Back to the 2025 RBC Global Healthcare Conference. My name is Greg Renza, one of the biotech analysts here at RBC, and we're pleased now to be joined by Cidara Therapeutics. Joining us from the company is the President and CEO, Jeff Stein. Great to have you, as well as the new CFO coming in with a bang, Frank Karbe. Great to see you both. We look forward to hearing more about Cidara and what's been going on. A really important inflection era for Cidara, especially coming off what has been quite a transformative several months and quarters now. Jeff, your long history with the company, with the technologies, is really worth exploring. Maybe for those who aren't familiar with Cidara, we could have an overview of what you've been up to. You're focused on CD388 and the Cloudbreak platform. I will acknowledge for the audience that we do have some slides to illustrate as Jeff talks. Sure. Yeah, let me just, I think this is a good place to start to give a high-level overview of Cidara. The platform technology is called the Drug-Fc Conjugate, or DFC. As you can see illustrated by the molecule on the left, which is CD388, our lead molecule, which is in a 5,000-subject phase IIB study. It's a hybrid molecule. It's a combination of a potent small molecule inhibitor. In this case, that inhibitor is a part of an approved drug called Zanamivir, or Relenza. It is stably conjugated to the Fc fragment of a human antibody. That is also part of approved drugs. It is a variant of the YTE mutant, which confers extended half-life. CD388 was designed to be a very potent inhibitor of an essential target in influenza. It's called neuraminidase. Neuraminidase mediates viral exit from the cell. If you can inhibit neuraminidase, which is an external cell target, you can prevent the proliferation of the viral infection, in this case, influenza. The Fc fragment confers that long exposure, or long half-life and high exposure. This molecule was designed to be administered once a flu season, once at the beginning of the flu season, and potentially confer protection, universal protection against all flu strains. Equally important in all people, because it's not a vaccine. That's something that particularly now is important to emphasize. This is not a vaccine. It's a long-acting drug. It doesn't have the limitations of traditional seasonal influenza vaccines. It doesn't have to be manufactured every year in response to whatever circulating flu strains there happen to be that year. It's the same manufacturing process, same molecule that targets a universally conserved enzyme on the surface of every flu strain. That's great. It's helpful to see the design up here, not just about the trial, but also, of course, about the construct and CD388. As you've covered this design and maybe the differentiation, there are many questions about how it does compare and differentiate it from other antivirals, other neuraminidase inhibitors, particularly with respect to the de-risking success. Maybe just talk a little bit about the highlights of what you're covering. I'll just add in here, when it comes to penetration in the respiratory airway, I think there are always, and tissues in general compared to others out there. Maybe just walk us through some of the appreciation that you have for its differentiation and effects. Yeah, that's an important question. We selected Zanamivir, which is the most potent of the known neuraminidase inhibitors. It's an exquisitely potent enzyme inhibitor. It actually targets a transition state of the neuraminidase enzyme, which is very challenging for the virus to develop resistance against without incurring a severe fitness cost. As good of an enzyme inhibitor as Zanamivir is, or Relenza is, it's a really poor drug. It is eliminated very rapidly, has very low systemic exposure, and consequently, it is formulated in a nebulized form, administered via inhalation. It is great because it does, and to your second part of your question, it is deposited in the respiratory mucosa, has high exposure in the respiratory mucosa. However, as anyone who's had the flu knows, influenza is a systemic infection. That's why you get fever, why you get chills and aches. That is a liability of Relenza. It has very little to no systemic exposure, but great respiratory exposure. Now, the alternative is monoclonal antibodies or vaccines, which elicit an antibody response. Antibodies are large molecules. If you look at the structure of CD388, basically, if you think about the kind of traditional image of an antibody, this is the stock of the antibody. It's missing the Y-shaped arms. We've replaced the arms with these small molecules. Consequently, CD388 is roughly one-third the molecular weight of a typical antibody, whether it's a monoclonal that is manufactured or a naturally occurring antibody that is generated internally in response to a vaccination. It has improved tissue penetration compared to our naturally occurring antibodies, it being roughly one-third the molecular weight. That's great. While there's all this focus on Navigate, we have clinical data to date that gives you the increasing confidence of translatability. Maybe talk a bit about some of those study