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

Good morning, and welcome to the SCYNEXIS Hospital Update Call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the SCYNEXIS website following the conclusion of the event. I would now like to turn the call over to Debbie Etchison of SCYNEXIS. You may begin.

Hello, everyone, and welcome to today's conference call to discuss our hospital pipeline. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations, including statements concerning our financial outlook for the future, leadership's expectations for our clinical results, future financial and operational performance as well as our business strategy. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Please refer to our filings with the Securities and Exchange Commission, including our most recent annual report on Form 10-K and quarterly report on Form 10-Q, included in each case under the caption, Risk Factors, and in other documents subsequently filed with or furnished to the Securities and Exchange Commission. All forward-looking statements speak only as of today, December 6, 2021. SCYNEXIS takes no obligation to update such statements to reflect events that occur or circumstances that exist after the day on which they were made. This presentation will discuss development programs with potential indications for ibrexafungerp that are not approved in BREXAFEMME labeling. The information presented here should not be interpreted as promotional to use with BREXAFEMME for unapproved indications. Joining us on today's call are: SCYNEXIS President and CEO, Dr. Marco Taglietti; Chief Medical Officer, Dr. David Angulo; and Dr. Martin Hoenigl from the Division of Infectious Diseases of the University of California, San Diego. Following our prepared remarks, we'll open the call to your questions. Now I will turn the call over to Dr. Marco Taglietti, President and CEO.

Thank you, Debbie, and good morning, everyone. [Foreign Language] Thank you for joining us today for hospital pipeline update call. While our commercial team is hard at work launching BREXAFEMME for vulvovaginal candidiasis, our research organization continues to press forward to expand the ibrexafungerp label. This call will provide some additional visibility to our plans for the hospital setting. First, you will hear from Dr. Hoenigl on the burden associated with invasive fungal infections, how these infections are treated in hospital patients and remaining unmet needs in the hospital treatment landscape. After Dr. Hoenigl, I will provide an overview of our strategic plan for penetrating the hospital market, which we have been working towards for quite some time, as well as anticipated time lines and opportunities in that segment. Next, Dr. Angulo, our Chief Medical Officer, will walk you through our upcoming hospital study, which aims to expand the ibrexafungerp label as an oral step-down regimen for the treatment of invasive candidiasis in the hospital settings as we announced this morning. David will also give you an update about our liposomal intravenous formulation as well as our continued progress in the FURI and CARES program, where ibrexafungerp is being evaluated in the salvage setting. After Dr. Angulo's presentation, we will open up the call to your questions. And now it gives me great pleasure to introduce you to the renowned Dr. Martin Hoenigl, Associate Professor of Infectious Diseases and Global Public Health at the University of California, San Diego, and the Section of the Infectious Diseases and Tropical Medicine at the Medical University of Graz in Graz, Austria. His contribution to mycology, the field of fungal infection, cannot be overstated. He is the President of ECMM, the European Confederation of Medical Mycology. He is a Founder of the European Mycology Clinical Trials Group. And he has published more than 250 articles in the field. It's an honor for us to have Dr. Hoenigl here with us today. Martin, please go ahead.

