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

Good morning, 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. Before we begin, please make note of the forward-looking statement slide. I'd now like to turn the call over to Dr. Jeff Stein, President and Chief Executive Officer of Cidara Therapeutics. Please go ahead, Jeff.

Well, thank you, Tara, and welcome to our R&D Day. It's been about a year since our last R&D Day. And at that event, we focused on the rezafungin program. This year, we're going to turn to our Cloudbreak program, and we look forward to sharing some interesting new data on that program. So those of you who are familiar with the company know us as a 2-platform company, rezafungin, where we focused last year's event on. Subsequent to last year's event, we reported positive Phase III data on the ReSTORE study. This is in the treatment of candidemia and invasive candidiasis. That study met all of the primary and secondary outcomes for the FDA and the EMA. And we look forward to filing the NDA shortly. We provided guidance on the NDA filing timing as mid-2022. It has not escaped our attention that we are, in fact, in mid-2022. And that should give you a clue about the -- when we will be announcing the filing of that NDA. We are still enrolling in the ReSPECT study, and we look forward to keeping you all updated as that program advances as well. The focus of today's event is on the bottom part of this slide, this is on the Cloudbreak program. We have a number of programs that are ongoing in Cloudbreak. The ones that we will focus on today are shown here, the CD388 program, which is partnered with Janssen that is in Phase I clinical studies and unless we'll provide a brief update on that program, and how that program actually came to be and the approach that we use to advance it into the clinic with Janssen. We will focus also on the SARS program and importantly, and the main focus of today's event on our oncology program. The reason we focused on these 2 for today's event is not only their state of advancement, but also they provide an opportunity to really highlight a strong point of the Cloudbreak DFC program, and that's the opportunity to make combination therapies with SARS, we'll speak briefly about the opportunity to create a universal SARS and flu molecule. And in oncology, we will talk about the opportunities to create combination molecules in the immune checkpoint pathway. So one area that Cidara has been particularly adept at is in the execution, the timely execution of partnerships. In 2019, we announced the partnership with Mundipharma, where we license rights outside of the U.S. and Japan based on the strength of the Phase II data. And just last year, based on the strength of the preclinical data on our influenza program, we highlighted -- we signed the deal with Janssen Pharmaceuticals. Both of these provide a stream of near-term and long-term potential revenues in the form of upfront payments as well as ongoing milestone payments. Now make note of the fact that with respect to rezafungin, we still hold rights to the U.S. and Japan. And an important update on rezafungin is our intent to partner those 2 territories. So we're taking the opportunity today to provide you an update on rezafungin that Cidara does not intend to fund the commercial launch of rezafungin. In fact, with respect to U.S. and Japan, we plan to out-license the U.S. rights and then subsequently Japan rights. So that provides us an opportunity to focus on our Cloudbreak program, and this will be the main elements of today's event. So with us today to discuss the opportunity in oncology are 2 preeminent oncology physicians, Ezra Cohen, UCSD and Perry Nisen of Quanta Therapeutics. They are also the 2 newest members of our Scientific Advisory Board. Joining them in the first part of the program is Cidara's Chief Scientific Officer, Les Tari, who is also the primary inventor of the Cloudbreak DFC program. So we'll start off with Les providing the scientific overview of the Cloudbreak DFC program. What are these molecules and importantly, what they are not. And then to discuss our perspective on what the advantages of the DFC molecules offer over more conventional therapies. We'll then turn to our oncology program. We'll share some of the data that we have, and then we will have a discussion with Perry Nisen and Ezra Cohen. So with that, let me turn it over to Les, and he'll give you an overview of the program. Les?

