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

Good afternoon, and welcome to the Cidara Therapeutics R&D Day. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cidara website following the conclusion of the event. I'd now like to turn the call over to your host, Dr. Jeff Stein, President and Chief Executive Officer of Cidara Therapeutics. Please go ahead, Jeff.

Great. Tara, thank you for the introduction, and welcome, everyone. This is a pivotal moment for Cidara. And I mean that in the real term, as we transition the emphasis of the company, from our most advanced program, rezafungin, which is now commercialized to our Cloudbreak platform, and we'll get into that in greater detail in a moment. So I will kick off the program with a brief overview of both of our platforms. We'll describe our DFC or drug Fc conjugates and how they work. I think a lot of you are already aware of this, but I'll go through a high-level overview of the program. I'll provide an update on our collaboration with J&J and some of the new data that has emerged from the clinical program. Many of you will note that in the announcement, we did have 2 of our colleagues from J&J as participants in this program. They unfortunately had a last-minute conflict arise that precludes their ability to participate, but they have graciously provided us with their slides, and I'll be going through those slides. And so these are today's speakers. Myself, obviously, President and CEO. We will then transition the program to Nicole Davarpanah who is our Senior Vice President of Translational R&D; and Les Tari, our Chief Scientific Officer. And we are joined by our 2 key opinion leaders, Stephen Schoenberger of the La Jolla Institute for Immunology; and Ezra Cohen, Chief Medical Officer of Oncology for Tempus. So as mentioned, these are our 2 platforms. Up to this day, most of the emphasis and it makes sense that -- is on rezafungin, our most advanced program. In March, rezafungin was approved for the treatment of candidemia and invasive candidiasis as a once-weekly therapy. And we are still running the prophylaxis study, and that is over 60% enrolled, and we look forward to providing updates on that program. Rezafungin has been partnered in the U.S. with Melinta. I'll give you a brief update on that. and outside the U.S. and outside of Japan with Mundipharma. So the emphasis of today's program is going to be on the bottom of the screen. Earlier this year, we have provided an update on the early data from our most advanced program, our development candidate, CBO-421, which is directed against CD73. And for the first time today, we will be providing some data on our combination molecule and our chemokine receptor program. So very pleased to announce that Melinta has done a great job in the launch of REZZAYO that was launched formally on July 31 of this year. So less than too months on the market and has been done -- being doing very well. It is on a number of formularies and so -- doing surprisingly well in this early phase of launch. As many of you know, that can be very challenging for infectious disease companies. But I can say that I can't think of a Better partner for the U.S. than Melinta. They have done a remarkable job. They are very experienced in the commercialization of long-acting antibacterials and they're providing that experience to rezafungin. We expect that to do even better as the NTAP and reimbursement codes become effective next month. So we look forward to providing updates on that in our quarterly earnings calls as royalty revenues start to come in for REZZAYO. So the focus of today's program is on the bottom part of this slide, which is our Cloudbreak program, and we'll now get into some more details on that. Well, let me start by giving an overview of what DFC is. Drug Fc conjugate is comprised of 2 fundamental elements: a proprietary Fc for which we can have various types of flavors and a targeting Moiety. Most of these are small molecules and as you can see from this image, there are multiple copies of that, and this is very important, and I'll highlight why that is in a moment. So it's important, just out the gate here to note that DFCs are fundamentally different. It should not be confused with ADCs or bispecific antibodies. You can see here that there is no -- the part of the molecule that engages with the target is not an antibody. It's a small molecule or a small peptide. Unlike ADCs, the purpose of a DFC is not to deliver a cytotoxin to kill the cancer cell rather it engages with cell surface receptors. And unlike bispecifics, the multiple targeting moieties are not antibodies. Just from this image, you can clearly see that DFCs are smaller than either ADCs or bispecifics. That is very important, and Les will show you some data to that effect later in today's program. So the 2 components are the Fc Moiety. These are proprietary to Cidara. There are multiple types, 2 examples of which are ones that have been focused on antivirals. Our lead program, CD388 or JNJ 0953 is a PK extended version of the Fc. And as I will show you in a moment, this has the potential as a once-per-flu season universal flu preventative. For oncology, we have other types. One example is the immune silent version in which the IgG1 has reduced immune effector function. So similarly, we have multiple types of targeting moieties. This is the part of the molecule that engages directly with cell surface receptors or other targets. On the top most of these, you can see most of these are small molecules and as depicted by the different colors. We can actually have multiple small molecules that hit different targets. In the case of CD388, we have a single small molecule that has been optimized to inhibit neuraminidase on the surface of the influenza virus. We do have small peptides that can be attached to the Fc. And an example there is our novel proprietary PD-1 peptide, which Les will describe later in the program. So 2 really important elements here to emphasize. Number one is potency. And that potency comes from -- is delivered in 2 ways. Number one, because DFCs do not enter the cell, we can optimize these small molecules for potency, irregardless of having to make them orally bioavailable. So imagine the universe of diversity in small molecules, much of that universe is inaccessible if you have to make these orally available. So we can optimize these molecules for exquisite potency. The second mechanism is by virtue of having multiple copies. So a single DFC can engage with multiple receptors on the surface of a single cell or can engage with multiple cells or viral particles. This helps explain the exquisite potency of these molecules. Helps explain why we don't have to make as much of it as compared to a small -- a monoclonal antibody and which translates to improved cost of goods. So the other important element here, obviously, is toxicity. Because these molecules do not enter cells, we do not have unexpected toxicities from targets inside the human cell. And what I'm showing you here is actually some real data depicting that. This is data from our chemokine receptor program where we have been able to optimize very potent inhibitors of CCR target. On the bottom right, you can see when we just take that small molecule targeting moiety by itself, and put it into a hERG inhibition assay at 10 millimolar. You can see that there's 77% inhibition. Conversely, if you then attach that small molecule in multiple copies to the DFC, and you can see and then do it in the same -- put it in the same assay. You can see it's actually the hERG inhibition is below the lower limit of detection in this assay. So it's direct evidence coming from our programs that the DFCs are safer than small molecules, and this opens the doors to a number of opportunities. So our lead program is CD388 or J&J-0953 has completed a Phase IIa study and several Phase I studies. And I'm pleased to announce that it has achieved the target product profile as shown in the table on the left. And that target product profile