Thank you so much, Marco, for the nice introduction. And on this slide, you can also see my conflict of interest. So I will talk today starting off giving a background on fungal infection and then really jump into our main topic today, which is invasive candidiasis, moving on just towards the end on a few slides on aspergillosis and then mucormycosis. So of course, these times are dominated by a viral pandemic, by COVID. But what became obvious pretty soon into the pandemic, even last year, was that this pandemic is complicated by fungal infections. So we have increased reports of, first, Candida auris outbreaks in ICUs, in COVID ICUs, that really add mortality and morbidity in these patients. And then we, of course, also have big outbreaks of Candida auris in the United States, where this pathogen is becoming more and more prevalent. And then it's not only Candida, but we also have aspergillosis. We have COVID-associated pulmonary aspergillosis that's increasingly in the media and complicating ICU patients with COVID-19. And last but not least, more recently, we have these huge reports of the outbreak of the black fungus, mucormycosis, particularly in India, where more than 50,000 cases have occurred to date and the numbers are climbing each day. Starting off with the epidemiology of fungal infections. So we have been dealing, and this before COVID, with about 50 million cases of pulmonary and invasive fungal infections, if you believe the 2017 numbers. And if you look on the graph on the right side, the one thing that becomes obvious here is that with advances in medicine, with medicine becoming modern and with more breakthroughs in medicine, we see more fungal infections. We started off with development of intensive care units, organ transplantation, the HIV pandemic, but this continues now with introduction, for example, of the small molecule therapy for hematological malignancies. While the prevalence of IC continues to increase generally, we also have some methods to decrease the prevalence again, and this is antifungal prophylaxis, which we really give to the most at-risk patient groups that we're dealing with. At the same time, new patient groups come every day that also are at risk for developing invasive fungal infections. Key for these things are that we need to diagnose early and treat early in order to give the patients a reasonable chance to survive their fungal infections as mortality can range between 20% and 80%. In contrast to the increasing number of fungal infections, we still have a very limited number of antifungal treatments, and currently only three classes available at least until a few months ago. Only one class of these three had an oral formulation. And if you look under the antifungal pipeline since early 2000, there was really not a lot happening with only one new agent, isavuconazole, approved in 2015 but an old class, from the class of azoles. And more recently, there's more exciting development with one new class, when it is finally approved in 2021, with BREXAFEMME in ibrexafungerp tablet for vulvovaginal candidiasis. I'll start off with invasive candidiasis, the main topic of my talk. So there is a lot of unmet need, I mean, in dealing with invasive candidiasis. So we're dealing in the United States with about 100,000 invasive candidiasis cases annually, probably more, with a high mortality of 30% to 40%. IV echinocandins are the first-line treatment. And the total treatment duration is typically at least 2 to 3 weeks but can be much longer in more complicated cases that we are seeing in our hospitals. What's important is that we want to switch from IV to oral as early as possible in order also to allow patients to go home and complete the therapy cycle at home. But only the azoles and mostly fluconazole are available for oral step-down, and they don't have the same quality and the same evidence for efficacy as the IV echinocandins. A significant number of invasive candidiasis isn't in treated empirically with no culture being able to confirm fluconazole's stability and mycological response, which further complicates our approach that we need to step down to a less effective agent. And the cumulative cost of candidemia are reported to be about USD 40,000 per patient. Here are the recommendations for treating invasive Candida infections. And these are the estimate guidelines that clearly show that all three echinocandins, anidulafungin, caspofungin, micafungin, are strongly recommended with a high quality of evidence. While here, fluconazole is only marginally recommended for initial treatment of Candida infection. The Americans and the IDSA guidelines are pretty much in line with their recommendations, also recommending echinocandins as first-line treatment for neutropenic patients and non-neutropenic patients with invasive Candida infections with fluconazole or liposomal amphotericin B being the alternatives. What everybody agrees on, the Americans and Europeans, are the duration of treatment of candidemia should be at least 14 days after the first negative blood culture. What's further complicating treatment is, of course, that there's a growing problem of fluconazole resistance. And here, in this graph, I just show you the proportion of non-albicans Candida species, which is really increasing worldwide. Now over 40% of invasive candidiasis are caused by non-albicans Candida species. And in these species specifically, there's an increased concern for fluconazole resistance. Not all of them are fluconazole-resistant, but the most prevalent ones, Candida glabrata, are very often fluconazole-resistant. In terms of treatment, Candida species definitely matter. The good news here is that it don't matter so much for the preferred initial therapy because echinocandins, as you can see here, remained a choice for treatment, for first-line treatment, for all of the Candida species. But once we move on to alternative initial therapy or preferred step-down therapy, things become more complicated, specifically for glabrata, krusei and auris, non-albicans species that -- where we really don't have an alternative option for a step-down oral options available. I will quickly show you very recent results that we just presented this year at some of the major conferences, from the ECMM Candida Registry, from the CANDIDA III study, which really tries to paint a representative picture of candidemia in Europe, really allowing, depending on population size to countries and average maximum [indiscernible] cases, those number of