Thanks, Jeff. As you can see from this image, our DFC or drug-Fc conjugates platform is a new and another unconventional modality. We have it protected by both allowed and pending patent applications. DFCs are built from 2 main elements: the proprietary Fc domain, which acts as the carrier, and small molecules or peptides conjugated to it that are directed at different therapeutic targets. There are different flavors of the Fc domain that we've tailored for specific applications. We have a PK extended version with immune effector function that we're using for our long-acting antivirals and immune silent versions that are tailored for oncology applications. Next. The cargo we attach to FCs are called targeting moieties, or TMs. For enzyme and small molecule receptor targets, we use small molecules as TMs. With the small molecule conjugates, we can control how many small molecules we attach to enhance potency, and we can also generate DFCs with different small molecules conjugated to DFC to make drug cocktails on a single carrier. For targets where the DFCs need to disrupt protein-protein interactions, small molecules perform poorly, and we use peptidic TMs. The flexibility to use both types of TMs expands the universe of targets that we can inhibit with DFCs. Next. In our current programs, we're using both approaches against validated targets, with small molecule TMs for influenza and oncology, and peptide fusions in our SARS programs. We're also evaluating DFCs that combine both to generate drugs against multiple viruses as you'll see. Next. DFCs possess several potential advantages over small molecule and antibody therapeutics that will be highlighted in this next section. It will also be important to touch on what they can and can't do. But before doing that, let's delve in a bit to what differentiates our approach from antibody drug conjugates, or ADCs, which our platform often gets confused for. ADCs are used mostly in oncology where they're designed to do fundamentally different things than the DFCs. They target epitopes that are overexpressed on cancer cells. Next. Binding to those antigens causes them to be internalized by those cells. Once inside, the ADCs utilize special linkers that are sensitive to intracellular proteases, which get cleaved to release cytotoxic payloads that destroy the cancer cell. Next. DFCs don't enter cells and they don't carry or release toxic payloads. The small molecules conjugated to DFCs are designed to selectively inhibit or functionally disrupt extracellular targets that are important for disease progression. Next. For example, in our most advanced oncology program, we have DFCs that inhibit a target that's frequently overexpressed on the surface of tumor cells called CD73. CD73 generates adenosine, which shields the tumor from clearance by the host immune system. Next. DFCs are much smaller than ADCs and they can be elaborated with multiple types of targeting moieties as was already highlighted. Next. As combinations of small molecules with a biologic carrier, DFCs have the same limitations that other biologic therapies do. They're not orally bioavailable and they only act on targets on the outside of the cell. That second point is important, because it limits the range of targets DFCs can be used against, but those limitations aside, for the targets DFCs can be applied to, they combine the strengths of small molecule therapeutics and monoclonal antibodies, but they also possess potential advantages over both of those modalities. Next. We've generated data in our clinical stage, influenza and preclinical oncology programs that highlight the potential advantages of DFCs over small molecule therapeutics. Multivalent TM presentation can be used to amplify the binding affinity to the drug targets, and we have much more freedom in how we're able to optimize those TMs to achieve that potency, since we aren't limited by the same constraints that small molecule drugs are. And the limitation that I flagged up earlier, that DFCs don't enter cells, has the benefit of minimizing potential for off-target binding by reducing toxicity and drug-drug interaction liabilities. In 1 of the oncology programs we're pursuing, there are known safety liabilities with small molecule therapeutics that have hampered development that DFCs could help to address. Next. Some of the advantages that DFCs have over small molecules also apply to antibodies. We can load up that Fc with multiple copies of the TM to enhance potency. But doing that doesn't significantly increase the size of the DFC, it's still much smaller than a monoclonal antibody, so it can distribute more quickly and more deeply into tissues in solid tumors. Perhaps the most important feature differentiating DFCs from antibodies is that they allow for a relatively straightforward installation of different targeting moieties or different targeting groups. As you can imagine, the ability to turn DFCs into drug cocktails opens the door to creating potentially highly differentiated assets in multiple therapeutic areas. Next. Let's turn our attention to the clinical stage program that we partnered with Janssen Pharmaceuticals for influenza -- universal influenza prevention, which was the program that really has validated this platform. Next. What inspired us to go down the DFC path was the unmet need that we saw in influenza prevention. Despite considerable efforts for a long time now, robust universal prevention options don't exist. Influenza virus presents a unique challenge. There is only 1 small region on that virus, the neuraminidase active site pocket, that's fully conserved across all influenza strains, and the only way to engage that site with precision is using small molecules It is impossible to access that pocket in the same manner with monoclonal antibodies, including those derived through vaccination. We saw DFCs as a perfect approach to address that problem. Next. Once we built the requisite infrastructure, we were quickly able to advance potent long-acting influenza DFCs. The potency enhancements gained by making neuraminidase inhibitor conjugates with DFCs compared to small molecule inhibitors against the same target, we're frankly, better than we'd hoped, and our development candidate, CD388 even inhibits neuraminidase inhibitor resistant strains. More details and data on our program are posted on our website at the link below. The strength of our preclinical data captured the interest of Janssen Pharmaceuticals, and that partnership has allowed us to quickly advance CD388 into the clinic. We're all excited by the potential to advance the first agent to the market that could provide single-dose universal seasonal flu prevention. CD388 is in Phase I testing now. It has shown encouraging pharmacokinetic trends in Phase I, and we and our partner, Janssen, look forward to sharing the full details as soon as they become available. And more information on the clinical trial can be found at the link at the bottom. Next. Based on our success with influenza, we started the DFC program, which was a pilot program to see how we could do to address -- against addressing SARS too. We are, of course, aware of the fact that this is a challenging and competitive area, but also that there remains an acute unmet need for new therapeutic options. We've all seen how hard it is for therapeutics and vaccines to keep pace with the virus that mutates so rapidly. 18 of the 19 FDA-authorized antibodies for SARS2 treatment have already been rendered obsolete with only 1 that still covers all of the current Omicron sub-lineages. So we adopted the same approach in this program that we did in our influenza program, to target the virus where it has the least optionality to mutate. The program has rapidly advanced, and we have compelling proof-of-concept data in hand that highlight the potential of our DFC approach to have an impact in this area. Next. The site we focused our efforts on is the ACE2 receptor binding site of the viral spike. It, of course, plays a pivotal role in virus host cell fusion and is hence highly conserved. The difference between this program and the influenza program is that we aren't inhibiting an enzyme, we're disrupting a protein-protein interaction. That took small molecule options off the table, so we pivoted to using peptide fusions. We have DFC leads now that are optimized for in-vivo stability, and we're engineering them to improve suitability for inhaled dosing. And perhaps most importantly, we're engineering our peptide fusion DFCs to be compatible with small molecule conjugation to allow us to transform these molecules into multi-virus targeting cocktails. Next. Here, we're looking at a blowup of the ACE2 receptor binding sites on the spike of the Delta variant. This is from a crystal structure with the ACE2 receptor. It highlights the saddle shaped site where our DFC binds. And there are 2 features of that pocket to highlight. First is that 1 we jumped from the earlier variants exemplified by Delta here to the Omicron variants and sub-lineages, there's a constellation of 9 mutations that the DFC needs to accommodate, to expand coverage to the new Omicron variants. Our DFCs do that, as you'll see. When we -- and when we enter the realm of the variance that we have to worry about now, the Omicron sub-lineages, the group spanning BA.1 through the latest BA.5 sub-lineage are fully conserved with BA.1 as the only outlier with a single point mutation that's shown here in orange. That makes our prospects for covering the Omicron sub-lineages with a single molecule excellence. So taken together, particularly when considering the conservation across the Omicron sub variants, the data on the next slides support the notion that our -- our SARS DFCs have the potential to provide durable coverage against all SARS2 variants. Next. This next series shows spike binding data against the early variants and the newer Omicron sub-variants represented by BA.1 and BA.2. Our DFC engages the spike domain with exceptional potency. It's binding with 130 to 150 picomolar IC50s across the board. A control antibody isolated from an infected SARS patient against an early variant shown here in brown, performs well against those early variants. Next. However, against the Omicron variants, it drops significant binding activity, particularly versus BA.1, shown here where it loses fortyfold. Next. It is also less potent against BA.1. Testing against spikes from the newest circulating versions -- variants, I should say, rather, particularly BA.4 and BA.5 will be conducted as those reagents become available for testing. And again, given that there is almost complete conservation between all the Omicron sub-lineages in the binding site that we're engaging, we expect that our leads will bind those with similar potency to BA.1 and BA.2. Next. The potent spike binding data has translated to efficacy in Syrian hamster efficacy models. Our DFC demonstrates a robust statistically significant reduction in viral lung burden against the Omicron BA.1 strain that I showed you on the last slide with a single inhaled prophylactic dose. This was a proof-of-concept study to gauge whether we are on the right track, and based on this data, we think we are. A series of follow-up studies are planned in the near term with optimized molecules where we'll evaluate efficacy and PK with inhaled and parenteral dosing to choose the dosing route that we'll select in the clinic. Our optimization efforts are progressing fast. We're planning on driving this program to a development candidate by the end of this year. Next. The unique attributes of DFCs have opened the door to an exciting avenue that we're now exploring. We're in the process of building and testing dual-acting DFCs that combine influenza and SARS targeting groups that have the potential to prevent and treat the 2 major respiratory viruses. We'll provide a more fulsome update on our SARS program in a future presentation, so please stay tuned. I hope that these examples highlight the strengths of the DFC approach. So now I'll pass back to Jeff, so we can turn our attention to how we're applying this platform to attacking cancer and hearing from our panel.