clearly shows that CD388 has the opportunity to be the first truly universal influenza preventative that can be administered once a flu season. That has been the objective since the preclinical development program. So now we'll get into the slides provided by our colleagues from Janssen. So we'll be referring to this as also as J&J-0953. So I think this audience is very aware of the need of an effective universal preventative. But when you think of the term universal, most of us think about, well, universal against all influenza strains, and that's certainly the case for J&J-0953. It is effective against every influenza strain A and B, whether seasonal or pandemic strain that we have tested it in. And you can see this will be a tremendous advantage when you look at the vaccine efficacy across time on the left. From year to year, it varies. However, by and large, it is certainly not optimal and especially in the immune compromise. And that's going to be the initial focus of this development program. Looking on the right, you can see that the vulnerable patient population that typically has a depleted immune system, that do not respond well to vaccines are really a target of the early development as we advance this program. So the objectives of the early development, meaning Phase I and Phase II are shown here. PK, can this be administered as a once or twice per flu season, subcutaneous or intramuscular injection. Two, obviously, if you're going into a broad population at some point in the development program, it clearly has to be safe. And finally, it has to be effective. So here are the 3 studies, and I'm going to provide just a high-level overview. Our colleagues at J&J intend to share more detailed results at the World Vaccine Conference in November. So the data that I'll highlight in the following few slides represent the results of 3 randomized studies. One is the first in-human study. Secondly, a Japan bridging study and then finally, a proof-of-concept study, a human challenge study. So I'm pleased to inform you that CD388 JNJ-0953 has been safe and well tolerated up to the maximum dose tested in these studies, which is 900 milligrams. The target dose is 150 milligrams which I'll show you in the next slide is the dose that we believe can provide efficacious exposure against all of these strains of influenza. You can see on the left is the number of patients in each of the 3 studies, the first in human, the Japan bridging study, the human challenge study. And you can see the number of subjects at each dose in each of those studies. Summary -- safety summary is on the right. And you can see that this drug has been very well tolerated up to the maximum dose. And in fact, I would argue that the safety summary can compete with that of most vaccines. So because this is going to be administered as a subcutaneous or intramuscular injection, it's really important that this is safe and well tolerated. So here is the PK coming from those studies. You can see 3 groups here, 3 groups of lines. They represent the dose of 50-milligram dose, 150-milligram dose and 150-milligram dose. The solid symbols are the intramuscular administration of JNJ0953 and the open symbols or the subcutaneous. Two things emerge here. Number one, you can see that those 2 are virtually superimposable. So this drug can be administered either intramuscular or by subcutaneous administration with the same exposure. The second thing that emerges here is that our target dose of 150 milligrams which is this middle pair of lines, maintains efficacious exposure above the target exposure of 1 microgram per ml. That target exposure was determined from mouse legal challenge studies and a variety of influenza strains in immune-compromised host. And so as you can see here, if you just extrapolate to the right, you can see that, that 150-milligram dose maintains efficacious exposure for 4 to 5 months, well beyond the target average 13-week influenza season. So we're very pleased with that outcome. Earlier this year, we shared the results, the interim results of our Phase IIa study. Based on those results, we actually discontinued enrollment right after that because it achieved the objective. The red box is the primary endpoint, which is confirmed influenza infection as determined by QT-PCR. The attack rate, which is the rate of infection placebo was lower than what was expected and is typical in these types of clinical studies, 50%, you typically want to see above 70%. And so because of the attack rate was lower than expected, it's more challenging to show separation nonetheless, you can see there's a substantial differential between the subjects receiving 0953 and the placebo subjects. Now with QT-PCR, you can get false positives. And so these are new data that we're sharing with you today. This is looking at viral culture data. So this is actually looking at the presence of live virus. And here, we see more separation and the results confirm what we saw in QT-PCR, both on the left, looking at viral data over time and on the right, looking at the peak viral load. So a clean separation between JNJ0953 and placebo in this clinical study. So in summary, the clinical program achieved all the objectives. It is active against all the tested influenza strains in nonclinical studies. It's clearly -- it has the potential of a once-a-flu season drug and it is very safe and well tolerated. So based on the strengths of those results, 2 weeks ago, J&J provided us with their election to proceed. What that means is they are formally taking responsibility for the program. That triggered a $7 million milestone payment as well as the potential for $685 million in future milestones with royalties on top of that. Now it was also recently disclosed that J&J is exiting the infectious disease space which means that they intend to license this program to another pharmaceutical company. And suffice to say, we're working very closely with our colleagues at J&J. We've had a great relationship with them. We look forward to continuing that relationship as we transition this program to another pharmaceutical company. And with that election to proceed, we can now add the economics coming from our CD388 program to those coming from our rezafungin program. So this could provide up to $1.8 billion in potential near-term, medium-term and long-term value to Cidara and our intention is to apply that value to the completion of our prophylaxis study of rezafungin but most of that value is going to be applied to our oncology programs. And today, we highlight 3 of those programs, the most advanced of which is our development candidate, CB0-421. The data you will see clearly shows that this has the potential to be a best-in-class CD73 inhibitor. You will see data, which shows that when combined with another PD-1 inhibitor, we get complete responders and CB0-421 as well as all of our other molecule shares with CD388, our influenza molecule, excellent safety and attractive cost of goods. So the first time today, we will be sharing some data both nonclinical and clinical data from our first combination DFC or multi-specific DFC. So this is a single molecule, which has both CD73 inhibitors as well as a proprietary PD-1 inhibitor. And then finally, we have made tremendous inroads in the chemokine receptor arena. We'll share with you some data on our CCR5 program. Those of you who are familiar with this set of targets know that very important targets in oncology, but also in autoimmune disease. And we look forward to sharing data from the autoimmune programs at a later date. But with that, let me hand over the presentation to Nicole. She will host the remainder of the program, which is focused on oncology. Nicole is the latest member of our senior executive team here at Cidara. She joins us from Genentech Roche, where she has been responsible for the advancement of a number of immuno-oncology programs, both into and through the clinic. So we're very pleased to have her join our executive team. So let me turn it over to Nicole. Nicole?