cases per country are capped at a population size to paint a representative picture. About 500 cases of invasive Candida infections from 47 institution and 16 European countries were included in this study. And what becomes very clear is, first of all, the initial echinocandin treatment is now given the majority of cases, although there is some variation when you go into Eastern Europe, where it's not always available. But the overall mortality is still 37.3%, so very high overall mortality, very much to the range of 30% to 40%. Echinocandin treatment in this study was associated with a higher rate of complete response, 35% versus 27%, significantly higher. And this really gives emphasis also in real world that echinocandin should be first-line treatment for invasive candidiasis. But there was also a longer duration of hospitalization post diagnosis in those receiving echinocandins versus those receiving other drugs, 20 versus 14 days. And the reason for that was really that the step-down to fluconazole was only performed in about half of cases receiving echinocandins. Only half of them could be stepped down to an oral treatment to fluconazole. And the main reason why this was not possible in the other cases was resistance to fluconazole, which was frequently seen in many of the Candida species, including Candida krusei, Candida glabrata but also Candida parapsilosis, for example. And when investigators were asked, they really indicated that hospital stay was prolonged due to parenteral echinocandin therapy in 21% of patients. So 21% of patients stayed longer just to complete the parenteral echinocandin therapy for candidiasis. As said, I will finish up my presentation, giving a little bit of information also about invasive aspergillosis, where we currently are seeing about 46,000 cases in the U.S. every year. We are also dealing with a very high mortality rate, 25% to 60%. And it's really difficult to diagnose the infection and remains unrecognized for prolonged periods. Aspergillosis requires a long course for treatment, at least 6 to 12 weeks. And voriconazole is still the first-line treatment, although we have now two other azoles, posaconazole and isavuconazole, as alternatives. The problem with the class of azoles is that they are prone to drug-drug interactions. And there's also some significant toxicity often requiring therapeutic drug monitoring. And last but not least, azole resistance is growing worldwide. And there are some countries with over 10% azole-resistant already. Also important for aspergillosis is that in terms of mortality, really no changes were observed in the last 2 decades. So since voriconazole was introduced, none of the new agents like isavuconazole or posaconazole, did better in terms of mortality. Both of them maybe are a little bit better tolerated, a little fewer drug-drug interactions, but in terms of mortality, really no improvement. The only exception, potential exemption is this study that looked into combination therapy for invasive aspergillosis, combining an azole, voriconazole, with an echinocandin, here in this case, anidulafungin. And what they found here is that in the overall population, there was a trend toward reduced mortality rates, reducing mortality from 27.5% in the voriconazole monotherapy arm to 19.3%. However, this finding missed significant, just missed significant, although you can imagine that this 10% decrease or like 30% -- close to 30% decrease in mortality could be clinically meaningful. In subgroups, they found a significant result, particularly in those with greater evidence of invasive aspergillosis with galactomannan positivity plus radiologic signs of aspergillosis. The main limitations of this study was that the combination was given only for 2 weeks, followed by monotherapy for 4 weeks. So although this arm, this randomized arm combination therapy, the combination was already given for 2 weeks due to the fact that, of course, anidulafungin as the echinocandin was only available as parenteral formulation. So it really remains to be seen once we have similar oral antifungal available, better that the -- the difference between these two groups may be even larger. So I'm really excited to see these results. And last but not least, I also want to spend a little bit of time on mucormycosis. So for mucormycosis, we are seeing fewer cases in the United States, about 1,000 cases. But worldwide, it's a big problem with over 900,000 cases. And particularly in India, we see a lot of mucormycosis. The cost to patient is significant, over USD 112,000 in the United States. This is also because of long-term antifungal therapy, at least 12 to 24 weeks, but also because these infections require an extensive surgery, as you can imagine, when you see the pictures of this terrible infection on the right side. Mortality is 40% to 80%. But of course, even those who survive, for them, it's still a life-changing disease that changes their life forever through the extensive debridement and surgeries that are required to control these infections. Liposomal amphotericin B is a first-line treatment. But of course, we know that it can be nephrotoxic, so this is causing a problem. And isavuconazole and posaconazole are currently the alternatives, the only available oral alternatives. But we're definitely looking for future treatments that may also be better synergistically or allow for combination therapy to further improve outcome of these devastating infections. To summarize my talk, we really have a problem in the field of clinical mycology with big problems, particularly cost, but the limited antifungal armamentarium we're currently having up here. We have increasing rates of Candida resistance, particularly fluconazole resistance is increasing. But also echinocandin resistance is emerging and increasing. And yes, also, of course, pan-resistant Candida auris, which now can be transmitted from patient-to-patient, really caused big ICU outbreaks. We have complicated patients with multiple co-morbidities that really make antifungal treatment, specifically with azole that are really prone to drug-drug interactions with many other drugs really complicated in these patients. And we have limited antifungal treatment options, currently only three classes with only one class available in oral form, although this is changing in the near future. And more antifungals with oral options are really necessary to optimize patient care and are really needed to improve outcomes in clinical mycology. Thank you so much.

