of a new class of innovative antifungals, the fungerps, may be a potential solution to the fungal infection crisis. If approved in 2021, as we anticipate, it will be the first new antifungal class introduced in the market in more than 20 years. Given its versatile profile and favorable attributes, Ibrexafungerp could be used both in the outpatient community settings and in the hospital setting. In the community setting, we are currently developing the product in vulvovaginal candidiasis, an indication with clear unmet needs, and for which we believe potential peak sales of $400 million to $600 million in the U.S. alone can be reached. We are in Phase III in this indication with the NDA submission anticipated in the second half of this year. But today, the focus of our presentation will be about Ibrexafungerp in the hospital setting, a multibillion-dollar market with only handful of systemic antifungals available, and where there is a desperate need for an alternative treatment, especially an oral agent, to the currently available antifungal classes. Many of these classes are failing because of the development of resistance. Slide 5 shows our ongoing development programs in the outpatient community setting and in the hospital setting. Specifically in the hospital setting, Ibrexafungerp is in Phase III in refractory invasive fungal infection, the FURI study; and in Candida auris infection, the CARES studies. And it is in Phase II, the SCYNERGIA study, in combination with standard of care for aspergillosis infection. With regard to the FURI study, we shared the positive results of the first preliminary analysis in January of 2019, and I'm delighted to have Dr. David Angulo present to the positive results the second interim analysis of the FURI study. So without further ado, let me turn the call over to David so that he can jump into the second set of interim results as well as share some detailed case studies. David?