Well, thanks, Les. And I hope we've conveyed the sense of momentum in this program. And as we see the opportunities unfold to create single molecules that have enhanced potency, because of just the nature of how these molecules are built, and -- but especially this opportunity to create multimodal mechanisms of actions or single molecule drug cocktails. And it occurred to us that this last feature should be particularly useful in cancer, where the application of drug cocktails are quite common. And the particular area is in the immune checkpoint pathway. This is where we elected to focus initially. This is a well-known pathway. In particular, you're probably aware of the PD-1, PD-L1 access, where there's some well-known commercially available drugs such as Merck's KEYTRUDA. So these drugs have been shown to be quite effective in augmenting chemotherapy, where many solid tumors, in particular, are refractory to chemotherapy. And they've proven to be quite effective in that combination. However, as monotherapies, as you can see at the top of this slide, they've been shown to be less effective. So we asked ourselves the question, is there an opportunity for a DFC approach, and in particular, in the adenosine pathway. Can we interrupt CD73 to produce adenosine or the A2AR receptor on the T cell to recognize adenosine? And so this is the area of focus, but before we get into the results of that program, let me pause and then just get the perspective of Perry Nisen and Ezra Cohen. And so we'll turn it over to them and maybe we'll start with Perry. Perry, what are your thoughts on the greatest unmet needs in the immune checkpoint pathway?