Thank you, Dr. Good morning, good afternoon. Yes, I am the newest member of the Cidara team and I joined in large part out of excitement for the platform that we're about to share with you today. In oncology, in terms of offering patients consistent and durable results with currently available immunotherapies, we have hit a roadblock. We prescribe immune checkpoint blockers for nearly half of our patients, yet the majority of them do not respond due to innate resistance or the upregulation of immune escape pathways in the TME or tumor microenvironment. Very few therapies address the TME directly. We have learned that single agent I/O is not enough and the future lies in combinations or more importantly, in multimodal agents that target interdependent pathways in the TME. It is also important for these targets to have low activity in off-target receptors and provide safe and durable responses. Furthermore, the types of molecules that we have available have significant limitations in addressing the unique challenges of immunomodulation. The next breakthrough class of oncology therapeutics will overcome these challenges by combining the best attributes of small molecules such as their size and ability to target small receptors, put the best attributes of monoclonal antibodies, such as their ability and long half-life. We believe that DFCs may be this next breakthrough class. [That] shared data on physical properties of GFCs that make them uniquely suited to oncology. In this next section, we will discuss our selection of targets, the rationale for those selections and the preclinical data that supports DFC's advancements over the limitations of currently available therapies. Each of our drug candidates target clinically validated pathways of tumor immune evasion. It's our most advanced candidate targets CD73, the key regulator of adenosine production in the tumor microenvironment, which acts as a potent suppressor of multiple immune cell lines. The second is a multispecific DFC that simultaneously targets CD73 and PD-1 pathways. In human colorectal carcinoma samples, CD73 expression was able to predict which patients would and would not respond to immuno [indiscernible] blockade. This suggested that these immune innovation pathways are interdependent and provided the rationale for creating a single molecule that would target the 2 pathways without the dual added size that might come with function -- dual function biologics. The third, CCR5 is a member of the chemokine receptor family, which is an independent pathway that facilitates tumor growth and immune evasion. Members of this drug class are approved as HIV therapies, but its use in oncology has been underutilized in part due to the limitations of the small molecule form. We believe CCR5 is a pivotal pathway to target because it makes tumors resistant to therapies in 3 important ways. First, it activates DNA repair tumor cells making tumors unresponsive to DNA altering chemotherapies. Second, it facilitates pro-tumorigenic immunity, making tumors unresponsive to immunotherapies. And third, it homes tumor cells to metastatic sites, quickly facilitating angiogenesis, vessel permeability and rapid growth of metastases before therapies have a chance to work. It's now my great pleasure to introduce Dr. Stephen Schoenberger, Professor at the Center for Immunotherapy at the La Jolla Institute for Immunology. He will speak to us today about the translational and clinical unmet need in cancer immunotherapy. Welcome, Stephen.