Thank you. Thank you, Martin, for this great review of the invasive fungal infections field. So let me start with just saying that our vision for developing ibrexafungerp into a valuable and consequential tool in the antifungal armamentarium for a broad range of infection in both the community and the hospital setting is becoming a reality. Ibrexafungerp represents a new class of antifungals, the first one in over 20 years. And ibrexafungerp has the potential of becoming a cornerstone of antifungal therapy. Last week, the magazine, Popular Science, for its Best of What's New awards included BREXAFEMME among the top 100 inventions of 2021, together with game-changing products such as the COVID vaccines. We are extremely proud of this recognition. BREXAFEMME in vulvovaginal candidiasis has the potential to achieve peak sales in the $400 million to $600 million range and helping millions of women. But as I mentioned in the past, VVC in the community setting is just the beginning of the journey of ibrexafungerp. In fact, today, we want to share with you our plans for treating hospital infection, where we believe we can benefit and save the lives of many patients and bolster the value of ibrexafungerp brand as well as to trigger further interest in potential international partners. Here is what makes us excited about the opportunity in the hospital setting. As Dr. Hoenigl just outlined for you, there are significant gaps in care for patients with invasive fungal infections. But doctors treating patients with invasive fungal infection in the hospital are waiting for a product like ibrexafungerp to address the shortcomings of currently available treatments. So let me walk you through this busy slide that summarizes the commercial opportunity for ibrexafungerp in invasive candidiasis. Based on prescription data, there are about 175,000 patients who start treatment every year with an echinocandin for suspected fungal infections. And by way, for the data-driven guys, you can find out all the references at the bottom of the slide. Out of this 175,000 patients, about 100,000 will be invasive candidiasis cases. Unfortunately, about 30%, about 1/3 of these patients, as we have heard from Dr. Hoenigl, will not make it. As you can see in the purple boxes on the left, about 35,000 patients, according to the 2019 CDC report, are azole-resistant. This is our core target population because these patients cannot take oral fluconazole, and there are no oral antifungal therapies for them. Ibrexafungerp will be the only alternative to azoles as an oral treatment for these patients. Out of these 35,000 patients, about 2/3 of them, 23,000, are treated today as inpatients with echinocandins. We believe that we can capture about 2/3 of these patients, so they can be discharged sooner from the hospital. For other 12,000 patients treated with echinocandins as outpatients, we believe we will capture most of them because the doctors want to discharge these patients on an oral product, not an intravenous one. But they have no alternative choices today. With ibrexafungerp, they will have a choice finally. There are also 30,000 patients that are discharged on fluconazole as highlighted in the middle dark boxes. 5% to 10% of them, let's say, about 2,000, will fail. It's just the way things go. And their only oral alternative option will be ibrexafungerp. But we also expect to capture some, at least 25%, of the patients receiving fluconazole because many doctors will be more comfortable continuing oral treatment with an oral glucan synthase inhibitor than shifting to nasal. You have seen in Dr. Hoenigl presentation, how have glucan synthase inhibitor strong evidence of activity against Candida in these type of patients. And finally, in the light blue box on the right, there are patients, based on our experience with FURI, who will have refractory infections, especially deep-seated infections, like bone infection or retroperitoneal abscesses, that do not respond well to currently available antifungals. In summary, we expect the hospital indication to achieve conservatively between $300 million to $400 million net sales at peak with the rest of the world representing an opportunity similar in size to the U.S. We have carefully considered our alternatives to identify the most rapid path with the highest chance of success to bring ibrexafungerp in the hospital setting. Based on our estimates and expected execution, we believe that we may be able to submit an NDA for the step-down indication in invasive candidiasis in 2024 with an FDA approval possible late in the year. In parallel with this NDA submission, we plan to submit a larger and more comprehensive data set from FURI and CARES trials via the LPAD pathway for regulatory approval in the salvage setting. The interim data from FURI and CARES, combined with a large data set from the VANISH trials are compelling. And we believe that they contributed to FDA agreeing on a step-down study design for our next trial. I cannot stress enough the innovation of the design of a step-down study that we agreed with FDA. The design of Study 302 is a first for hospital anti-infectives. And ibrexafungerp will be the first antifungal ever approved, specifically as a step-down after IV treatment with another product. By the way, we refer to the step-down study as our MARIO trial. That's a great name that is easy to remember. It stands for mycology assessment of a regimen of ibrexafungerp as oral step-down, the MARIO trials. We are still planning next steps for our IV formulation after the successful Phase I study. And we will have an update for that program in the future. There is another point where I want to stress in these slides. We are creating a stream of potential approvals that started this year with the approval of BREXAFEMME in June. And this stream of approvals will continue over the years. It is our pipeline in a product. This is the way you build a blockbuster anti-infective franchise, when you have 14 years of exclusivity as we do. The proposed development approach for a step-down IC indication following IV echinocandin is by far the fastest path to approval. And we believe it has a very high probability of technical success. The MARIO study we are implementing is a very innovative approach agreed with FDA. And it is the result of multiple collaborative interaction with the agency. And as I mentioned before, we believe ibrexafungerp is perfectly suited for this indication with its broad spectrum of activity, oral bioavailability and safety profile. Besides addressing significant medical needs, the market opportunity for this indication is considerable, as you have seen. And additionally it will clearly increase the attractiveness of ibrexafungerp to potentially partners, maximizing ibrexafungerp's global reach. Now I will hand it over to Dr. David Angulo, our Chief Medical Officer, to provide more details about the MARIO study and other plans for ibrexafungerp in the hospital setting. David?