Well, let me say there are many -- did -- do you want me to introduce myself or not.

Yes, yes, please do.

Yes. So just to say on a physician scientist with a long career with 1 foot in the laboratory and the other in the clinic. I was a Professor University of Texas Southwestern Medical Center led, inaugural Head of Abbott Oncology many years ago, started the Venetoclax program more than 1/4 of a century ago. My God. Moved on to GlaxoSmithKline where I also headed oncology R&D there. I was the Chief Medical Officer of the company for a period and other roles, the portfolio under my watch was sold to Novartis for many billions of dollars. I was the CEO of Sanford Burnham Prebys here in [indiscernible] which has an NCI-designated cancer center. I've been an executive partner with Sofinnova investments in private equity, which led me to come in as a Chair -- Executive Chair of 1 of the companies call Quanta and then chose to step in as its CEO. I've been on the Board of Directors of Teva Pharmaceuticals for many years, chairing its Science and Technology committee for the Board and chaired for several years, several scientific advisory Boards of MD Anderson Cancer Center. So a long career, every imaginable scar of drug discovery and development and still very good to talk about it. I'm delighted to talk to you a little bit about my perspective regarding unmet needs in this very, very busy space. I probably don't need to tell this audience that it is incredibly crowded. There are 7 approved PD-1, PD-L1 inhibitors, at least 20 new approaches in clinical development, probably north of 1,000 clinical trials of monotherapies and combinations. Notwithstanding all of that, the current therapies, KEYTRUDA and other great drugs, very successful commercial drugs, but they're at best 20-ish percent effective in patients. There are about 19 or so indications, but don't forget there are hundreds of other cancer indications histologically and otherwise. So where there's still -- there are no approved therapies for those -- patients with those indications, lines of therapy. There's some nascent activity around sort of science-driven histology, non-histology or histology agnostic indications like microcell instability, mismatched PD-1 expression, but a lot of other ways 1 could go there, addressing the tumor microenvironment, the cold tumors or don't seem to be particularly amenable to this kind of therapy. Toxicity is nontrivial of which we could talk about later. There are resistance issues, durability issues. So I'd have to say there's an abundance of opportunities in unmet need, notwithstanding the magnitude of efforts underway to seek new approaches that are more effective, broader efficacy, a better safety profile, enhanced combinability and myriad opportunities, I believe, are out there.