Thank you very much, Nicole, and to all of the people watching. I'm speaking to you from the NCI, probably appropriately on this topic. These are my affiliations and Nicole should give me 1 and then 5 clicks in a row. So these are the areas of my translational research. The reason that I'm showing you these is that in work that I've done in my research lab, we've discovered that cancers of every kind that we've looked at so far actually do have T-cell targets. They have neoantigens, and they can be susceptible to immune attack if we're able to change the tumor microenvironment and make it -- make it permissive for immunotherapy. And that's the message that I'm going to tell you about because I think that the DFC platform has a unique opportunity to achieve that. If you would click once more, Nicole. These are the clinical trials that I have done together with Dr. Cohen and others at the Moores Cancer Center. And all of these are predicated on the idea that there are neoantigens in cancer types that we didn't think had that because of their low tumor mutational burden. One more click, please. So this really speaks to the unmet needs and the strategic opportunities that Nicole touched on in her brief statements. Click once more. So basically, the tumor is not a willing participant in its own destruction by the immune system, and it brings different adapter resistance mechanisms to bear to the natural immune response and that which would be induced through vaccines or other immunotherapies. If you click once more. This is shown basically in the graphic and that there is a phenotype in most tumors of a cold tumor. And by cold, we mean there's a lack of inflammation, and it's poorly infiltrated and that this really -- the tumor achieves this through a number of mechanisms. If you click once more. And these are a few of the mechanisms not to get into the needs of molecular and cellular immunology, but these mechanisms can be targeted. And I believe that the DFC platform offers a unique approach to this because of what's been seen in the -- in its use in the antifungal and the influenza setting, this is really a proven platform that has the ability to achieve a long half-life and dwell time within the body. And the simplicity of small molecule targeting rather than the complexity of antibody or antibody drug conjugates is another advantage that has the potential to -- click once more -- to modify the TME and turn a cold tumor into a hot tumor by delivering adjuvants and adjuvants or small molecules or chemotherapeutics to exactly where they're needed. If you click once more. So what are the cancer types in the patient types that are -- that were failing to meet all of their needs? If you click once more, you'll see that there is incomplete -- there's compelling data, but incomplete objective response rates in melanoma, lung cancer, renal cell cancer, head and neck and a number of others. Where there's this clear signal that it is working for some patients, but not for all. And I think that modifying the TME is the way forward to increase the frequency of objective responses in these cancers. Click once more. There's also a number of cancers with sizable patient populations for which there is little or no signal of a new checkpoint blockade. And as I mentioned at the outset, we find that these patients do have T-cells that could be brought to bear in the fight against the mutations expressed by their cancer if the TME could be modified. Click once more. And this is really where I think the DFC platform is unique and differentiated from all others that I'm aware of. First of all, the evolutionary selective pressure to make the Fc protein is unquestionable -- unquestioned in its ability to function effectively and be a long-lived available protein within the immune system. I think that the DFC, I hate to use the metaphor, a Swiss Army knife, but it really is a Swiss Army knife and that you can attach whatever targeting moieties that one wants. If you click once, the others will talk about this more in data, but you can attach functional payloads of small molecules and targeting moieties to target specific costimulatory pathways or cell surface targets. So I see a very bright future with a rich target environment and a unique way to address these. You click once more, and this is a statement that I stand behind the -- because I truly believe this is that we will only be limited by the expertise of the medicinal chemists, which is superb at Cidara, and it's really a company that I'm very excited about, and I think they have a great product and a great future. Thank you very much.

Thank you, Stephen, for that wonderful perspective. I think that beautifully sets us up to talk in more detail about our different oncology programs. In our most advanced oncology program, CBO-421, we are advancing a development candidate towards IND, which targets the CD73 receptor expressed on tumor cells and infiltrating immune cells. The workhorse of the tumor cell is ATP. As the tumor cell proliferates, copious amounts of ATP are released into the tumor microenvironment. The TME then attempts to adapt to create homeostasis by converging the large amount of ATP into adenosine. CD73 is the rate limiting and final step in this process. As adenosine builds up, it has immediate and far-reaching deleterious effects on almost every immune effector cell in the TME. I think Stephen touched upon this nicely. Adenosine in particular, as you can see in the graphic, upregulate cells that create tolerance and diminish the immune response, such as empty macrophages, myeloid derived suppressor cells and regulatory T-cells. Most importantly, it directly suppresses the immune cells that destroyed tumor, including cytotoxic T-cells, natural killer cells and antigen-presenting cells. Currently, there are clinically available adenosine pathways molecules in Phase I and Phase II studies with promising results. And the natural question might be, why do we need another one? Ultimately, we believe that the utility and the combinability of these agents will be limited by their drug class, as they are all either small molecules or monoclonal antibodies. I'd now like to introduce Dr. Les Tari to share the exciting preclinical data that compels us to move this drug candidate forward in oncology.

