Cidara Therapeutics, Inc. (CDTX) Earnings Call Transcript & Summary

Greetings. Welcome to the Cidara Therapeutics data call. [Operator Instructions] Please note, this conference is being recorded. I will now turn the conference over to your host from Lifesci Advisors, Brian Ritchie. You may begin.

Thank you, operator. Good morning, everyone, and welcome to Cidara's Conference Call to provide top line results from the ReSTORE Phase III clinical trial of rezafungin for the treatment of candidemia and invasive candidiasis. Before we begin, I'd like to let you know that on this call, the Cidara team will reference data that are presented on a set of slides that you can access from the homepage of Cidara's website. The complete set of top line data from the ReSTORE Phase III trial is contained in this morning's press release. Joining me on the call from Cidara are Jeff Stein, President and Chief Executive Officer; Taylor Sandison, Chief Medical Officer; Paul Daruwala, Chief Operating Officer; Preetam Shah, Chief Finance Officer and Chief Business Officer; and Shane Ward, Chief Legal Officer and Corporate Secretary. Before I turn the call over to Jeff, I would like to note that all the information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. I caution listeners that during this call, management will be making forward-looking statements. Actual results could differ materially from those stated or implied by forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in Cidara's SEC filings, including its annual report on Form 10-K. I would also like to point out that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, December 14, 2021. Cidara undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. I will now turn the call over to Jeff Stein, President and CEO of Cidara.

Thank you, Brian, and good morning, everyone, and thank you for joining the teleconference to discuss this important milestone for Cidara, the announcement of positive top line data from the ReSTORE Phase III clinical trial of rezafungin for the treatment of patients with candidemia and invasive candidiasis. I will make some high-level remarks concerning the ReSTORE Phase III trial in our rezafungin development program, and then you'll hear from Taylor and Paul, who will review the results of the trial and discuss their commercial implications in more detail. We will then be available to take your questions. On Slide 3, I want to remind you about our overall Phase III development program for rezafungin, which includes 2 trials, ReSTORE, which will be the focus of today's discussion and ReSPECT, which is an ongoing trial for the prophylaxis of invasive fungal disease in patients undergoing allogeneic blood and marrow transplantation. To remind everyone, ReSTORE was focused on the first-line treatment of documented candidemia and invasive candidiasis. It was a prospective double-blind, randomized international multicenter trial to evaluate the efficacy and safety of once-weekly IV rezafungin versus once-daily IV caspofungin in 187 patients with a 1:1 randomization of rezafungin to caspofungin. The FDA endpoint of the trial was all-cause mortality at day 30 versus the comparator caspofungin assessed with a predetermined 20% noninferiority margin. The ReSTORE trial, together with our STRIVE Phase II trial in the same population will serve as the basis for global regulatory filings expected mid next year. On Slide 4, and you can see the design of the ReSTORE Phase III trial. Patients were randomized 1:1 to receive either rezafungin administered IV once-weekly for 2 to 4 weeks or daily caspofungin administered IV according to its label dosing with an optional stepdown to oral fluconazole. Rezafungin patients received active drug on days 1 and 8 and at the discretion of the investigator, days 15 and 22. They then received daily placebo infusions in between their rezafungin doses and also received placebo oral fluconazole, if stepped down to oral medications in order to maintain the [ wide ]. Investigators and study staff were not aware of which doses of study drug are active and which are placebo. In addition to the primary endpoint of -- for the FDA of all-cause mortality at day 30, the trial assessed the primary EMA endpoint of global cure at day 14. Global Cure is defined as clinical cure plus mycological eradication as well as radiological cure for qualifying invasive candidiasis patients only. On Slide 5, we summarize the most important findings from our ReSTORE Phase III trial. We are pleased to announce that the ReSTORE trial met all primary and secondary endpoints, both the rates for all-cause mortality at day 30 and global cure at day 14 were similar between the rezafungin and caspofungin arms for the treatment of serious more life-threatening candida infections. And within the predetermined noninferiority margins established with the FDA and EMA. In addition, secondary early efficacy endpoints, day 5 global cure and day 5 micrological eradication were similar or numerically higher in the rezafungin arm. With respect to the prespecified exploratory endpoints, which were not powered to detect statistical differences, the time to negative blood culture was faster in the rezafungin arm. In addition, the median duration of ICU stay was 9.5 days shorter in the rezafungin arm, nearly double the 5-day difference observed in the STRIVE Phase II study. In terms of safety, as one might have anticipated for 2 drugs of the echinocandin class, rates of adverse events and SAEs were similar between the 2 arms. I would now like to turn the call over to Taylor to walk through the results in more detail. Taylor?