Great. Thanks, Perry. Ezra, so, let's turn to you, perhaps you can give a little bit about your background, and you're very active in the clinic in particular, in the area of solid tumors. Would love to hear your perspective.

Yes. Thanks, Jeff. And I certainly would agree with Perry. And we've had an opportunity to work together in the past here in San Diego. As mentioned, I am at the University of California, San Diego, where I served as a Co-Director of the Solid Tumor Therapeutics Program, the Cancer Center as well as the Associate Director for Clinical Science, and the Division Chief for Hematology Oncology. I've been doing early-phase drug development for a couple of decades now and for the last several years have focused on early phase immunotherapy. My anatomic area of interest is head and neck, but I would say about half of the patients that I see now are heterogeneous tumors from -- with patients looking for early phase immunotherapy studies through our precision immunotherapy clinic. So thanks for the opportunity to join this session and comment. As I said, I would agree completely with Perry. I think there are many unmet needs. We've clearly broken a barrier in cancer with respect to immunotherapy, 1 that we have been trying to break for a century. And PD-1, PD-L1 antibodies were the answer, but they are by no means the complete answer. Perry highlighted the opportunities to improve efficacy in tumors that are currently responsive to anti-PD-1 or PD-L1 and that those response rates are, I would say, still modest, and we're certainly not curing everybody with advanced cancer. In fact, the majority of patients are continuing to die due to the disease. And then there are malignancies in large populations that are relatively unresponsive to anti-PD-1 and PD-L1. I would highlight microsatellite stable colorectal cancer, hormone-positive breast cancer, prostate cancer -- castrate-resistant prostate cancer. Those 3 combined make up a significant portion of the cancer population that we see, probably upwards of 50%. So there are clearly inroads that still have to be made. And it's not that those cancers don't form an immune response. It's that they are unresponsive to anti-PD-1 and PD-L1. And in fact, for some of those cancers that I mentioned, this pathway of CD73 and adenosine receptor targeting may be quite applicable. So there are lots of opportunities to improve on current efficacy. And as Perry mentioned, there are many, many cancers that are still -- we have a long way to go in terms of improving immunotherapy, even though PD-1 or anti-PD-1 targeting has worked well. And of course, non-small cell lung cancer falls into that category, head and neck cancer, bladder cancer, multiple others triple-negative breast. So thanks, Jeff. I hope I've answered your question.

You did. One follow-up question for you, Ezra, is do you see tolerability or patient management issues representing a developmental or commercial challenge in this area?

Yes. Without a doubt, we recognize that we're trying to stimulate the immune system. But with anti-PD-1 and PD-L1 and in fact, many of the agents that are being developed, that stimulation is nonspecific, that is not specific to the cancer only. And patients do get into issues with toxicity, that can be dose limiting. Ironically, the patients who seem to benefit the most are most at risk for developing those toxicities, especially as they continue therapy for longer periods of time. And so as we begin to think about IO or immunotherapy combinations, we do have to be mindful that some of these are going to increase toxicity. As an example, the combination of anti-PD-1 and anti-CTLA-4, just about doubles or actually close to triples serious adverse events compared to anti-PD-1 alone. Now we've learned to manage those, but that management has to be quite active. And certainly, the idea of adding an agent or a mechanism that delivers efficacy without added toxicity would be definitely welcome.

Great. Well, thanks Ezra. So let's turn back to the area of focus that Cidara is working in right now. Conveniently, Ezra you mentioned, colorectal cancer, we will now show you some results in some colorectal cancer models with our CD73 program. And I think you'll see, it shows great promise either as a monotherapy, in combination with the PD-1, PD-L1 inhibitors or in combination with A2AR. So let me turn it back over to Les and he can walk our audience through the data. Les?