Thank you, Nicole. Jeff, Stephen and you have nicely set the stage for this section of the presentation. Where over about the next half hour, I'll take you through some of the preclinical data on our CD73 program and oncology expansion programs that we'll be presenting data on here for the first time. Our goal in the CD73 program has been to generate a best-in-class CD73 inhibitor that combines the unique strengths of monoclonal antibodies and small molecule inhibitors. We feel that the emerging preclinical data on CBO-421, our lead, which -- some of which I'll describe here highlights that potential. So a functional assay that measures the ability of adenosine pathway inhibitors to restore the activity of T-cells that are suppressed by adenosine was used to compare CB0-421 to the most advanced clinical stage comparators in the CD73 space in the table on the top and against other adenosine pathway targets shown at the table on the bottom. The 2 cell -- immune cell types that we measured reactivation of are the CD4 helper T-cells and CD8 cytotoxic killer T-cells in the table. Lower EC50 values correspond to higher potency in this assay. Looking at the data, CBO-421 performed best in this assay, followed closely by the small molecule inhibitor, AB680. The lack of activity with oleclumab, highlights the difficulty in generating antibodies that block small molecule receptor sites. And if we look at the table on the bottom, the superior activity of CD73 inhibitors compared with inhibitors that block other adenosine pathway targets suggest that CD73 is a good target choice for adenosine pathway inhibitors if it inhibits a key step in that process. The activity that we saw in vitro assays like this translated well to activity in preclinical murine cancer models where CBO-421 monotherapy at relatively modest doses, 10 mg per kg, was able to reduce tumor volume in an MC38, a murine colorectal cancer cell line by about 65% compared to vehicle control. So to be therapeutically effective, an anticancer drug has to access its target inside the tumor. One limitation that is seen with many anticancer biologics, monoclonal antibodies is their limited capacity to permeate tumor tissues to get to those targets. Since CBO-421 is approximately 2.5x smaller than a monoclonal antibody, we expected that it should exhibit better tumor penetration than a monoclonal antibody that hits the same target. So using a tumor spheroid model, which is a laboratory generated mimic of a tumor where you aggregate tumor cells, in this case, they were MD Anderson breast cancer cells. We were able to establish, and you can see that qualitatively, these are confocal microscopy images of an equatorial slice of representative tumor spheroids where the labeled test articles, oleclumab and CBO-421. You can see how far into the tumor they permeate. And we could see that CB0-421 indeed does penetrate to a greater extent than oleclumab, which doesn't reach that central region of the tumor. So that's the qualitative picture that conveys the key message here. We quantitatively assessed the differences between the 2 agents. And we used -- in the middle, you're looking at a radial distribution plot that shows what the fluorescence intensity is as you go from -- in shelves from the outside to the center of the tumor. And then you take the centroid of those distributions and what we measure from that is a mean penetration distance and CB0-421, the take home is that it has a statistically significant improvement in tumor penetration compared to oleclumab. So the high potency of CBO-421 and its capacity to penetrate tumor tissue, we think likely contributes to the performance we're seeing in tumor efficacy models and highlight its potential for differentiation. So as Nicole described, clinical and preclinical data on CD73 PD-1 combination suggest that CD73 inhibitors can augment PD-1 activity and help to overcome resistance to PD-1, PD-L1 axis monotherapies. We evaluated CBO-421 combinations with a murine PD-1 inhibitor called RMP1-14 in an MC38 colorectal carcinoma model. The combination arm of this study where we combined CBO-421 with the anti-PD-1 antibody outperformed the monotherapies as measured in 2 ways. On the left table -- on the left, you can see that the combination arm generated the highest percentage of responders which are defined as animals where we saw cessation of tumor growth or reduction in tumor volume over the course of the experiment. And if you look on the right, if you measure it by average reduction in tumor volume, you can see that the combination arm had the best response in that regard. So our next test for CBO-421 was to see if we could generate durable tumor responses. To do that, we chose a murine memory tumor cell line, EMT6, that's more difficult to address with monotherapies like PD-1 inhibitors, and we ran out the study longer so that we could measure -- to see if animals -- if we could identify complete responders. And what we saw was that the monotherapies did not significantly impact survival. And we also measure tumor volume reduction, and we didn't see a significant reduction in tumor volume with the monotherapies. But in combination, PD-1 and CBO-421, we saw that 40% of the mice in that arm demonstrated complete responses, complete eradication of the tumor. And all of these responses were durable. The complete responders survived for the duration of this experiment, which in a month's lifetime was quite long. It was 100 days. And at day 62 what we did with the complete responders was we rechallenged them with the EMT6 tumor cells. And what we saw is that the complete responses persisted. That is to say all of the rechallenged animals demonstrated immunological memory and were immune to the tumor cells. So again, when we look at these studies in their totality, they highlight the potential clinical utility of CBO-421 combinations with PD-1 inhibitors.