Thank you, Jeff, and good morning, everyone. Before showing the efficacy results, I want to turn your attention to Slide 6. Slide 6 shows the baseline demographics and characteristics, including gender, age, race, the number of candidemia and invasive candidiasis patients and the severity of disease in patients as indicated by the APACHE II Score that were all evenly distributed between rezafungin and the caspofungin arms. Also note that the overall rate of invasive candidiasis was 30%, which is higher than the 20% observed in our Phase II STRIVE trial and higher than the rates observed in prior registrational trials in this indication, which were approximately 10%. Slide 7 shows the efficacy results of our analysis of the primary endpoint for the FDA, day 30 all-cause mortality. The 30-day all-cause mortality rates were similar with 23.7% in the rezafungin arm compared to 21.3% in the caspofungin arm. The upper limit of the confidence interval is 14.4%, which is within the 20% noninferiority margin established with the FDA, meaning the ReSTORE trial met its primary endpoint. Slide 8 shows the efficacy results of our analysis of the primary endpoint for the EMA. Day 14 global cure rates were also similar across study arms. 59.1% in the rezafungin arm compared to 60.6% in the caspofungin arm. The stratified point estimate of that difference in cure rate is 1.1%. The lower limit of the confidence interval is negative 14.9%, which is within the negative 20% noninferiority margin established with the EMA, meaning the ReSTORE trial also met this primary endpoint. Slide 9 shows the efficacy results for day 30 all-cause mortality and day 14 global cure broken out by patients with either candidemia-only or invasive candidiasis. The reason one looks at these subgroups separately in these trials is because these are often different patient populations with different risk factors for candidal disease and different outcome rates. And anemia patients tend to be patients with central venous catheters who are often critically ill and/or immunosuppressed with infection in the blood alone, whereas the invasive candidiasis population are often post-surgical patients with deep tissue and organ infections that are often more difficult to treat, require surgical drainage and may need prolonged antifungal therapy. The results for day 30 all-cause mortality and day 14 global cure were comparable across both study arms within each subgroup. Slide 10 compares the day 5, day 14 and day 30 global cure rates. As a reminder, global cure is a composite of clinical cure, mycologic eradication and were relevant for invasive candidiasis patients radiological cure. The day 14 results were shown previously and have been included here, so we can see the trend across multiple study visits. The similar results for global cure between the rezafungin and caspofungin arms were consistent across multiple time points. Slide 11 shows the efficacy results from mycologic eradication at day 5, day 14 and day 30 in the candidemia-only population. This outcome measures the percentage of surviving patients that had clearance of Candida from the blood without a change in study drug on the day of assessment. The early results are numerically higher for rezafungin at day 5, while the results at day 14 and day 30 are similar between the 2 study arms. Slide 12 includes a few results from secondary and exploratory analysis focusing on the early outcomes after the start of study and on the duration of stay in the ICU. First, the evaluation of clearance of blood cultures in patients with candidemia demonstrates that more rezafungin patients had negative blood cultures by 24 and by 48 hours. This trend is similar to the faster clearance of blood culture also observed in the Phase II study. Now moving to day 5, here is the result from mycological eradication in the candidemia-only population that was presented on the previous slide and shows the consistency of the efficacy outcomes in this population across early time points. Finally, we observed that the difference in median length of stay in the ICU was 9.5 days. Since we have previously shown median ICU stay for the Phase II trial, we have included this exploratory analysis here. Please note, the analysis for this outcome was not powered for statistical comparison. At this point, it is unclear what a difference of this magnitude means in the setting of other statistical clinical comparisons that were more comparable between study arms, but it is consistent with what we observed in the Phase II trial, where the median difference for ICU length of stay was 5 days lower in the rezafungin arm. Slide 14 shows a comparison of the Phase II STRIVE and the Phase III ReSTORE trials for day 30 all-cause mortality. As you can see, the overall day 30 mortality