Thank you, Marco. I'm excited to share the results from the second interim look at the data from our ongoing FURI study, that is aimed to provide a treatment alternative to patients with difficult-to-treat fungal infections that have very limited treatment options. Most patients enrolled in the FURI study had complex and severe underlying conditions, such as malignancies, hematopoietic or solid organ transplants, chronic immunodeficiencies, complex intra-abdominal surgeries, complicated diabetes mellitus, among other conditions that make them more susceptible to severe fungal infections frequently associated with high mortality. For instance, the mortality rate for patients with invasive candidiasis ranges from 20% to 40% depending on the underlying condition and treatment. I should also note that the treatment options for severe fungal infections are very limited with only 3 main classes: Echinocandins, azoles and polyenes. So it is easy to imagine that when a fungal pathogen develop resistance against 1 or 2 of these groups, the treatment options get even more limited and sometimes, nonexistent. As a quick recap of the FURI study, it is a multicenter, open-label, non-comparator, single-arm study to evaluate the safety and efficacy of Ibrexafungerp in patients with a documented invasive or severe mucocutaneous fungal disease that meets 1 of the following 3 criteria: The infection is refractory to standard of care antifungal treatment, which means that they should have a documented failure to an approved antifungal drug; or the patient is intolerant to a standard of care antifungal treatment showing evidence of toxicity or risk of toxicity, for example, due to drug-drug interactions; or fungal infections for which currently available oral antifungal options are not appropriate for a continuation of therapy after an initial IV antifungal, specifically, patients with azole-resistant Candida strains for which a stepping-down to an oral azole is not adequate. Keep in mind that the ability to step down to an effective oral therapy is key for the optimal management of most fungal infections that actually required treatment for several weeks. And so far, only the azoles have the oral option available. However, there are several Candida strains that now show resistance to azoles. This is a global study, and we are currently -- have centers open in the U.S., Germany, the U.K., Spain, Netherlands and Austria. The patients in this study receive an initial loading dose of oral Ibrexafungerp of 750 milligrams twice a day during the first 2 days and then followed by 750 milligrams once a day. Patients are assessed several times during the study with the efficacy being evaluated at the end of Ibrexafungerp therapy. Patients are then followed for 6 weeks after the end of treatment. The version of the study protocol that was effective at the time that the patients we are reporting here were enrolled included only patients with Candida infections and allow for the treatment for up to 90 days. The type of fungal infections and the maximum treatment duration has now been expanded and extended with the recent protocol amendment, details of which I will cover later. Early last year, we reported a positive outcome of the initial cohort of 20 subjects reviewed by the data review Committee or DRC. A new cohort of 21 subjects were recently reviewed by the DRC, providing us now with data from 41 subjects treated in this study. The analysis included subjects who have completed this study as of the end of October 2019, and this data is considered interim and preliminary since the database is not locked. These studies are still enrolling and many patients are still on therapy and have not reached the point of clinical assessment. The mean duration of treatment for these 41 subject was approximately 37 days. Around 60% of these patients had invasive fungal disease and about 40 had severe mucocutaneous infections. The fungal diagnosis in these patients included candidemia, intraabdominal abscesses, esophageal candidiasis, oropharyngeal candidiasis and bone infections, to mention a few. The most common fungal pathogens were Candida glabrata, Candida albicans and Candida krusei. The DRC is made up of independent experts and they assess the efficacy of Ibrexafungerp at the end of therapy. As mentioning before, this analysis represents results from 21 additional treated patients, resulting in a combined data set of 41 patients analyzed to date. Let me remind you of the definitions of complete, partial or stable response in this particular population. Complete response means complete resolution of all sign and symptoms of infection present at baseline, plus negative cultures from any areas that were positive. Partial response means substantial resolution of the sign and symptoms, plus negative cultures. A stable disease could mean a improvement or not progression of the fungal disease while on therapy. In this particular population, which is very susceptible to fast progression of the fungal disease, complete, partial and a stable disease are considered positive outcomes with significant clinical benefits. The results from the first interim analysis and the second are displayed in these slides, and you can see a very good consistency of the outcomes observed in these 2 cohorts. Oral Ibrexafungerp consistently showed clinical benefit in the majority of the patients. A total of 34 out of 41, or 83%, saw a clinical benefit with 23 patients achieving a complete or partial response and 11 patients in a stable disease response. Of the 41 patients treated to date, only 6 patients did not respond to Ibrexafungerp, but none of them died to the progression of the fungal disease. The outcome was considered indeterminate in 1 patient who was lost to follow-up. The results are very encouraging in a salvage therapy setting and are consistent with outcomes observed in older salvage trials conducted with intravenous antifungal agents. Not surprisingly, the great majority of the patients have fungal infections caused by Candida species that are often resistant to 1 or multiple antifungal agents, particularly Candida glabrata and Candida krusei. Candida albicans typically account for about half of invasive candidiasis cases in the United States and is generally considered susceptible to most antifungals. However, as we can observe here, the frequency of patients enrolled with infections due to Candida albicans that were not optimally treated with the standard of care options, hence enrolled in the FURI study, is not insignificant, stressing the importance of developing new antifungal agents with a broader spectrum of activity that includes resistant strains. On the safety side, oral Ibrexafungerp was generally safe and well tolerated with the most common related adverse events being mild to moderate gastrointestinal events. One death was observed during the treatment phase of the study, but was deemed to be due to the progression of the underlying condition and not related to the study drug. No safety signals warranting changes in the study were identified. Now that I have shared the aggregate findings, let me go to 2 real examples from the FURI study to give you a perspective of this difficult-to-treat fungal infections. The first case is a 71-year old male patient with history of prostate cancer, diabetes mellitus, nephrostomy and urinary stents and multiple catheters. The patient had urinary and blood cultures positive for Candida glabrata. The patient started therapy with fluconazole, which was switched to caspofungin when the species was known since Candida glabrata is frequently resistant to fluconazole. After 4 days of caspofungin IV therapy, the patient still required antifungal treatment but was otherwise ready to -- for hospital discharge. And unfortunately, the standard of care oral options available were not considered adequate. Oral Ibrexafungerp was administered for 13 days, allowing for outpatient treatment, with negative blood and urine cultures and continued clinical improvement up to the end of therapy when the subject was considered to have achieved complete response. No drug-related adverse events were reported in this case. The second case is a 49-year old male patient with history of malignant thymoma, COPD and respiratory failure, arrhythmia and intermittent oropharyngeal candidiasis that was considered resistant to fluconazole and refractory to intravenous micafungin with multiple antifungal courses in the past 2 years. The patient was involved in the study with symptomatic oropharyngeal candidiasis and a chewing and swallowing and positive cultures for Candida albicans. Ibrexafungerp was initiated and the symptoms result within the first 7 days and remained absent through the end of therapy. This subject also achieved complete response. Let me stress again that the patients enrolled in the FURI study are seriously ill with limited remaining treatment options and as a clinician, it is encouraging to see patients with previously inadequate treatment options responding favorably to treatment with Ibrexafungerp. Results from this ongoing study continue to encourage us around Ibrexafungerp's potential as an antifungal agent able to address a significant unmet medical need across a variety of indications. And we look forward to discussing this preliminary data with the FDA and gather information regarding potential next steps. In the meantime, we will continue to enroll patients in the FURI study and to release additional details in patient cases from this interim analysis at upcoming scientific meetings. As mentioned before, we recently amended the FURI study protocol to allow the enrollment of patients with other fungal infections for which there are very limited treatment options, including aspergillosis, both acute invasive and chronic; coccidioidomycosis, also called valley fever; blastomycosis; histoplasmosis; and recurring vulvovaginal candidiasis, among other indications. We have also extended the treatment duration up to 6 months since many of these conditions require long treatment duration. This amendment comes as a result of extensive in vitro and in vivo efficacy evaluations in difficult fungal infections as well as extended toxicology studies allowing us to offer longer treatment durations. We are very pleased with the opportunity to offer Ibrexafungerp to a larger and more diverse group of patients in need. Before I turn the call back to Marco, let me take this opportunity to thank the patients that have participated in our studies, the physicians that are acting as investigators and the data review committee that analyzes the cases. Marco, back to you.