Thanks, Jeff and panel. Since it's now so well established that adenosine plays a prominent role in immune escape and tumor progression and the key targets in the pathway can be inhibited by small molecules, we saw a compelling opportunity to generate differentiated assets with DFCs that hit the adenosine pathway in 2 spots. Next. The CD73 that generates the adenosine cloud that surrounds the tumors. Next. The A2AR receptor on T cells and other immune cells that mediate adenosine signaling. Today, you'll see data on our most advanced program against CD73. Our A2AR program is close behind, and we'll be sharing more details on that program in a future presentation. Next. Data from the next 2 experiments highlight efficacy with lead molecules in a mouse syngeneic models against a murine colon cancer cell line called CD26. As a positive control, we used AB680, a small molecule CD73 inhibitor developed by Arcus, which is in clinical trials against various solid cancers now and we dosed at using a regimen described in a similar model from the peer-reviewed literature. As you can see that positive control AB680 trended towards a small reduction in mean tumor volume. Next. But when we look at our DFC, it demonstrated a more robust mean tumor volume reduction of about 50%. Next. And it did so despite the fact that our DFC was dosed at half the frequency and at 2/3 of the dose. But that's not the whole story. Next. On a molar basis, the relative amount being dosed is much lower. If you look at the comparative dosing histograms on the bottom right, you can barely see the amount of DFCs getting dosed relative to the positive control. It corresponds to about 150th of the dose at each dosing interval. And I think this data corroborates what we saw in our influenza program, where the multivalent presentation of molecules with the DFCs can really help them outperform small molecule therapies. Next. To test the hypothesis that the adenosine pathway inhibitors could augment PD-1 and PD-L1 therapy, we conducted an experiment where we evaluated a combination therapy of our DFC with an established murine PD-1 binding antibody, which we used as a control. And we did that versus the same cancer cell line used in the prior study. To provide context for the extent of tumor growth in syngeneic models like this, typical tumor sizes at the initiation of treatment and at the primary endpoint of the experiment at day 21 are shown. Next. And the contrast is quite stark. The tumors grow rapidly in the untreated mice with many tumors growing to more than 10% of the body weight of the animals by the endpoint of the experiment. Next. As we look across the groups, the PD-1 antibody treated group shows a modest average reduction in tumor volumes versus vehicle. Next. It gets better with our DFC where we're seeing again about a 50% mean average reduction in tumor volume, similar to the performance of the molecule in the last study. Next. The most interesting result is the combined study arm where the average tumor reduction improved further yet. And for the first time, we're seeing cessation of tumor growth in 1 of the animals, and we saw a full remission in 1 of the animals that's shown on the right. This study, again, demonstrates the robust in-vivo activity of our CD73 DFCs and it highlights the potential benefits of combining therapies that inhibit these 2 nonoverlapping immune checkpoint pathways. We're following up now with additional combination studies, efficacy studies using other cancer cell lines, and we're doing some more detailed PK/PD analysis to really nail down dosing. There's more to come soon. So please stay tuned. And I'll pass back to Jeff.

Well, great. Thanks, Les. Well, I hope you share our sense of enthusiasm and momentum with this program. What we're seeing here is similar trends that we saw in our influenza and now in our SARS program. Turning to oncology, what we are offering here is a fundamentally new approach, both as a single agent and the potential to make single molecule cocktails. This is our pipeline, and you can see where we are forecasted to be by the end of this year. We hope to initiate IND-enabling studies with our single molecule CD73 program. And then you can see where we will be advancing our combination therapies with the earlier stage program being the PD-1, PD-L1 program. So just to wrap this up. Obviously, this is an enormous area in immuno-oncology, as Perry indicated. So how could Cidara be effective in this area? One response is just our focus, in an area where there is relatively limited competition. All current programs that we are aware of are in Phase I/II clinical trials, for a fewer programs than in other areas in immuno-oncology. And as we've shown with these early data, we believe that this new approach can really make a difference either as single agents or in combination with other agents and perhaps the most exciting opportunity in our view is the opportunity to create the single molecule cocktails. So with that basis, let's turn back to Perry and Ezra. And Ezra, we -- let me start with you this time and then we'll turn to Perry. I think collectively, the 2 of you have probably saved the lives of tens of thousands of mice in your long careers. Seeing the data that we have shown, albeit early stage data, what are your thoughts, Ezra, on kind of the appetite for oncologists to have drugs that will effectively target the adenosine pathway.