was about 10% higher in the Phase III trial. The primary differences between the Phase II and Phase III trials are listed on the right, but we do not know what impact these differences may have had on the outcomes in ReSTORE. I want to add that the Phase II STRIVE trial was also a double-blind randomized trial versus caspofungin and is supportive of the ReSTORE trial and will be part of our NDA package to support registration. Slide 15, again, shows a comparison of our Phase II strive at our Phase III ReSTORE trials but in day 14 overall cure versus day 14 global cure. Overall rates of day 14 global cure did trend lower than in the Phase III trial compared to overall cure in the Phase II. Additional differences between the 2 trials are again listed on the right of this slide. I want to pause here to note that 75% of the ReSTORE trial was enrolled during -- enrolled since March of 2020 during the COVID pandemic. To conduct an infectious disease trial in hospitals during the global pandemic took unbelievable courage and persistence on the side of the patients and the entire ReSTORE investigator community, many of whom were the same infectious disease staff taking care of patients with COVID around the world. So thank you to all of you for your perseverance. Moving along. Slide 16 shows a summary of the adverse events from a total of 196 patients that were included in the ReSTORE safety population. Overall rates of adverse events and serious adverse events were comparable between rezafungin and caspofungin. Rates of serious adverse events related to study drug were low in both arms. Rates of adverse events leading to study drug discontinuation were also similar for rezafungin and caspofungin. In general, both drugs were well tolerated with comparable safety profiles. We did note that there was a higher percentage of subjects with related adverse events in the rezafungin arm and did take a closer look. As a reminder, in this study, rezafungin is administered once weekly starting on day 1 with daily placebo infusion of saline on the other 6 days of the week. And when stepdown to oral medication occurs, the caspofungin arm receives active fluconazole and the rezafungin arm receives oral placebo. Determination of whether an adverse event is related to a study drug is assigned by the principal investigator in a blinded manner, meaning they do not know which study drug is being administered and whether a particular infusion or oral medication is active or a placebo. Among those AEs considered related to study drug in the rezafungin arm, 5 of those adverse events were directly associated with administration of study drug, which unblinding of data administration demonstrated to be placebo given within the rezafungin arm and not active drug. Of those 5 AEs, 2 were considered serious adverse events and are listed on the next slide. So here we see the list of related serious adverse events that were recorded in the trial. All of these adverse events led to discontinuation of study drug. The 2 SAEs considered related to rezafungin are good examples of the nature of a blinded trial and the assignation of a relationship with study drug. The first SAE of an infusion-related reaction occurred during an infusion of saline placebo on day 3. The second SAE of urticaria was considered related to oral study drug, which in this case was placebo. For caspofungin, there were 2 episodes of serious liver inflammation or injury resulting in stoppage of drug and replacement with another antifungal. The final SAE was anaphylactic shock, which occurred during an active infusion of caspofungin on day 3. I want to end by once again summarizing our top line conclusions. We are pleased to say that rezafungin met both the primary efficacy endpoint for the FDA new drug application submission of all-cause mortality at day 30 and the primary efficacy endpoint for the EMA marketing authorization application submission of global cure at day 14. Both results demonstrated statistical noninferiority of rezafungin dosed once-weekly versus caspofungin dosed once daily, which is the current global standard of care for the first-line treatment of candidemia in evasive candidiasis. The secondary efficacy endpoints of global cure, day 5 and day 30 and mycological eradication at day 5, day 14 and day 30 were either similar or were numerically higher in the rezafungin arm. The blood cultures were cleared more quickly in the rezafungin arm though the difference was not significant, and duration of ICU stay was shorter in the rezafungin group compared to caspofungin. For safety, rezafungin was generally well tolerated, had a similar safety profile to caspofungin. Given these positive top line data, we intend to file our NDA and [ EMA ] for ReSTORE by mid-2022. I will now turn the call over to Paul.