Thank you, David. We are absolutely very pleased with these results and as David mentioned, we will continue to advance this study and share further details as they become available. So to summarize all the key findings from this second interim analysis. First, the results from the second cohort were very consistent with the first interim analysis, which is always a good sign and shows how robust the study is. Two, we have again confirmed the strong clinical antifungal activity of oral Ibrexafungerp in patients with difficult-to-treat, severe mucocutaneous and invasive fungal infection. Three, we have also confirmed the same clinical antifungal activity of Ibrexafungerp against strain refractory to both azoles and echinocandins, which as I stressed before, is becoming a major crisis for physicians and patients. Four, Ibrexafungerp was generally safe and well tolerated. Five, these results enforce the potential of oral Ibrexafungerp to be a much-needed alternative to existing fungal therapies. Six, being available as an oral treatment, Ibrexafungerp may provide an effective oral alternative to long-term intravenous treatment, as illustrated in the first patient case presented by David. And lastly, but very importantly, these results further support a potential future submission under the limited population pathway for antibacterial and antifungal drugs, the so-called LPAD regulatory pathway. So before we open the call to questions, let me remind you of the key near-term milestones related to our ongoing Ibrexafungerp programs. Following our recent equity financing, we are starting 2020, a year of reaching milestones, in a strong financial position. We are developing Ibrexafungerp for the treatment of acute VVC. We recently reported positive results in the first pivotal trial, the VANISH 303 study; and we expect top line data from our second pivotal trial, VANISH 306, early next quarter. With a positive outcome in the VANISH 306 studies, we expect to file an NDA with the FDA in the second half of this year and potentially be approved mid-2021. In the Phase III CANDLE study for the prevention of recurrent VVC, enrollment is also progressing. And pending a positive outcome in the second half of 2021, we anticipate filing a supplemental NDA with the FDA shortly thereafter. Finally, work continues on preclinical studies for the liposomal-based IV formulation of Ibrexafungerp. With that, let us open the call up. Operator, please go ahead.

[Operator Instructions] Our first question comes from Oren Livnat with H.C. Wainwright.

Congrats on the steady efficacy you're seeing there with Ibrex. Can you just give us a little color on what you see as potential LPAD pathway to market at this point? Obviously, we don't have a lot to go on. I believe you participated in that workshop last year. So I'm wondering what you took away from that experience, and what that allow you to bring -- I guess, to put in front of the FDA in, hopefully, a relatively near-term meeting. And I have a follow-up.

So as -- just as a reminder for everyone on the phone call, LPAD is this new regulatory pathway that was introduced at the end of 2016 as part of the 21st Century Cures Act, and allows FDA to approve a antibacterial or antifungal drug based on a limited amount of data for a limited targeted population. So clearly, FDA actually did a workshop last year, and the outcome is really that it's a case-by-case. FDA will look at the actual data, and they can be a mix of in vitro; in vivo; and of course, clinical data, if appropriate, in order to give one of these -- one of these approval. Recently, 2 companies received approval. One was Insmed for Arikayce and the other was the TB Alliance the -- that were able to get approved based on LPAD. So the -- what we are doing here is to continue to develop substantial evidence that will be a combination of in vitro, in vivo and clinical data that we believe will support the use in a limited population of patient with multidrug-resistant or refractory type of infections. And our plan, as David mentioned, is to share this data with FDA and discuss potential next steps. At this point, this is what we can share, where we stand with regards to this.

Okay. And just on -- updates on this front, on the FURI front. So it's been about a year, I guess, since your last update. Do you think, based on where patients are in treatment now, that we'll get more data, I guess, sooner than another year from now? And maybe start to see a bigger picture of a -- a bigger set of total data to bring to the FDA sooner?