Jeff, certainly compelling data, the tumor model that you selected is relatively resistant to anti-PD-1 as you showed in your experiments. And truly, that's what we see in humans is that many patients -- most patients don't respond to anti-PD-1 or PD-L1. And of course, those that do rarely have a complete response. So there's -- as we discussed earlier, room for improvement in this area. And it does -- your experiments do demonstrate that not only does CD73 or CD73 adenosine receptor 2 targeting have activity on its own, which it should, but that the 2 together, not only combine well with respect to toxicity in the mice, but more importantly, with respect to efficacy. And the fact that you are seeing some of the mice with no evidence of tumors, that is presumably the tumor has been eliminated is quite encouraging. So I think this is a great demonstration of -- in a preclinical model, that would be relevant to going to the clinic. Again, I think this is a target that is ubiquitous. It will take advantage of tumor sites that have been relatively resistant to anti-PD-1 and PD-L1. And there really is a tremendous opportunity for agents like this. Part of the challenge will be focusing on specific tumor types and making those calls to hopefully see an early efficacy signal, but that's -- in a sense, it's a good challenge, because you have a lot of opportunities. So that's good.

Well, that's great. Thank you, Ezra. Perry, in our last conversation, Ezra commented on drug toxicities being a limitation. Would love to hear what your thoughts are and in particular, with respect to A2AR and if could a DFC approach make a difference on that front?

Yes. Happy to do that. So I echo everything that Ezra just said. I think what's been -- we have seen in terms of trying to seek combinations or dual therapies, the efforts thus far to combine 2 kind of checkpoint inhibitors as Ezra exactly said, have been associated with very significant toxicity witnessed the challenge of CTLA-4 and PD-1 and PD-L1. And efforts with other checkpoint inhibitors that people have been trying like [indiscernible] from the others, they don't really work very well and it brings a lot of added toxicity. What seemed particularly interesting, at least to me, is the ability here to combine checkpoint PD-1, PD-L1 with another -- an agent that wants another local inhibitory mechanism specifically, this adenosine pathway, which by itself, people have been playing with them, frankly, including me quite a while ago, but it's not enough. So I think that ability to combine with a pathway that's different provides the opportunity, a, for improved efficacy and also, to your point, more importantly, I think the potential for greater therapeutic window and safety that is really encumbered many, many of those dual therapies. So that's what I find particularly attractive about this 1 approach. As you've been saying, I think it was a very clever choice of target. There's been a lot of interest and expanding interest, by the way, in this adenosine story today on the biotech wires. There was a deal just made with BMS funds to Bison like 3 more adenosine approaches. I think the concept that these are, again, extracellular and the technology and the platform that you have, which addresses extracellular activities, the ability to take molecules in 1 case where you could recruit and attract, be that T cell recruitment or dendritic cell recruitment, together with a targeted therapeutic, also is very appealing and to bring into context again, as you said small molecules and other strategies also uniquely attractive here. So I think there are a penopoly of approaches that could leverage this platform in a unique way, the ability to combine not just trying to find the next PD-1, but other mechanisms of local immunosuppression, are compelling. And the preclinical data that you've generated to date are compelling. You're shrinking tumors in that preclinical pharmacology is compelling.

And let me just add to 1 thing that Perry said, we have to keep in mind, and sorry to interrupt you, Jeff, but this is a pathway that is highly expressed, particularly in tumors. So as opposed to other checkpoint inhibitors, namely CTLA-4, LAG-3 that our physiologically expressed any time there's an immune event where T cells are trying to be primed or T cells are activated and then trying to be suppressed. This is a pathway that's particularly active in cancer and therefore, really does become an attractive target in the oncology space. I think that's important to just keep in mind.

Ezra, thanks for that comment. So clearly, we have separate programs making DFCs CD73. We showed some of those data. We'll be showing kind of the single mechanism of action A2AR DFC activities shortly, and then an individual PD-1, PD-L1. In your view, what set of data would you like to see next, either combining these individual molecules separately or creating a single molecule cocktail with 2 or more of these mechanisms? Is there any 1 of those in particular that you would be interested in seeing data from? Ezra?