Thank you, Les. The preclinical experiments that you talked us through really bring home the features of CBO-421 that make us excited to put it into clinical trials. First is the superior avidity of the receptor for the cytotoxic T-cell as demonstrated by the EC50 levels. This really increases the potential for efficacy in a clinical setting and also reduces the potential for off-target toxicity. Next, and perhaps most compelling, we saw the complete penetration of the tumor cell by the drug activity, Allowing potential for complete responses, which we, in fact, saw in combination and potential for preventing metastatic disease from a very early stage. Next, you showed us that in combination with PD-1 inhibitors, we saw immunologic memory formed and sustained complete responses. This has been a key limitation of the immune checkpoint monotherapies. I think also the preclinical experiments as a whole, highlight the potential of the DFC drug class. They have a reliable and consistent manufacturing process with low cost of goods. And the platform offers modularity where avidity, half-life can be altered to be fit for purpose in any given tumor space. I think we're very excited to move these features forward. And because of that, we've developed a robust clinical development plan for CBO-421. Here, you'll see that we are planning our first in-human safety, PK and dose escalation Phase I study in mid-2024. In this study, we plan to enroll patients with advanced solid tumors, which are more usually resistant to immunotherapy as monotherapy. These include late-stage non-small cell lung cancer, microsatellite stable colorectal cancer, gastric cancer and late-stage renal cell cancers. After dose escalation an optimal dose will be selected in line with FDA's project Optimus, guidelines, and this will be advanced in both monotherapy and combination cohorts with immunotherapies. An interim and efficacy analysis for both these cohorts will then inform the study design and population for our Phase II. I think what's very exciting about the DFC platform is that as we expand our roster of DFCs against new targets. Each new target has the potential to be combined with all the other ones to create novel combinations and multi-specific therapies. We're going to discuss 2 more oncology drug candidates with you. The first is our CD73 PD-1 multi-specific inhibitor. In Phase I clinical trials, CD73 targeting drugs enhance the activity of PD-1, PD-L1 access drugs, particularly in tumor areas historically resistant to checkpoint blockade. This, along with the preclinical combination study shown by Les really support the rationale for creating a single drug that can target both these pathways simultaneously. Second, we chose to target a new area of the TME that has been historically difficult to create drugs against, and this is the CCR5 pathway. A drug in this class, as you'll know, is currently FDA-approved for use in HIV, and it's been clinically validated as a feasible combination partner with PD-1 for colorectal cancer. However, as a small molecule, this class of drugs developed significant hepatotoxicity and cardiotoxicity at increased -- at increasing doses. And this actually halted the development of many drug candidates in the class. The CCR5 DFC candidate is fit for purpose for oncology. It's designed to minimize off-target binding. This will allow a wider therapeutic window to achieve the desired results in combination for human cancers. I'm now going to return to Les to tell us more about these 2 DFC candidates.