Thanks, Taylor. Good morning, everyone. I would also like to thank all of those who have made these results possible. I'm excited about the positive outcomes of our ReSTORE trial, which now provide an excellent foundation for the launch of rezafungin. I'd like to draw your attention to Slide '19. Let me remind you that there have been no new treatments for this indication in the last 15 years. As Taylor mentioned, we intend to file our NDA and [ MEA ] for ReSTORE by mid-2022. Preparations for launch are ongoing. We'll continue to be highly strategic and cautious as we evaluate our go-to-market approach and spend as well as options for commercialization. Importantly, the antifungal market is a highly concentrated and efficient one with half the market coming from just 340 accounts in the United States, many of which are large cancer centers and teaching institutions. So the effort under any circumstance, be it on our own or with a partner will be a highly targeted one. We also continue to analyze launch dynamics in the COVID era to help shape our approach before making significant investments. Importantly, we've ensured that our supply chain is in place, and we have launched supplies on hand. Rezafungin as fast track, QIDP and orphan disease designations, which will be helpful as we progress with our regulatory filings. And over the last few years, we've built a very strong relationship with our partner, Mundipharma; we are working closely, and we're working closely together so that rezafungin could be launched in their territories at the earliest possible date post approval. I also want to take this opportunity to remind you of some advantages that a drug like rezafungin has to offer here on this next view on the right. It's the only drug in development to be compared successfully head-to-head in a Phase III trial versus the standard of care in echinocandin for first-line therapy. It's the first and only once-weekly antifungal drug under development. The old mantra in infectious disease to hit the pathogen early and hard with the right drug remains true today. Rezafungin is not only a once-weekly drug but exhibits high front-loaded dosing and tissue penetration. Additionally, there have been no drug-drug interactions requiring dosage adjustment for either rezafungin or other drugs seen thus far. Rezafungin may also enable earlier hospital discharge in certain patients and is active against difficult-to-treat Candida strains, including Canada auris and azole resistant Canada. Over the course of the last several years, we've been asking practitioners the following question. Assuming the primary endpoint for ReSTORE is met, in which patients could rezafungin most fulfill an unmet need for the treatment of candidemia and invasive candidiasis. To set up the answer to this question, here's a bit of background. Patients almost always begin their battle with a candida infection while in the hospital, often, though not always, in the ICU. Most received empiric antifungal therapy with a standard dose echinocandin for a suspected infection per guidelines. In roughly 30% of these patients, an infection is then confirmed or documented. And most often, the echinocandin has continued for a period of time. Echinocandin have been shown in 2 separate Phase III trials to be superior to azoles in the treatment of Canada. Some patients may step down to an inexpensive oral fluconazole while in the hospital, while 30% of patients need to continue first-line therapy with an echinocandin often for several more weeks. So with that backdrop, on this slide, we have laid out the feedback from practitioners, defining the Candida treatment opportunities for rezafungin in the inpatient and outpatient settings. First, and in line with the ReSTORE trial, clinicians want to use rezafungin to treat documented infection more so than suspected ones. Second, they suggest that the higher front-loaded dosing may be a critical benefit in critically ill patients. Those most often noted are neutropenic patients, obese patients, burn patients and those whose condition is more rapidly declining. They also describe patients who cannot step down to an azole and where there's a potential for a once-weekly drug to enable patients to be discharged earlier from the ICU or the hospital, which has consistently been noted during the COVID period. In the outpatient setting, be it in home health or infusion clinics, the patients noted are those who are infected with an azole-resistant Candida pathogen, have drug interactions or azole toxicity or a deep-seated Canada infection. Rezafungin is noted in research as an obvious future choice to enable the continuation of standard of care in echinocandin class while at home. I'd like to conclude by reminding everyone of the overall goals for the rezafungin program. The program is intending to meet important unmet needs and market potential in both Candida treatment, which we've been discussing today; and fungal prevention in the alloBMT hematology population. The unmet needs in prevention are quite different, but as significant and mainly driven by patients with hematologic malignancies, many of whom cannot take azoles due to drug-drug interactions, causing contraindications with their primary cancer therapies or they suffer from toxicities of azoles and Bactrim. These patients most often continue antifungal prophylaxis into the outpatient setting during prolonged periods of immune suppression, where a once-daily IV echinocandin can't be adhered to practically and once-weekly rezafungin is noted in research as going this significant unmet medical need. Antifungal drugs, which in the past have successfully pursued first-line development programs to meet unmet needs in both treatment and prophylaxis have also done well commercially, as you can see on this slide, with annual peak sales of $800 million to $1 billion globally. With that, I will now turn it back over to Jeff for closing remarks before we take questions.