Thank you, Marco. I will start by outlining our progress in our development program for ibrexafungerp. As illustrated in this slide, our development program for ibrexafungerp is designed to address several of the unmet needs mentioned by Dr. Hoenigl. In the area of invasive candidiasis, the most common of the fungal infections in the hospital setting, we have previously completed a Phase II study evaluating oral ibrexafungerp as a step-down from an IV echinocandin. We are currently conducting our CARES study focused on patients with infections caused by Candida auris, a multidrug-resistant pathogen. And as Marco mentioned, we are initiating our MARIO study, a Phase III study of oral ibrexafungerp as a step-down from an IV echinocandin in patients with invasive candidiasis. This study is designed to be the basis for an indication of oral ibrexafungerp for invasive candidiasis. And I will provide more details regarding the study design in subsequent slides. As many of you are familiar with, our ongoing FURI study enrolls patients with a variety of fungal infections that are refractory to other antifungal agents or patients who do not tolerate them. And finally, we are evaluating oral ibrexafungerp as combination therapy for invasive pulmonary aspergillosis in our Phase II study, SCYNERGIA. The development program of ibrexafungerp is designed to take advantage of key attributes of the drug, such as potent fungicidal activity against Candida species, including most species resistant to other antifungal agents; broad spectrum of activity, including aspergillus and other molds and yeasts; able to address the needs associated with multiple fungal infections; favorable safety profile and limited risk for drug interactions, optimal for administration in patients with multiple co-morbidities and concomitant medications as it is typical of patients with invasive fungal diseases; and the opportunity for oral administration, which is key to optimize patients' care, considering that the typical treatment duration for invasive candidiasis or invasive fungal diseases often last from weeks to months. Now let me elaborate more about why we are so excited to initiate our Phase III program for oral ibrexafungerp in invasive candidiasis. Ibrexafungerp has shown activity against all medically relevant Candida species because its mechanism of action as a glucan synthase inhibitor, there is no cross-resistance with the azoles. The azoles are currently the only option for all other step-down therapy in invasive candidiasis. And fluconazole is the most used azole for this indication. However, there is a significant number of patients harboring infections caused by Candida species with reduced susceptibility to fluconazole, particularly common in non-albicans Candida strains. In these cases, fluconazole does not provide the optimal option for safety and effectively stepping down from an IV echinocandin. The proportion of patients with non-albicans Candida species varies by country. But it is globally increasing with typical rates more than 40% of all the invasive candidiasis cases. Another point to consider is that because timely initiation of antifungal therapy is critical for survival in these cases, antifungal treatment is often initiated when the risk for invasive candidiasis is significant even without having a positive counter for Candida and that Candida may never be actually isolated. In these cases, it is not known if the Candida strain is susceptible or resistant to fluconazole, making the step-down to fluconazole a risky and suboptimal approach. As you can see, this problem is significant. And we believe that ibrexafungerp, with its activity against fluconazole-resistant strains, is perfectly suited to provide a much-needed alternative option. Ibrexafungerp also retains activity against the majority of echinocandin-resistant strains. And also echinocandin resistance is not yet a significant global problem. This activity provides an additional potential benefit for use in salvage treatment, when the response to echinocandins is not optimal or resistance is suspected. Finally, the volume of distribution of ibrexafungerp is very large, about 600 liters, which results in high tissue concentrations in the organs that are often involved in invasive candidiasis. This high volume of distribution is a distinctive feature of ibrexafungerp and maybe even be an advantage of echinocandins, which have a sixfold lower volume of distribution. Particularly in deep-seated Candida infections of certain organs such as liver, spleen, et cetera, high volume of distribution is important. As we heard from Dr. Hoenigl, the typical treatment flow for an invasive candidiasis patient is started with an IV echinocandin, followed by a step-down to an oral azole when appropriate or continuation of an IV echinocandin with the oral azole is not a good option. The treatment duration of each treatment phase varies, depending on the condition of the patient and the response to therapy. The IDSA guidelines indicate that transition from an IV echinocandin to oral fluconazole may occur within 5 to 7 days of initiation of treatment. The overall treatment duration varies, depending on the type of invasive candidiasis. When Candida is only identified the blood, referred as candidemia, the guidelines recommend treatment for 14 days after cultures become negative. If deep-seated infections is suspected, for example, in the liver, peritoneum, spleen or kidney, the treatment duration would likely be extended to several weeks or months and the resolution of the organ involvement is confirmed. And where do we see ibrexafungerp play in a role in this treatment algorithm? We believe ibrexafungerp could play a key role in the treatment of invasive candidiasis patients by providing a step-down option with the same overall mechanism of action as the echinocandins, glucan synthase inhibitors that have demonstrated to be a superior to azoles in treating invasive candidiasis. Ibrexafungerp will be a step-down option without compromising the strong efficacy of an echinocandin, a step-down option adequate for both, fluconazole-susceptible and -resistant strains, making the step-down medical decision easier. And it has the potential added benefit associated with its large volume of distribution, which permits us to penetrate two organs to treat deep-seated infections. By having an oral glucan synthase inhibitor option to step down, it is possible that physicians will be more comfortable in stepping down to an oral therapy even sooner than the current standard that goes around 5 to 7 days, when the conditions of the patient are adequate. Fluconazole will likely continue in use in settings in which resistance is not a concern. In the MARIO study, which design is outlined in this slide, study patients with invasive candidiasis will initiate their treatment with an IV echinocandin. All three echinocandins are allowed. They will be randomized while on the IV echinocandin to either oral ibrexafungerp or standard of care. The inclusion of the patients in the study will occur at any time prior to or during the IV echinocandin treatment, which gives this study a unique flexibility for enrollment. Typical invasive candidiasis study only allow 2 days of antifungal therapy prior to enrollment, which results in losing many potential patients for enrollment. Once the patients have met a standard criteria for stepping