Thanks, Nicole. And as you stated already, our preclinical results with the CD73 PD-1 inhibitor combinations really compelled us to generate our first multi-specific targeting DFC against these 2 targets. So to do that, we developed a proprietary PD-1 inhibitor, as shown on the right, which is a genetic fusion of our Fc with a PD-1 inhibitor peptide, and then we conjugated that with our small molecule CD73 inhibitors from constructs like the one shown on the left. And the resulting multi-specific conjugate I should highlight is still considerably smaller than a monoclonal antibody. It's about -- still about 2/3 of the size of a monoclonal antibody. And you can see that when you compare the activities of the monotherapies in the functional assays of binding assays we use, which are shown underneath each of the constructs, with those in the multi-specific version, it retains the full activity of the monotherapy components. And we have an efficacy study that is actually still running now. And we've been excited, what I'm showing you here is an interim read on that. And we're -- we're very excited by this interim read because -- it is, again, in a murine colorectal carcinoma model using human PD-1, PD-L1 knock-in mice and an engineered tumor cell line that expresses human PD-L1. And this kind of model now allows us to test it against commercial PD-1 inhibitors. And in this case, one of the comparators is pembrolizumab. And the take-home message is that at 1/3 the dose of the monotherapy, so the combination -- the multi-specific molecule performance is shown on the far right, we're looking at a snapshot of tumor volume at 15 days post initiation of dosing that it reduced tumor growth by more than 60%. And importantly, it demonstrated a statistically significant improvement in activity compared with the pembrolizumab by a similar. So we would ask you to stay tuned for updates as we continue to flesh out the data package on this molecule and optimize it and advance our first multi-specific DFCs. So now I'll talk about our last expansion program today, the CCR5 program. So as Jeff has already described, and Nicole, CCR5s are a difficult class of target to drug. But has also been described, CCR5 is a validated target that can be a major driver in cancers that rely on the CCL5, CCR5 signaling pathway. Several classes of tumors secrete chemokine antagonists of CCR5 called CCL3 and CCL5 that in an autocrine fashion can promote tumor growth metastasis and chemoresistance. And simultaneously, they can recruit immunosuppressive macrophages and myeloid-derived suppressor cells to the tumor microenvironment. We have quickly been able to generate potent lead DFCs that are single-digit nano-molar antagonist of CCR5. And -- so this -- I'll describe another in vivo proof-of-concept study with this lead molecule on the next slide. So upregulation of CCR5 expression has been observed on several human tumor classes, breast and renal cell carcinoma as an example. And preclinically, CCR5 -- the CCR5/CCL5 axis has been implicated as a significant driver of immune evasion in tumors like the murine colorectal MC38 cell line. In the study shown on the left, the investigators made a genetic knockout of CCL5. So those tumors no longer were able to secrete CCR5. And what you see is that compared to wild-type mice, when they're implanted with these tumors, it has a profound effect on tumor growth. It basically shuts down tumor growth in the CCL5 knockout mice. On the right is our attempt to recapitulate this pharmacologically by dosing in our CCR5 DFC. And what we see is that it's able to accomplish a similar degree of tumor reduction as the genetic knockout. So this is an exciting early read on the potential effectiveness of a CCR5 DFC. And again, stay tuned for updates on this program and other programs as we advance assets in these different areas.

Thank you, Les. I'd now like to bring the discussion home by returning to our focus on patients. It's my great pleasure to introduce Dr. Ezra Cohen, Chief Medical Officer at Tempus and most recently, the Chief of the Division of Hematology and Oncology at UC San Diego, Moores Cancer Center. He will talk to us today about how DFCs can potentially transform care of patients in the clinic.

Great. Thanks, Nicole, and thanks to the Cidara team for allowing me to participate in this seminar. What I really want to do is now bring all of the data that you've seen back, as Nicole said, to the patients. And what we do realize is that there's tremendous potential for these targets in multiple cancer types as was demonstrated and alluded to in the prior presentations. What's really interesting is that GI cancers, especially and specifically have been interesting with respect to some of the targets that you've heard about CD73 and CCR5, for a couple of reasons. First, these cancers tend to be relatively refractory to immunotherapy approaches, at least in the sense of checkpoint inhibitors. And secondly, for I think many of us realizing on this call, this is a large group and a high tumor burden for cancer in not only in the United States but all over the world. Highlighting that is colorectal cancer, which is the third most common cancer and the second cause of cancer-related deaths worldwide. Despite some advances, certainly over the last couple of decades, the overall survival for patients with metastatic disease remains relatively poor with a median overall survival of about 30 months. Mortality interestingly has increased actually over the last several decades by about 0.5% to 3% annually. Now you add that up over a span of 50 years, and we have a major health issue in this country with respect to colorectal cancer. And as I said before, immunotherapy although effective for DNA repair deficient or microsatellite unstable tumors, for the great majority of patients with colorectal cancer, and that is about 90% to 95% who do not have these mismatch repair deficiencies, quite simply, immunotherapy has not worked. And that's illustrated in the survival curves or the kaplan-meier curves that you see on the right of the slide. showing overall survival in cohorts with colorectal cancer, those that have mismatch repair do relatively well. This was actually the original publication demonstrating the utility of PD-1 blockade in these patients, while those with mismatch repair proficient colorectal cancers really did not do well with these agents. So there's a great unmet need that remains particularly for these microsatellite stable or mismatch repair proficient tumors. Having said that, we've seen some data, at least attempts to try and change that outcome in MSS metastatic colorectal cancer with, I would say, unfortunately, very little success. Here, you see a table of some of those attempts combining immunotherapies such as nivolumab and a ipilimumab in the CheckMate 142 trial, yielded a progression-free survival of 1.4 months. Really signaling a lack of effectiveness of this combination. The cancer trial group CO26 study that undertook a similar approach, also an anti-checkpoint inhibitor this time in anti-PD-L1 with anti-CTLA-4, progression-free survival of 1.8 months. IMblaze 370 used atezolizumab combining with small molecule inhibitors a MEK inhibitor cobimetinib and a VEGF receptor inhibitor, Regorafenib, showing a median overall survival of 7.1 months with anti-PD-L1, which numerically was higher in the combinations, but not statistically significant. Most recently, we saw data for Leap-017 that combined pembrolizumab with lenvatinib. Of course, we have a lot of hope for these combinations because they did demonstrate efficacy in other tumors, but unfortunately, not in MSS colorectal cancer. No statistically significant improvement in overall survival. And then most recently, nivolumab and regorafenib with, unfortunately, an objective response rate of only 7%. There are other trials in progress. One such example is a LAG-3 inhibitor from BMS combined with nivolumab, their anti-PD-1 and where we have yet to see data there. However, when we look at certain aspects of colorectal cancer, including the propensity for liver metastases, we realize that their -- these cancers really are adept at immune escape. Especially when the malignancy travels to the liver and we see hepatic metastases. The curve at the bottom of this slide is meant to illustrate that this is overall survival in patients with MSS colorectal cancer with or without liver metastases treated on one of these studies, and you can clearly see that patients with liver metastases fair worse and likely because this is a relatively immune escape site. Now having said that, you've seen data presented in the last 40 minutes. So illustrating how we might be able to overcome this specifically with this technology developed by Cidara, the DFCs, they really do offer an opportunity to uniquely target the tumor micro environment, not only based on the modality of targeting, but also the targets that are being employed. CD73, for instance, the targets, both soluble and membrane-bound CD73. That's what the DFC is able to do. And we believe that high levels of soluble CD73 in patients with specifically liver metastases is quite important to survival. You saw the preclinical models demonstrating enhanced tumor penetration compared to monoclonal antibodies, which, of course, may be incredibly important to not only develop -- not only deliver response rates, and especially complete responses, but durable responses as well. We -- or the Cidara team did a very nice job demonstrating the preclinical models using -- demonstrating immunologic memory, which again, may reflect durability of response once we go into people. And then with respect to CCR5 DFC, the preclinical model really does demonstrate a similar degree of tumor reduction. And of course, some added futility in combination with anti-PD-1. This is the first CCR5-targeted molecule specifically designed for oncology. The DFC platform allows for multi-targeted mechanisms of action. You saw some of the combinations that are being developed, especially with PD-1. And then promising non-GLP animal safety illustrating that these agents are likely to be well tolerated when the human clinical trials begin. So really the combination of potent efficacy in a tumor model that has been right now fairly refractory to immunotherapy that is MSS colorectal cancer and the added benefit of the likelihood of a very favorable toxicity profile certainly makes us quite excited as these agents go into the clinic and this technology begins to be used in human clinical trials. So with that in mind, I'll turn it back over to you, Nicole. Thank you for the opportunity to present and happy to stay around for Q&A.