Well, that is a good question, Oren. Let me just say that -- the point I want to stress, we don't give usually update with regards to enrollment, as you know. However, I would like to point your attention that last year -- the end of last year, we had to amend on the ClinicalTrials.gov, the number of maximum patients enrolled in the study, which was 60. And I just to leave to that, that enrollment is actually progressing very nicely. And the reason is because there is clearly a great interest in the medical community in testing our drug in patients that do not respond to other treatments.

And our next question comes from Alan Carr with Needham & Co.

Can you give us a little more on your plans here in terms of how this might work commercially in a hospital setting versus -- VVC, difference in dosing? And then also with respect to duration of treatment. In this particular trial or under this protocol, it only goes out to 90 days. But how many are going past that? And what would you expect to happen commercially? I think you have up to 6 months now in this expanded access. How many are going out past 90 days?

So let me start to address, first of all, the question about -- about the VVC and hospital setting in terms of dosing. Just as a reminder, VVC is a 600-milligram dose that -- 1-day treatment. The dose for hospital is 750 milligrams, which is a 25% higher dose. And so we don't -- we believe that actually, after testing the market, we believe that the pricing for VVC and the hospital setting will be quite compatible. Of course, these are very 2 different type of patients population. VVC, as I mentioned, is a 1-day treatment. But as this is a repeated dosing, sometimes even chronic, in some patients, you may need to treat for a much longer duration. The reason we amended the protocol is because we had enough toxicology to treat patients up to 90 days, and 90 days certainly covers the vast majority of patients with fungal infections. With Candida, usually the treatment is 4 to 6 weeks; and for aspergillosis, probably it can be 2 or 3 months. But now that actually, we are allowing also treatment for chronic fungal infections. We need to expand it, the duration of the treatment. And we completed recently -- actually reported last year, we completed a long-term chronic toxicity studies. And therefore, we were able to expand the duration of treatment for 90 days to 6 months that certainly provide adequate coverage for this type of chronic infections that we are now treating. Any other question? Any other...

Yes, I'm wondering how many of these 41 patients have been treated for longer than 90 days. And is it your sense -- your average, you said for this set, is 37 days, but I'm wondering if it might skew even higher than that once you go beyond 90 days to 6 months. I have a follow-up -- yes.

No, you're right, Alan. We have several subjects in this particular subset that reached the 90-day maximum treatment duration under the protocol, and they were allowed to continue therapy under our expanded access program. Since the protocol was itself just allowing 90 days, the way that we managed this in order to allow them to continue receiving the therapy that they needed is that we moved them to another program, which is expanded access. And we have several of those. I don't have the precise number in front of me at this point. But I think that is probably, I don't know, in the -- 7 to 8 patients, something like that, I'm guessing right now. But in these particular cases, the treatment duration is not accounted when I'm giving you the mean for this analysis of 37 because they are officially or formally treated outside of the FURI protocol. And that was because the previous version of the protocol only allow us to get up to 90 days. Now we will have the opportunity to keep accounting and keep following these patients for longer treatment durations when needed. What cases typically require, even with Candida infections, long treatment durations, which is probably also important to stress. So for instance, bone infections. The bone infections require typically from 6 to 12 months of treatment. And we actually have -- I think that we reported last year, a couple of cases with bone infections that can receive up to 1 year of therapy, which is typically what these patients may require. Patients with the chronic immunocompromise that may respond well to the Ibrexafungerp therapy, then the physicians want to continue providing what is called secondary prophylaxis, which means they want to continue providing suppressive antifungal therapy in order to prevent those infections that are known to be recurring very easily in these patients to prevent them from recurring. So we do have some cases that are, let's call it, in secondary prophylaxis because otherwise, with other therapies, they will -- the came -- the infection came back very rapidly. And right now, as Marco mentioned, in chronic aspergillosis is a condition that requires long-term therapy, typically between 4 and 6 months. So we are going to start seeing even patients, with this amended protocol, patients that are requiring longer and longer therapies in that sense.

And if I can ask one more. You enrolled both intolerant and refractory patients. Can you give us the breakdown between those 2 for -- percentage for each? And then which drugs were used in that refractory group? Were they -- were patients continued on those drugs? Was Ibrexafungerp added on to it? Can you tell us a bit more about that, what the pattern is?

Sure. We will be providing a breakdown in some of the scientific meetings regarding the specific numbers, but I can tell you that the great majority were either refractory cases. Not -- intolerant, we don't have that many in this particular 41 subset. And intolerance was mostly related to the azoles due to hepatic or...

Insufficient.