down to an oral antifungal, such as being clinically stable, able to tolerate oral medications, identify the Candida isolated, et cetera, they will be given their assigned oral study drug, either oral ibrexafungerp or oral fluconazole, in a double-blind fashion. If the patient has an infection caused by a fluconazole non-susceptible strain, they will not be given blinded study drug but will be given oral ibrexafungerp if they were initially randomized to ibrexafungerp or best available therapy such as continuation of IV echinocandin or other antifungal if they were originally randomized to a standard of care. The expected treatment duration of each phase is outlined in this slide. And the protocol allows transition from IV to oral as early as day 3. The total duration of treatment will depend on the type of invasive candidiasis. And as previously mentioned, for a candidemia case, it is typically 14 days after negative culture. The primary endpoint for this study will be all-cause mortality as assessed 30 days after initiation of antifungal therapy. The study is aiming to enroll approximately 220 patients and will be run in the United States, Europe and potentially other regions. The start-up activities are ongoing. We anticipate having top line data in mid-2024, rapidly followed by an NDA submission for a potential approval in late 2024. Summarizing, we believe this program will enable ibrexafungerp to become a much-needed option in the treatment of invasive candidiasis for physicians and patients, facilitating the step-down decision with a safe and effective drug that provides greater flexibility by ensuring adequate antifungal coverage. It will likely result in overall cost savings by allowing earlier hospital discharge and decreasing the need for IV infusions after discharge. Moving into our intravenous development programs. We have developed a liposomal formulation of ibrexafungerp for IV administration. And this new formulation was specifically designed to increase local tolerability at site of infusion, which was a dose-limiting finding in previous formulations. To ensure that the liposomal composition of this new formulation would not adversely affect the efficacy of the drug, we tested it in a mouse model of invasive candidiasis. The IV liposomal formulation showed efficacy in this model at the expected exposures, achieving more than 4 log reduction in kidney fungal burden at an exposure of 11 micrograms per milliliter per hour, and more than 5 logs reduction with higher exposures. Subsequently, we conducted a Phase I study to evaluate the safety and pharmacokinetics of the liposomal formulation. This study evaluated several single and multiple doses up to 7 days in 64 healthy volunteers. Intravenous ibrexafungerp was generally well tolerated with no serious adverse events reported. Most common adverse events were mostly mild, few moderate reactions at the site of infusion, and they were not dose-limiting. The dosing was successfully progressed until the target exposure was achieved, which is an AUC around 11.2 micrograms per mL per hour, which is the exposure that has been associated with efficacy in the animal models. This graph illustrates the exposure of day 1, day 2 and day 7 of a multi-dose regimen of 200 milligrams on day 1, followed by 150 milligrams on days 2 to 7. As you can see, all days have an exposure or AUC that is greater than the target for efficacy. We are very excited with these positive results that now allow us to plan the integration of our IV formulation into our subsequent development plans. As next steps, we will be discussing with regulatory agencies, the adequate bridging strategy to bring the IV formulation into our development programs. Now I will briefly update you in our other hospital development programs. The FURI and CARES study continue progressing well. As you may recall, we have conducted previous interim analysis of these studies with positive results. And we are anticipating having a new interim look at the data from these studies in Q1 of next year. The SCYNERGIA study, which is evaluating oral ibrexafungerp in combination with voriconazole for the treatment of invasive pulmonary aspergillosis, a condition with very high mortality, as previously discussed by Dr. Hoenigl, combination therapy has shown potential advantages in patients with this condition, while the enrollment in this study over the past year was affected by the COVID situation, and we will keep the study open to allow continued enrollment in 2022. We have anticipated top line data by the end of next year. As mentioned, the preliminary analysis of the data from the FURI and CARES study are very encouraging. Oral ibrexafungerp has shown to provide a benefit to the majority of the patients enrolled with more than 60% achieving complete response or partial response or complete or partial response in their fungal disease. The CARES study showed 8 out of 10 subjects achieving complete response, which is very encouraging, considering the multidrug-resistant nature of this infection and the limited treatment options. This slide provides an outline of the type of fungal infections we're observing in these studies, including candidemia, intraabdominal candidiasis, bone infections, severe esophageal and oropharyngeal candidiasis, among others. And the Candida species identified are as expected, those that are frequently resistant to other antifungals, including Candida glabrata, krusei and auris. With the positive data we have observed so far from these two studies, we have an ongoing discussion with the FDA regarding the data package needed to support a salvage treatment indication under the LPAD program. And certainly, the FURI and CARES data will also be supportive of the invasive candidiasis indication. Finally, let me share with you recent encouraging findings from an animal model that speaks about the broader spectrum of potential clinical utility of ibrexafungerp. Mucormycosis, as mentioned before, is a life-threatening condition with a high mortality rate, about 50% in the best care. Amphotericin B is typically the first-line treatment option for this condition. The findings from this in vivo study, that I will be briefly describing in the next slide, have allowed us to consider opening the enrollment of patients with mucormycosis into our FURI protocol. This was a mouse model of mucormycosis conducted by Dr. Ibrahim, a very well-known expert in the field and under the sponsorship of the NIH. The study evaluated ibrexafungerp as well as amphotericin B and posaconazole alone and in combination. Ibrexafungerp by itself showed activity. But even more encouraging was the improved efficacy in this model that was observed with a combination of ibrexafungerp and amphotericin B, as illustrated by the orange lines in the survival graph. The combination of amphotericin B with ibrexafungerp resulted in 65 survival -- 65% survival in contrast with 30% with amphotericin B alone. And the combination significantly increased the median survival to more than 21 days in contrast with 13 days with amphotericin B alone as displayed in the table. We continue evaluating the opportunity for ibrexafungerp to play a significant role in multiple fungal diseases and findings that these ones are extremely encouraging, illustrating the significant potential of this drug. With this, I will end my presentation to allow time for questions. Thank you.