Well, I think yes, yes and yes. So I'd love to see a comparison of single targeting versus dual targeting. And that -- I think that -- my guess is that, that will demonstrate a greater efficacy of the dual targeting, and I think that will position you well to have that -- to lead that into the clinic. Intuitively, 1 would imagine that dual targeting, especially dual targeting of the same pathway, but let's keep in mind that CD73 initiates the conversion to adenosine. There's a middle step that involves CD39 and then, of course, the molecule or ligand receptor interaction. So the dual targeting of the same pathway, I intuitively, I would think, would completely shut down that mechanism of T cell suppression. So that would be nice to see. Now if you have the ability to do a triple, in a sense, inhibition to include PD-1, and because you would be able to focus that at the tumor, conceptually, you may be able to deliver targeting of both that adenosine pathway and the PD-1 pathway with very little toxicity to the patient. And that would be an incredibly welcome step and progress in the clinic.

Great. Thanks, Ezra. Perry, what are your thoughts?

No, I concur on exactly what he said. The other place -- and I think it would be helpful to generate the data is to leverage what you've described already to a degree is the ability of these particular constructs to distribute better to where they're supposed to go. 1 of the places where I think a lot of these therapeutics have been encumbered is they don't really get very well to where they need to go with this, why we've not had any impact, for example, pancreatic cancer this. So you've at least work from what I've seen preliminarily, there are some pretty compelling data that the physiochemical properties and pharmaceutics of these constructs may well distribute to where they need to go better. And I think that, too, is very -- potentially very important in addition to everything, but as Ezra said, about which I 100% concur.

Great. Thank you, Perry. Well, I think this will end the formal part of today's presentation, and I would really like to thank Ezra and Perry for their comments. They will be available for now our Q&A session. I want to thank our audience for their attention, and we look forward to sharing additional details of our programs as they advance. So with that, let me turn it back over to Tara. And Tara, do you want to take us into the Q&A section?

Yes. Great. Thank you, Jeff. At this time, we'll be conducting a Q&A session with our speakers. [Operator Instructions] So our first question is from Karbi Lung from Cantor Fitzgerald.

This is Karbi on for Louis from Cantor. Our first question is on the competition side for oncology. Like you mentioned, it is a crowded space, especially in the combo setting. So maybe you can expand a little bit more on competition, other existing technologies that closely resemble your DCFs for the use of oncology, and what are your competitive edges over very similar products? Secondly, it was more broad. We're thinking about which opportunities are you most excited about? Is it more on flu -- influenza, more on SARS or in oncology?

Great. Well, for that first part of the question, let me turn it to Les to really address our perspective on how DFCs differentiate from existing modalities. Les?

Yes. Thanks, Jeff. Good question, Karbi. So there are a number of advantages that we have. So if we look at -- let's compare to monoclonal antibodies. As I highlighted earlier, we're about 1/3 the size of monoclonal antibodies. And we've seen in our influenza program, that size difference translates to much faster and much better penetration into tissues. And there is other evidence in the literature that dropping the size from the monoclonal antibody down to an Fc like this, should significantly improve penetration of solid tumors. On the toxicology front, since we aren't entering the intracellular space, we have a lot more opportunity to optimize our molecules for potency, because we aren't having to worry about navigating the myriad of targets in the intracellular space to avoid off-target binding. So there's the advantage on the safety side there. And specifically in these programs with A2AR, these -- our DFCs would be the first long-acting molecules in the class, so that we could apply sustained pressure in the tumor microenvironment with higher exposures, which -- and on top of that, we're not going to cross the blood-brain barrier, because you'll recall that in the A2AR space, many of the molecules that have been advanced are repurposed Parkinson's drugs with significant blood-brain barrier penetration, and that limits dosing for oncology application to avoid the CNS-related AEs. And that's an issue with DFC we won't contend with.

Great. And I know that both Ezra and Perry already commented on their perspective of the advantages that this DFC approach would entail. Let me address your other question about where are we most enthusiastic, whether it's flu, SARS or oncology. Clearly, the momentum here is going towards oncology. The flu program is partnered with Janssen has provided both validation and proof-of-concept clearly, an important unmet need in SARS, and we advanced that program really to initially demonstrate that the DFC approach can be used to interrupt protein-protein interactions as effectively as a small molecule DFC can target an extracellular target. So there's still an unmet need there. But clearly, with the exciting data that we've shown on the cancer DFCs in the adenosine pathway, this is the area of momentum for us, and this is where you'll see a lot of news coming forward. Thank you.

Our next question comes from Nathan Weinstein from Aegis.

Can you guys hear me?