Insufficient. Not necessarily insufficient, but hepatic toxicities; or to the amphotericin B due to renal toxicity. Those were the most common cases of intolerance that really lead the patients to be enrolled in the study. We have 1 or 2 patients that also have significant drug-drug interactions while on an azole. And the great majority of -- the majority of refractory, certainly. And the drugs that the patients are refractory to most commonly are the azoles and also the echinocandins. As you can see, one -- in the second case that I presented today, this patient had been receiving IV micafungin for several courses and it was just having 1 case of oropharyngeal candidiasis after the other, after the other, after the other. So we have both azoles and echinocandins. Refractory to polyenes is not commonly seen. Polyenes, typically what they lead to is to toxicity, not to refractories, no. I think that, that answers the first part of the question. And then you have some other questions...

Yes, it was an add-on.

Yes. That's a good point. In this -- in the initial portion of this -- the version of the study that was ongoing up to this point did not allow for combination therapy. So in all cases, Ibrexafungerp was given as a single agent for treatment. However, now in the new version of the protocol, the protocol amendment, we are allowing for combination therapy in very -- in some special circumstances. Special circumstances such as invasive aspergillosis in which the mortality is extraordinarily high, and combination therapy, typically an azole or a polyene, plus a glucan synthase inhibitors, has somehow indicated a potential benefit. So in those particular cases, we are allowing a combination therapy in the new version of the protocol. However, all the cases reported to date, Ibrexafungerp was given as a monotherapy.

Our next question comes from Steve Brozak with WBB.

Congrats. Since most of the questions have been asked and answered, I would just actually like to follow-up on the last train of thought or the last series of questions. What would the alternative be if Ibrexa wasn't available to these patients? And how deleterious are they in terms of side effects? And how efficacious are they? And one follow-up after that, please.

Well, that's a -- Steve, that's a very good question. And the issue really is that there are really not too many alternatives when a patient becomes refractory, let's say, to azoles and sometimes to azole and echinocandins. Basically, amphotericin B remains. Probably someone may add other antifungals, but they're not commonly in this type of situation, like terbinafine or FEU. The bottom line is that, unfortunately, what happens in this type of patient is that -- just the doctors tend to -- what is the expression? Throwing the sink to the patients and really giving combination and adding multiple antifungals, hoping that something will stick and something will work out. So there are really no alternatives. And this is why, let me just stress this important point, it's so important, so important, that we continue to develop. And when I say we, I mean as a society, we continue to develop novel antifungals and there are just not enough alternatives to current antifungal therapies. Luckily enough, we -- there are a couple of companies, and SCYNEXIS certainly is one of the most advanced in developing novel antifungals, but it's just simply that are not enough alternatives, neither available, nor actually in development. It is -- and this is what the high hope of that some of the recent events, especially with strains like Candida auris, will actually give a new strength to the effort to provide support to the development of new antifungals. This is a big crisis that is coming, and we can foresee coming.

And the last question. In previous presentations, and both at conferences and in -- on the phone, you've talked about some patients, anecdotally, that were refractory, that were debilitated for literally years. Have you followed up with them just to see what the quality of life, status of life is with these patients? And what can you tell us in terms of have there been any relapses? Are there any situations that you can talk? And I know the numbers are small, so this would be entirely anecdotal. But what can you tell us about any of these patients that you've seen? Have you kept contact with either them or their clinicians? And then I'll hop back in the queue.

Sure. Thank you. Thank you, Steve. So certainly, within the protocol itself, we do follow the patients for 6 weeks after the end of therapy. The follow-up or formal follow-up beyond that point is limited and is limited because certainly we don't have the rights to do so. But however, certainly, anecdotally, from the treating physician, we -- sometimes, we do receive the information back from them saying that, "Hey, this patient really continues having a -- you made a very substantial change in their life, of these particular patients, because they have been able to really do things or progressing their life in the way that they were not." Obviously, each case is quite different. And you can see here that many of them are with underlying conditions that are difficult to really understand. The final impact -- many of them, obviously, have died over the years because of the underlying condition. However, it's -- we have been very pleased to receive comments from the physicians letting us know, or specific cases that really tell that Ibrexafungerp made a significant change in their life after they received this treatment after having failed multiple therapies. So that's extraordinary rewarding to us, as you can imagine. And this is very, very stimulating to us in that way. Formally, it will be very difficult for us to really provide an analysis of that because, as I mentioned, within the protocol, we are only legally allowed then to follow for the duration of what the protocol extent is, which is 6 weeks after the end of therapy. However, for the patients that we have in the expanded access program, that's less formal. However, we do get letters from the investigators or from the physicians that provide Ibrexafungerp to these patients under what we call -- previously was called compassionate use basis. And that is what we do have a sense of really the substantial impact that Ibrexafungerp is having in the life of these particular patients that otherwise were left with little or no options.