Thank you very much, David. And Tara, if we can open the floor for questions?

[Operator Instructions] Our first question comes from Wayne Wu from Cantor Fitzgerald.

So first, once the MARIO data available, how should we interpret them? I mean, like what's the result of the current standard of care? And then on the second, the commercial -- on commercializing strategy, so as you show on Slide 29, what group of patients are you planning to focus on initially? Or are you going to go after other groups?

So let me start with actually your last question, talking about our focus. As I mentioned and as shown in my slide, there are three distinct groups for which doctors are waiting an oral glucan synthase inhibitors, like ibrexafungerp, are the 35,000 cases of azole-resistant; the 30,000 cases of patients discharged on oral fluconazole but that could actually move to an oral glucan synthase inhibitor, as shown by David in his presentation, this is certainly an area where doctors will be more comfortable moving to oral glucan synthase inhibitor; and then are the patients with refractory infections, the ones that we're treating currently in the FURI and CARES study. And we will approach all these together simply because they are a group of patients intertwined, all of them with great unmet medical needs. Your first question was about the epidemiology or the question about the epidemiology? Wayne, you may be on mute.

Yes, I was just asking about like how should we interpret the data once the MARIO data is available?

Well, how to interpret the data, you will see the results, what we expect actually will address all these type of patients. There will be two arms, one comparing to oral fluconazole, so this will address the group of patients that I mentioned, the 30,000 patients discharged on oral fluconazole. But of course, there will be an important arm, which is the one for azole-resistant cases, patients that right now don't have an alternative, an oral alternative. And that is what the MARIO study will also provide. So these data, together with the LPAD data, the data of FURI and CARES for refractory infection, really will provide an opportunity to address all these type of patients. And this actually will be in our labeling.

Our next question comes from Michael Higgins from Ladenburg.

Congrats on the start of this trial and the announcement of it. This goes back to the original thought of what ibrexafungerp would be used for, a step-down therapy, so coming out of hospitals. So great to see this. A couple of questions on the design and the powering specifically. What's the powering for the mortality endpoint for each arm? And then for the azole-resistant patients, what are those powering assumptions? And if it only hits, God forbid, an azole-resistant patient, could that be used for a filing? Appreciate it.

David?

Sure, happy to address. Thank you, Mike, for the question. So the primary population for analysis in this study is actually intent to treat population that includes both groups. It will include -- it will analyze together the mortality for both groups because it will include everyone who is randomized. So it will include those that are going into the double-blinded fashion but also the ones that go into fluconazole-resistant. The study is currently powered with 90% power to demonstrate a difference in the -- to demonstrate a non-inferiority for the primary endpoint, which is all-cause mortality by day 30. So it's 90% powered as typical for Phase III studies.

Just a bit more on that as a follow-up, what are the expected event rates for each arm or for all four, I suppose?

Sure. The estimated mortality at day 30, most of the previous studies that have been conducted is around 30%. So mortality by day 30 is expected to be around 30% as an overall rate. And as a non-inferiority study, it assumes similar mortality rate in both groups. That is the assumption for sample size calculations.

Understood. Okay. Any help you can provide this MARIO on the cost of the Phase III? We have the timing. And also, kind of paired to that is have you talked to the EMA? What are their thoughts in this design?

Thank you. Yes, happy to address. The second part, we are in the process of gathering scientific advice from EMA with the same protocol. And the first part of your question was regarding the timing, sorry, Mike?

Yes, we have the timing. That's very helpful. We don't normally get that, so thank you. But the potential cost for this MARIO trial?

It's a typical cost for a Phase III program like this in invasive candidiasis. But I'm not sure that we have disclosed the overall cost for this one.