results, the human challenge study, how the data that you've accumulated over the years can help to support the development as a long-acting prophylactic agent. Yeah, so here's a summary of some of the clinical data we have to date. As you saw in the prior slide, we partnered CD388 with J&J very early in the development program as actually a preclinical molecule when we secured that partnership. Under that partnership, we advanced the program through two phase I studies and a phase IIA human challenge study. You can see some of the results on this slide. Importantly, a drug that is administered once a flu season that has high exposure for the entire flu season has to be very safe. That's a strong point of this modality. It does not penetrate cells. Consequently, there are no cytochrome P450 interactions. There is no hERG activity. There are no off-target toxicities that you might expect with a small molecule by itself. That's an important advantage. In nonclinical studies, we haven't identified a dose-limiting toxicity. In clinical studies, we've dosed this up to 900 mg, which is twice the highest dose that we're testing, with no concerning treatment emergent adverse events. That's really helpful when you're thinking about a drug that is administered at high exposure over the course of the flu season. In phase II A study, we determined that CD388 works. If you look at the results of the phase II A study, now these are human challenge studies. The way that you conduct these studies is you administer the drug, and then five days later, you challenge the volunteers with a kind of attenuated strain of H3N2 flu virus. This typically doesn't manifest in systemic signs and symptoms. What you look for is basically a binary outcome that you're looking for in the phase II wave. Are there signs that the drug works or does not work? What you see here is the primary endpoint is PCR positivity. Influenza is an RNA virus. You use qRT-PCR against conserved domains to detect whether or not there's any evidence of it working. You can see the difference in the PCR outcome comparing the placebo to the, and this is the lowest of the three doses that we're currently testing in phase II B. When you look across the endpoints, you look at the placebo-adjusted event rate, and you see about a 57% placebo-adjusted efficacy. That's a great outcome. It shows clearly that the drug is working. It's especially important given the mechanism of action. As mentioned previously, CD388 is a neuraminidase inhibitor. Neuraminidase mediates viral exit. It does not inhibit viral entry into the cell. You fully expect to see a PCR positive signal. What neuraminidase inhibitors are really good at is at preventing the proliferation of infection and limiting severe signs and symptoms. That is exactly what we want to show in phase IIB and consequently in phase III. Nobody cares about PCR positivity. What you really want to inhibit is severe influenza. If we look historically, there is some encouraging historical data based on other neuraminidase inhibitors, in particular Tamiflu, which is one that everyone is very familiar with. If you look at the relative response rate in the phase IIA of Tamiflu, you can see about a 24% relative response rate, the placebo-adjusted response rate, which again, is not unexpected. You do not really expect neuraminidase inhibitors to prevent PCR positivity. If you layer on top of that signs and symptoms of severe influenza, looking at fever, looking at respiratory signs or systemic signs, you see this leap in efficacy going from a phase IIA, in this case, to a phase III. That begs the question, what might we expect? We're about a month or so away from our phase IIB data of that 5,000-subject study. We're very encouraged that in our phase IIA, we showed a 57% response rate. Our bar for success could be lower than that challenge study. That would be unusual since typically with a neuraminidase inhibitor, it goes up substantially, as you saw with Tamiflu. Even if we're no higher than what we got in the phase IIA, that would be a win when you consider that the average flu vaccine is about 40% effective. That's in healthy, normal people. Our phase III, we're taking it into high risk and immune compromise, where the vaccine efficacy is 0%-20%. An outcome of anything higher than that is a real win. Remember that hitting viral neuraminidase is different from what vaccines hit, which is hemagglutinin. Those are two complementary mechanisms. If you can inhibit both neuraminidase and hemagglutinin by putting CD388 on top of a vaccine, you have this potential opportunity of having an additive benefit. That's great. Let's go deeper a bit on Navigate and the data that's coming. First, setting the stage, Jeff, on the latest northern hemisphere flu season, how this is compared historically and how it compares to your initial assumptions when the trial was designed in terms of severity and pattern. How was this all impacting the trial, the timing, and expectations? When you design flu trials, unlike most other areas, and even within infectious disease, it's a seasonal infection. You never know how severe that flu season is going to be when you're designing a