And our next question comes from Jason McCarthy with Maxim Group.

This is Mike Okunewitch on the line for Jason. Congrats on the data, it looks very positive, and the need for new antifungals can't be overstated. Let's see, considering that the Phase III is addressing a number of diseases, would we be expecting an approval for Candida alone, Aspergillus alone? Or would a novel antifungal with broad activity be approved for physicians to use on essentially any fungus that's sensitive to Ibrexa?

Well actually, if we look at the precedents, especially in the field of antifungals, what I'm -- what happens -- and there are 2 classic examples, caspofungin, the first approval of caspofungin for salvage setting in aspergillosis; and the approval of Isavuconazole for mucormycosis. FDA will really try to carve out a specific, well-defined population in which there is -- there are enough data to support an approval. So you should expect that usually, a LPAD approval will be very, very narrowly defined based on the available data. So the way it works is that we are collecting all this data in our programs, in our -- both in CARES and FURI. And this data with the data that we will present to the agency and discuss what are the patient population in which will be easier for and reasonable for FDA to define a labeling that will approve -- would be consistent with an LPAD approval. So this is the way it works. Again, it's a long work of negotiation with FDA, looking at the data, looking at also what additional data should be provided. And the labeling tend to be actually very narrow and well-defined, very narrowly defined.

All right. And then just one more. So you guys recently mentioned that you're heading in the Aspergillus infections. And as you know, molds are extremely difficult to treat even versus invasive Candida infections, which are tough on their own. So as you added more diseases and even more treatment regimens, as you mentioned before, possibly adding combinations in certain settings, should we expect to see the data more broken out by disease type, by treatment regimen, in future releases?

Yes, I think that, that totally makes sense. So the reality is that the outcomes in these particular conditions could be different. As you mentioned here in regards to -- let's say, once we have enough numbers of esophageal candidiasis or invasive aspergillosis, the outcome is entirely different or the expected outcome could be entirely different. So I think that it will make total sense, once we do have these different conditions, to really provide the data with a little bit more granular description of the outcome per the -- according to each one of these conditions, which could be, as you mentioned, entirely different one versus the other. That is the intention, for sure.

And our next question comes from [ Catherine Joo ] with [ Chang Capital ].

If you don't mind, can you just repeat the definitions of CR, PR and stable response? And also, what happened to the nonresponders?

Sure. So the definitions, a complete response is considered complete resolution of sign and symptoms, plus negative cultures in any place where the cultures were positive. Partial response is a significant resolution of the sign and symptoms and negative cultures from any of -- any place that the cultures were positive at baseline. A stable response could have positive or negative cultures, but it could mean that it's certainly not progression of the disease or it could mean a mild improvement of the condition. And progression of disease is clear evidence of progression of the underlying -- sorry, of the baseline fungal disease and persistent positive cultures. In this case, I think that it's important to mention that the most common reason why patients achieve partial response rather than complete response, in the most cases, is because of radiological findings. When a patient has a intraabdominal infections with multiple CT scan abnormalities, even at the end of therapy, the CT scan do not become entirely normal. That is the same case very commonly with fungal infections in the lung, CT scans do not become normal until months after end of therapy. So these cases in -- per definition, cannot be considered a complete response because there are still signs present of the initial infection. However, per the physician, the patient no longer requires antifungal therapy. And so they stop the therapy and they just continue following the patients. However, the DRC makes the adjudication of the case at the end of therapy. So many of these cases are, for that reason, considered partial response in those instances. And however, the clinical benefit means that the physician was able to really complete the therapy per -- according to what was their plan, and there was no evidence of really continued progression of the disease. Let's remember that these particular fungal diseases, if they left untreated or treated with an uneffective therapy, they are expected to progress. So none of them or none of these severe mucocutaneous or invasive fungal infections resolve by themself, they are expected to progress. So progression is the expected outcome with noneffective therapy. And for that reason, a stable disease, in many instances, is also considering the majority of the cases, is also considered a clinical benefit for these particular conditions. They are able to continue progressing with their other therapies, the other chemotherapies, et cetera, without really the progression of the disease. The patients who progressed or the patients who actually -- the cases who have -- who were not responding and were considered that the infection, disease was still progressing, the majority of them were put back into a combination antifungal therapy. So -- or they were put into another antifungal therapies, in most instances, were combination therapy. So we have, as I mentioned, 6 cases that were considered by the physicians not to be responding properly to the treatment with Ibrexa. And there is a variety of cases here. None of them died of a fungal infection itself, but they were just put back into a combination therapy. The physicians considered that another antifungal approach was needed, and the great majority was combination. I hope that is -- I hope that answered...