Thanks, Paul. We are truly excited about the positive outcome of our ReSTORE clinical trial. And today, we have announced an important milestone. This is the first time that any antifungal has shown the potential to be a safe and effective once-weekly treatment option for patients with difficult-to-treat and deadly invasive Candida infections, which may enable patients to leave the hospital earlier, safe health care treatment resources and improved care. I would like to thank all of the investigators and their site staff for their relentless hard work and dedication as well as the patient who made it possible for us to generate these data. The positive top line results of our Phase III program will allow rezafungin, if approved, to be marketed across distinct patient populations where there is an urgent unmet need for innovation. As mentioned, the ongoing Phase III ReSPECT trial is designed to evaluate rezafungin in the growing prophylaxis market in the hematology setting, and we continue to make progress on that front. With that, I'd like to turn the call back over to the operator so we can address your questions. Operator?

[Operator Instructions] Our first question is from Louise Chen with Cantor Fitzgerald.

This is Wayne on for Louise. Congrats on the data. So you've been talking about a higher front-loaded dosing and better PK for rezafungin for a really long time. Do you think that's the reason to drive the positive signals for Days [ 1-5 ] and ICU stay in the Phase II and now Phase III? And how important it is for the clinicians?

Yes, great question. Let me turn that over to Dr. Sandison to address it.

Yes. Thank you. Yes. So I think that is the case. We've had this hypothesis for a number of years now, indicating the high front-loaded exposure, leading to improved target attainment nonclinically and we're seeing these improved outcomes early consistently in our clinical studies. And certainly, I think that's going to be the primary driver that we see for the early efficacy outcomes for this drug.

Our next question is from Joseph Stringer with Needham & Company.

Congrats on the data. A few from us. One is on the ICU stay. Clearly, reza's showing non-inferiority with similar values on mortality and global cure, but it's trending on the exploratory ICU stay. I guess you touched on it in the presentation, but what are your thoughts on just the reason why you think it's trending lower for reza given some of the similarity or non-inferiority on some of the other values? And then it would seem that this could be important commercially, but what are the -- how would you plan to sort of leverage this data on ICU stay? And what are the barriers in terms of a real-world setting whenever those discussions are had around differentiation, specifically on the ICU stay? And then secondly, on the regulatory submissions here, are there any gating factors in terms of CMC or additional safety data that need to be done prior to regulatory submission?