Thank you, Ezra. That was phenomenal. And I'll hand over to Jeff now.

Great. Well, thank you all. Our speakers did a great job in describing our new programs and special thanks to both Stephen and Ezra for their perspective. I'd like to now open up the floor to Q&A. And Tara, I understand that you'll -- you have a few questions that are prepared for us.

Yes. Thanks, Jeff. So at this time, we'll be conducting our Q&A session. [Operator Instructions] So our first question comes from Louise Chen from Cantor Fitzgerald.

Thank you for the great presentation. It was very helpful. I wanted to ask you a few questions. First is, how does your flu technology compare to mRNA? Can you compare and contrast what we've seen in the data? And then what additional data will you be presenting or will we see at the World Vaccine conference? And then lastly, just when do you think we'll see an update on the new partner for CD388?

So yes, the first question was regarding our -- could you repeat the first part of your question, Louise?

Yes. I wanted to ask you, how does your technology compare and contrast to MRV?

Yes, yes. Got it. Yes, I'm glad you brought that up. As we've seen in the last month, there have been 2 notable Phase II disappointments for flu preventatives, one in monoclonal antibody and the other mRNA vaccine. I think with respect to any vaccine, it's going to be challenging if the patient cannot mount an appropriate immune response. That is irregardless of whether it's a regular vaccine or an mRNA vaccine. There's simply going to be a large fraction of the population that does not respond well. And so this is a particular strength of the CD388 program. Does not require an immune response to be effective. It's a long-acting well-tolerated drug. And the second part of your question?

What data do you expect to present at the World Vaccine conference?

Yes. So now that Janssen has taken over the program, that will be up to them. The intent is to disclose more detailed information from both the Phase I programs as well as the Phase IIa human challenge study. And then the last part of your question again?

Yes. Any thoughts on when you might announce or when Janssen will announce a new partner for CD388? Is it within this year or more likely probably next year?

No specific timing. As you're aware, each -- any business development transaction has a life of its own. We're pleased with the level of interest we've seen so far. We look forward to providing an update when a partner has been selected. Tara, anything else?

Yes. So our next question is going to come from Thomas Yip from H.C. Wainright. Please go ahead, Thomas.

So perhaps first question for our oncology experts today. We can see how the PSC platform can send a [indiscernible] versatile component [indiscernible]. Where the do you see DFC therapies [indiscernible] DFC therapies as they've been reserved behind first [indiscernible] as soon as possible [indiscernible]?

Thomas, your audio is breaking up, so I couldn't understand the question. I don't know if any of our speakers had better reception. Could you repeat that?