Yes. Another question. So with regard to the patients, the 41 patients, and then there's refractory and intolerant patients to standard of care, and also there's third category that you mentioned, pretty much they were taking Ibrexa as the step-down therapy. So I'm just wondering how many of those -- will those be pretty much considered a front-line therapy?

So the -- how many -- we will provide the breakdown in some of our upcoming meetings. I don't have the specific numbers here in front of me. However, the majority, as I mentioned before, are in the refractory category, the majority of the patients that we have enrolled. And certainly, the ones that are stepped down, so the agency, would they consider it first-line therapy? Yes, you could consider that here, the biggest -- here, the kind of the key message is -- or for us, is really to give the opportunity. These patients are considered to have a disease that otherwise could be considered refractory to azoles. That's why azoles are not an appropriate therapy for them. So they are considered to have either an infection that is resistant to azoles or has, in the past, not responded well to azoles. That is why a stepping-down from an IV echinocandin to an oral azole is not feasible for them. So in that sense, you could also consider these patients to have a resistant infection or an infection that is refractory to at least 1 group of antifungal agents, which are the azoles. And we are allowing them to step down to oral Ibrexafungerp because, as I mentioned, these patients typically require several weeks of therapy. How the agency will consider this particular subgroup, is this first-line or this is salvage therapy? It's something that probably we need to discuss with them, because you're right, these are patients that are in essence not necessarily failing a therapy that they are, which is an IV echinocandin. However, they clearly are resistant or refractory to another group of agents which is the only ones that are orally available, which is the azoles. So it could -- if this is considered a first-line versus a salvage therapy? It's something that we need to discuss with them, how the definition would be.

But I think, Catherine, you are really identifying one of the key points or one of the key areas where we believe Ibrexafungerp will make a significant difference, which is really the step down in patients with an infection, azole-resistant. And with the resistance to azole growing significantly, that can be a significant opportunity for us as a company. Thank you.

And our next question comes from Larry Lytton with Second Line Capital.

Your last answer kind of anticipated one of my questions. And I'm just thinking from a commercial opportunity, to the extent that this is at this point an oral-only therapy, how limiting is that to the market opportunity in that so many of these patients maybe cannot tolerate an oral therapy?

Thank you. Actually, thank you, Larry, for the question. First of all, let me say -- that to say that we are limited to oral therapy, I think, is maybe not looking really at the opportunity here. Actually, the strength of our product is that it's orally available and actually can constitute a really an alternative to the azoles where resistance is becoming a major problem. We have been -- actually, I think we had cases of patients that had the problem swallowing due to mucocutaneous infections of the esophagus. And still, we were able to, eventually, to be able to administer the drug. But of course, we believe that the oral -- we believe that the oral treatment is really the strength of our drug with both step-down. And most importantly, many of the patients that came in, in the FURI study were patients that are -- were refractory or not responding to intravenous treatment with echinocandins. And we have been able, actually, to work very effectively just with an oral drug. I think that sometimes, IV treatment is more of -- giving a security blanket effect to the doctors and a good, well -- bioavailable drug like ours can really do its job extremely well as an oral treatment only. But as I mentioned in my comments, we are still working also on the liposomal IV formulation and we continue to work and provide updates in the future.

And let me just add, Marco, that considering the duration of the treatment for the fungal infections that we're talking about here, really, the -- if there is availability for both IV and oral, the largest portion of the treatment is meant to be or is intended to be oral. Because these patients, certainly, many of them started therapy with an intravenous formulation, as Marco mentioned, because of the perceived notion that they may have a faster effect. However, the intention is to really step them down to an oral therapy that allows much more flexibility to be treated in the hospital, outside the hospital. And we're talking about, here weeks. We're not talking about 7-day treatments here. So we're talking about several weeks of treatment. So really, the significant unmet needs or the biggest unmet needs and in my opinion, the biggest commercial opportunity in terms of days of therapy is with the oral portion of a drug. And that's...

And one other question. So in terms of David's other comment about the partial response or the stable response is still showing some signs. Is that to suggest that if the CAT scan were taken later on, you would expect those partial responses to turn into complete responses?