And just to make -- just to stress this, Michael, the -- we are not changing our cash runway that is -- well, maybe an increase in some of our R&D costs for the next 3 years because of this study. Our cash runway remains unchanged into 2023. We had also -- our cash balance has been improving and being strengthened with the recent cash inclusion from the exercise of some of our warrants that were expiring last week. So we think financial -- from a financing point of view, we are very well covered.

That's great, appreciate that. One other one, if I could squeeze this one in here, the IV, fair to assume you take that into the hospital in the back half of 2020 -- I'm sorry, 2022?

So the next -- kind of the next steps for the IV formulation is something that we are going to be very actively -- once we have this positive data from the Phase I study, we're actively discussing with the regulatory agencies what will be the best way to bridge this formulation into our development programs. And it's likely that some level of assessment in patients, potentially a Phase II type of study will be required to be able to fully integrate into our Phase III development programs. But at this point, we are not guiding yet because we are still in the process of really discussing what is the most effective approach to really try to -- or efficient approach to really try to bring the IV formulation into the hospital programs.

I'll now turn the call back over to Marco to read any questions that may have come over the webcast.

Sure. There are a few -- of course, a few interesting questions. One other question is, is this a global study? And yes, as David stressed, this is a global study that will be carried out both in North America, Europe. And also, we are planning to have also some sites in Asia. There has been also some question about, can the study been enriched for flu-resistant infection? We think that actually the study will actually be happening by itself. That is we expect about a share between -- 80% between fluconazole-sensitive and 20% of fluconazole-resistant, give or take, probably a certain percentage. But as David was mentioning, this is going to be an intent-to-treat analysis. And we should have adequate number of patients for both type of arms. One other question is again what is the market size? Market size, as I mentioned in my presentation, with very conservative, conservative type of assessment and assumptions, we expect this to be a $300 million to $400 million net sales at peak. This is the type of product that doctors are waiting, an orally bioavailable glucan synthase inhibitor, something that can give confidence to the doctor that they are treating their patients with the best available therapy for invasive candidiasis. Let me see if there are other questions. Actually, there is a very good question actually saying that the cautionary history should tell us that when you have this type of pandemics and viral infections, you may expect more fungal infections. And that is absolutely true, as stressed by Dr. Hoenigl. The question asked, think about the HIV. And that is true with the case with HIV. That was an incredible number of fungal infections actually happening in patients affected by these viral infections. And we have seen Dr. Hoenigl as well stress this point. And maybe, Martin, you may want to share some of your experience on this last pandemic, what you have seen as a practice infectious disease specialist when -- with regards to the interaction between COVID and fungal infections.

Yes, I think it's a very important point. I mean, obviously, it's not new, right? We've talked about HIV. We've also seen in these cases, particularly for aspergillosis in influenza patients in our ICUs, right, before COVID. And then obviously, COVID came. And of course, this -- we had much more patients with COVID in our ICUs than we had before influenza patients in our ICUs. And yes, the important thing is that there is, of course, clinical risk factors that come with patients being the ICU with the medication for COVID, dexamethasone, [indiscernible], elotuzumab, that may predispose to some of these fungal infections and then long-term treatment in the ICU, of course. But I think -- and basic ventilation, of course, a major factor as well. But then there's also immunological mechanisms, I think, that are particularly relevant for the risk for fungal infection in these patients, where that immune system really is directed towards the viral immune response, right? And this leaves important niches for fungi to kind of like grow and also cause infection. And this is more and more explored. And this is particularly true for the mold infections. And I think that's why we expect this to continue to be happening with these respiratory infections that cause acute respiratory failure and lead to ICU admission because, yes, so...

Thank you, Martin. And let me take one more question, is the question about the LPAD pathway for FURI and CARES and the MARIO data. The way we see this is just as a full package with the MARIO data being randomized control being really the foundation. And with FURI and CARES -- by the way, we will enroll more and more patients in these two type of studies, providing additional support data in order to obtain also a salvage setting indication. And since we are approaching the hour, let me just finish by summarizing some key points. I really hope that you're leaving this event with four key takeaways. First of all, that we at SCYNEXIS continue to execute to maximize the growth opportunity for ibrexafungerp by pursuing an innovative path forward as an oral step-down therapy in the hospital setting. And following our productive discussion with the FDA, we believe we have conceived the best study design to bringing ibrexafungerp to patients who need it in the hospital with invasive fungal infections. Second, we plan to gain approval for this hospital indication, this group of hospital indication, the step-down and the salvage setting in late 2024. There is significant unmet medical need in the hospital market. So the third point I would like you to take home is that we project peak sales of $300 million to $400 million for the treatment of invasive candidiasis in the hospital alone. And if you combine this with the indication and with expected sales of BREXAFEMME in vulvovaginal candidiasis, we start to see the total sales you might expect for a novel antifungal in a new class. And finally, we have the funds and the resources to conduct this research with a cash runway into 2023. So thank you all again for joining us today, and we wish you a wonderful rest of the day. Thank you very much. Tara, we can close the session.