study. Consequently, you tend to be very conservative. You assume what's called the attack rate in the placebo arm of the studies. You can see the phase IIB Navigate study. It's a four-arm study, 5,000 subjects, which means 1,250 subjects randomized across four arms. If you look historically on the conservative side, you go into these studies assuming about a 2% attack rate in the placebo arm. If we assume 2% attack rate in the placebo arm, it's 2%x 1,250 in that arm, or about 25 breakthrough infections in the placebo arm that qualify for the primary outcome. Now, we assume, based on the phase IIA results we just showed, that the 150 mg dose, which is what we tested in phase IIA, would have a roughly 50% efficacy rate. Now, remember, that efficacy rate is against PCR, not against systemic, so it's likely higher. That said, you look at the 150, assume a 50% attack rate in the 150 mg arm. That would be about 12 infections there and consequently lower in the 300 and 450. With those small numbers going into the Navigate study last year, we did not assume and did not propose to introduce a pre-specified p-value. This was simply a dose selection study, as most phase II studies are. You want to select a dose to put into phase III. And secondarily is whether it's statistically significant. What transpired, as you indicated, is that we experienced the worst flu season in the last 17 years, which is terrible for people, but great if you're running a large flu trial. That caused us to rethink the statistical analysis plan. We believe that the attack rate could be higher than we initially expected. We engaged with the FDA in January. That is right after the first of the two peaks of this last flu season emerged. Started that conversation and have now achieved alignment with the FDA on the design of that statistical analysis plan to evaluate the results. We'll discuss some of the details of that tomorrow. We have an R&D day event about this time tomorrow where we'll discuss some details of that plan. R&D day tomorrow, laying out for data in June. Yeah, it's really helpful to provide the context as we and investors go into some of these disclosures. Of course, you mentioned with respect to the dose finding as primary objective, we'll come back to that. When it comes to the endpoint, maybe walk us through how patients are confirmed for their infection, the inclusion of body temperature at 38 degrees Celsius into this composite readout. A lot of interest on the verifications of infection. Maybe elaborate a bit on that design of the primary. Sure. Yeah. As with the phase IIA, you start with PCR positivity. You do not want to be evaluating subjects that may have COVID or RSV, which emerged during the flu season. You start with PCR positive. From there, you look at respiratory and systemic signs and symptoms. The inclusion criteria include two or more respiratory signs or one respiratory and one systemic sign. Now, one of the key systemic signs of infection is fever. That is a prerequisite. You have some choices with fever. There is the WHO definition, which is 38 degrees. There is the CDC definition, which is 37.8. It is easy to think, well, that is 0.2 degrees. Does that make a difference? It actually does make a difference. We selected 38 degrees as the key component of our primary outcome, which selects for the most severe signs and symptoms of infection. We believe that that will select for a more robust outcome in the CD388 arms because that really addresses the strengths of the neuraminidase inhibitors. Excellent. Excellent. Just to elaborate a bit, Jeff, just on the dose selection strategy as we think about the protective efficacy bars and some of the protection stats that you've cited. Across all the different cohorts and arms, how do you frame up the potential next steps in dose selection? Yeah. As mentioned, our a priori assumption is the 150 mg dose would be roughly 50% effective and 70% efficacy for the 300 and 90% for the 450. Any one of those doses would be acceptable to take into phase III. Let me just bring up the curve on the audience's lower right there. This is the PK curve from our phase I study showing the lowest and highest dose. The horizontal line is the target exposure line. That line was identified from a lethal mouse challenge model, basically challenge the administer drug, and then you administer a lethal dose of influenza. We've done this with just about every strain of influenza available. CD388 has a remarkably stable line across all strains. We identified this line, which in mice is 1 microgram per milliliter, which is the same as 1 mg per kilogram. That translates to a 150 mg dose. So that horizontal exposure line is the 150 mg dose. You can see that both that dose and the highest dose and presumably the middle dose provides exposure above the target exposure line for the entire flu season. What does that tell us as far as expectations for the results that we'll be reporting in just over a month? What that tells us is that for any infections that occur early in the flu season, we don't expect to see any differences in outcomes from those three doses. In fact, it's only towards the tail end of the flu season where