Yes. In many instances, yes. So -- and that is per -- let's remember that these are just standard definitions that are defined by MSE or TC in order to standardize clinical trials, are not definitions for use by physicians that are really treating these patients. So the definitions to treated these patients here, were you able to treat up to the point that you consider that infection is controlled or is subsiding? The answer is yes. However, the standard definition that you use in order to be able to analyze consistently fungal infections across many different studies, we follow definitions that are published by MSE or TC. And those definitions are particularly in regards to -- if you still have evidence in a CT scan or any other signs present is considered partial response. Partial response is still considered a successful outcome in these patients, no doubt about it. So from that point of view, yes, it's possible that if you were to follow these patients, continue following their CT scanning response, can you really see full resolution? The answer, most likely, is yes. And that is the case, for instance, for bone infections. For the bone infections, we presented 2 cases last year that in their initial assessment by the DRC, they were considered to have a stable disease because the CT scans at the 3-month follow-up were stable. However, these cases were rolled into an expanded access program. We had MRIs for them for up to 1 year. And at 1 year, they were considered fully resolved. So that's the situation depending on these fungal infections, particularly because they take long to resolve, those lesions typically may take long to resolve.

Okay. And lastly, biologically and mechanistically for people who are stable or maybe partial responses, is there any reason to increase the dosage to maybe get a full response?

Unlikely. It's certainly -- we are do -- measuring blood levels in these patients. However, the protocol itself right now does not contemplate modifying the doses. We have defined what is our target exposure based on PK/PD parameters, and we just want to make sure that the patients are really reaching the target exposure. Once they reach that, we are not considering increasing the doses. I think that it's most likely -- the situation is that most likely allow the time for the fungal infections to resolve fully in terms of anatomically resolution of that. That is -- I would say that it's unlikely that really modifying the dose will have a very substantial change. And let's remember that we're talking about here as a salvage therapy. And I don't know if you're familiar, but amphotericin B did a study of salvage therapy. Intravenous caspofungin did a study of salvage therapy. You do not expect 100% response in these cases. That's not realistic to spec. Those are cases that have very severe immunocompromised status. Many of them, they have had formal infections for years, many of them. So really expecting 100% response is unlikely. Really achieving more than 80% of patients that are either complete, partial or stable is extraordinarily good, in our opinion, and it's really totally in line to what other intravenous therapies have really been showed in the past as well. And for that reason -- and particularly, for instance, the most common numbers that you see of people achieving partial or complete response in salvage therapy programs for fungal infections in the 50% range, which we are better or above that number. So we feel that this particular data for oral Ibrexafungerp is extraordinarily positive and is really a reflection of the good activity and good penetration into relevant tissues.

And our next question is a follow-up from Oren Livnat with H.C. Wainwright.

I just want to get ahead of ourselves again on the potential commercial questions. Assuming you do get to market in some form of LPAD and it gets used either on-label or a broader off-label use, how do you think reimbursement would work in this setting given the paradigm of treatment of these underlying conditions? Do you think or do you know that this can be approved separately or as an add-on payment? Or is it potentially, an issue of bundling? I mean, there's obviously a pharmacoeconomic value of getting people out of the hospital, to do an oral step-down, which is probably quite compelling. So I'm curious what your research tells you on that front.

Well, actually, for -- with regards to antifungals, the situation has not been as difficult as it has been for antibacterials, and for 2 reasons. The first one is that, different from antibacterials, there are really not too many options for fungal -- for antifungals. The second reason is that the severity of the conditions, therefore -- usually, there are underlying conditions, like for example, patients with bone marrow transplant, the patient may have already costed to the system hundreds of thousands of dollars. And certainly, you don't want to lose a patient just because some problems in prescribing in antifungals. And the third point is that our drug will be the first representative of the novel class. So that will certainly help us and making easier to get on the formulary of hospitals and getting fully reimbursed. We don't expect actually this to be a problem, neither here nor in Europe with regards to hospital infection. Actually interestingly, in Europe, where price of a drug is based on value, cost of antifungals, systemic antifungals has been even higher than in the U.S. So it's an interesting situation where one of a few cases where in Europe where the price has been higher. Again, so we don't expect this to be an issue at all for Ibrexafungerp.

Thank you. And I'd like to turn the call back to Marco Taglietti for any closing remarks.

Thank you, operator. And thank you all again for joining us here this morning. At SCYNEXIS, we have remained committed to innovation in the antifungal space and addressing the many of unmet medical needs across a broad range of diseases. We are very, very encouraged by our achievements across our entire Ibrexafungerp development programs, and we look forward to sharing additional updates with you as we continue to advance this program and maximize the Ibrexafungerp platform. Thank you to the entire team at SCYNEXIS for their ongoing dedication and also to all of you for taking the time to listen this morning. So let me take also the opportunity to wish all of you a wonderful new year and a great new decade. [Foreign Language]. And thank you for listening to us.

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