Yes, Joe, I'll make a couple of high-level remarks, then I'll turn it over to Taylor and then Paul to answer your other questions. So with respect to ICU stay, yes, we did note that the trend was similar, though larger comparing STRIVE and the ReSTORE. So in the STRIVE Phase II study, we saw a 5-day difference in the ICU of patients receiving rezafungin versus caspofungin. And we were surprised to see that expanded to 9.5 days difference. As a note, these are the top line data. We don't have all of the details that can help us assess the rationale behind that. We suspect it might be related to the improvement in mycological cure. But let me turn it over to Dr. Sandison to provide some additional detail and then to Paul Daruwala to discuss some of the other implications from a commercial perspective and to address the -- your question on the regulatory submissions. Taylor?

Yes. So I think what we can say is that this has been repeated not just for ICU stay, but we see data for hospitalization, et cetera amongst the rezafungin arms compared to caspofungin in both studies and a relatively large magnitude. At this point, it's hard to say exactly why that is. And as Jeff mentioned, we are -- we have the rest of the data to come in, in January. So we're certainly doing a deeper dive on this, just to try to get to the bottom of it and certainly trying to help us explain why this might be. But it does -- and the reason we show it on this slide, it does go along with our hypothesis of clearance of blood cultures might be able to lead to earlier improvements and potentially earlier discharge. But a difference of this magnitude, I think, needs to be examined further. Paul?

Yes. I think that latter point there is important, Joe. So we'll obviously have to investigate this. And those same questions will be asked of us from clinicians and institutions who would contemplate the use of rezafungin in the ICU. So the hurdle will be burden of proof -- continual burden of proof. It is suggestive and that's important. This field is one that, again, does have a high unmet need. Clinicians are looking for options to clear blood faster disease, particularly in patients who are critically ill, who may have less ability to clear the infection themselves. And those are the patients that I mentioned, some who are neutropenic, others who have more rapidly declining conditions for a variety of reasons outside of just their fungal infection. So they're important. They do kind of raise the eyebrows when you look at the data and clinicians have certainly noted to us prior to these results that they would have wanted -- they would want to see the Phase III results before they commented on the ICE results from Phase II. Now we're seeing those results in Phase III. So I'll obviously have to go back to those same clinicians and have a good discussion about these data. On the CMC front, and regulatory submission front, as you would anticipate, well, firstly, on the CMC side, we've made a lot of nice progress on this where we have a global supply chain in place, supply materials ready. Obviously, we need to go through the traditional regulatory approvals for -- to validate everything that we've done and the regulatory submissions, we intend to file those in the middle of the year, next year, both for the FDA and the EMA and other global filings.

[Operator Instructions] Our next question is from Ed Arce with H.C. Wainwright.

This is Thomas Yip asking a couple of questions for Ed. First, congratulations on the very positive pivotal data set for rezafungin. Perhaps this first question, looking at the key secondary endpoints of mycologic eradication. Can you go over what are some possible reasons that looking from Day 15 to Day 14 and the rezafungin arm, it went down compared to those 2 time points, and then it went up for the caspofungin arm even though rezafungin is clearly superior on both time points compared to caspofungin?

Sure. Taylor, do you want to field that one?

Sure. Yes. So just to give you an idea, each of these are kind of a snapshot in time on Day 5 versus Day 14 versus Day 30. And they evaluate whether the patient has cleared their blood cultures, whether they're still alive and whether they have not started any other antifungals, right? So we don't allow any other antifungal. So the reason these things change is not because -- the reason the mycologic eradication numbers change is not because the Candida recurs generally is more about whether the patient is still alive or whether the patient is still taking study drug. So all those things play into it. The other part of it also is that if patients aren't evaluated on those specific days. So if they don't show up for their Day 14 or Day 30 visit, then that will be missing data, and it won't be assessed. So that would not count as a cure at that time point.

That makes sense. And then perhaps another question obviously. So are there different protocol in terms of standard of care for different clinical sites in U.S. and ex-U.S. as well and the ReSTORE versus the Phase II STRIVE study? And if so, can you go over some potential impact on data comparing rezafungin to caspofungin?

Yes, Taylor. Go ahead and take that one.