infections are waning would we expect to see any separation in outcome. That's where that 150 mg curve starts to dip below that target exposure line. That's actually the end of the flu season when we expect to get the most information from this study, assuming we have enough breakthrough infections at that point in time. Fantastic. Not to get ahead of ourselves, post data next month, Jeff, but maybe talk a bit about phase III plans, what you have been guiding to in terms of timing, also as far as the intermediate engagement with FDA and how that fares with really the next flu season. Yeah. Our expectation is to start phase III in the spring of 2026, southern hemisphere flu season. The reason for that is we're running up against some pretty tight timelines. If we report data of the phase IIB by the end of next month, you put in a meeting request, you hold a meeting hopefully within the statutory time, and then get meeting minutes within the statutory time, you're pretty much right. I don't know who that was. Okay. You're good. You're pretty much right on top of when you need to start your phase III study. It is really important that you start enrolling these flu trials before the flu season starts, which is exactly what we did last year. We have benefited from really rapid response from the FDA to date. I don't know whether that's because of the changes at the FDA, which you might expect would result in a different response, or the fact that this is such a tremendous unmet need. We're planning on taking CD388 into phase III, not into a healthy normal population, but in a high-risk and immunocompromised population. As mentioned, this is the population that has between 0% and at most 20% response rate to a traditional vaccine. High rate of hospitalization and death in this population, very low response rate to vaccines. It is a high priority area. We think that the FDA appreciates that. Now, we do not know if our rapid responses from the FDA will continue because we are in an area of unpredictability now. We cannot count on that. That is why our base case assumption is to start phase III in the spring of 2026. Maybe to that, do you have a sense of, you and the team have a sense of what you're looking for to detect that unpredictability or that responsivity of FDA? What about your interactions are you looking out for that could suggest that there's change? We're not the only company that has been experiencing fairly good interactions with the FDA, as we understand it. As long as your business with the FDA is kind of normal course, it does not require any kind of special escalation, that they've been very responsive. We have not had to go to the FDA with any special requests or something that requires an unusual response. Hopefully we do not have to test that. Excellent. Maybe in the last few minutes, I just want to give you an opportunity to talk about the initial addressable market opportunity. We talk about the high-risk population, but also that potential to expand. What does the TAM look like? How do you put the end opportunity into context? I'm going to give Frank some airtime. There you go. Let him respond to that. To address this. The two target populations that Jeff was alluding to make up about or are made up of about 50 million patients in the U.S. alone. In terms of pricing, we are looking at Beyfortus as a potential analog. Beyfortus is priced at $500 per injection. It is a very similar sort of setting where it is going after RSV in a very specific patient population. The patient population that we are going after in our case is substantially larger, but pricing might be very similar. If you combine those two, the size of the population with the expected price points, you could see how this translates into a multi-billion dollar commercial opportunity. Excellent. Following that up, Frank, just as far as capital allocation investment required, two parts when it comes to certainly a cash runway and what your needs are. Secondly, just the scalability and the manufacturing of CD388. How do those two work together for phase III preparedness? On the capital side, we ended Q1 with about $175 million in cash. Absence of starting a phase III study, that runway then carries us actually all the way to the end of 2027. Now, of course, the plan is to initiate phase III pending positive results from our phase IIB study. To get ready for that, we're currently evaluating all possible financing options. That includes really a number of different possibilities. We're looking at capital markets-based options, but we're also looking at more structured financing options such as royalty monetization, structured data options. We're also in partnering discussions. Excellent. As far as readiness with supply for CD388, what work needs to be done and how seamless is the manufacturing versus really other technologies, ADCs, et cetera? Yeah, we have the drug supply ready for phase III. We're assuming the highest dose, and so we're planning for that. If it's a lower dose, obviously we'll be prepared for that as well. Great. Great. So we look forward to tomorrow as well as the data in June. Jeff, Frank, thank you very much. Great. Thanks everyone.