Hello, and welcome to the Incyte Data Highlights on the Adenosine Program from AACR 2021. It's now my pleasure to turn the call over to Christine Chiou. Please go ahead.
Thank you, Kevin. Good morning and welcome to Incyte's Adenosine Program Highlights from AACR conference call and webcast. The slides used today are available for download on the investor section of incyte.com. I'm joined on the call today by Steven Stein, our Chief Medical Officer, and by Patrick Mayes, Incyte's Vice President of Biotherapeutics Research. Also joining for the Q&A session following our prepared remarks, Dash Dhanak, our Chief Scientific Officer.
Before we begin, I would like to remind you that safe harbor rules govern our remarks today and any forward-looking statements that we may make. I therefore encourage you to review the risk factors detailed in Incyte's SEC filings, included in our Form 10-K for the year ended December 31st, 2020. I will now pass the call over to Steven.
Thank you, Christine. We have a robust immuno-oncology pipeline composed of bispecific antibodies, small molecules, and monoclonal antibodies. We rationally design targets that are specifically chosen to be developed as both monotherapies or in combination. We currently have over 30 clinical trials with monotherapy or combinations of our immuno-oncology portfolio. I'd like to remind you also that our retifanlimab PD-1 PDUFA is in July this year, and we also expect the CD73 IND to be filed and clear in the first half of 2021. On the next slide, you'll notice that traditional immuno-oncology therapy has become focused on PD-1, PD-L1 inhibition.
While checkpoint blockade can be very effective and lead to long remissions, in reality, only 15% of the totality of cancer patients respond to checkpoint therapy. Even in immuno-oncology sensitive tumors like melanoma and non-small cell lung cancer, where upwards of 30% of patients respond initially to checkpoint therapy, repeated exposure can lead to T cell exhaustion and patients often relapse. There are multiple redundant and non-redundant immunosuppressive pathways in the tumor microenvironment, and this can at least partly explain the failure to respond or relapse on current immune checkpoint therapy.
Amongst these, the importance of the adenosine-mediated immunosuppression pathway will be the focus of today's presentation. The combination approach here will be important given the mechanisms of adenosine-mediated immunosuppression, and we'll go through some of the details of our approach in a minute. Of note, Incyte has a number of additional agents to activate the immune system against cancer. I won't spend time on PD-1 or PD-L1 because it's well known to this audience.
On our focus on immunosuppressive cells, AXL and Mer are overexpressed in many solid tumors and hematologic malignancies. The aberrant activation of AXL/Mer plays an important role in tumor growth, survival, angiogenesis, metastasis, and drug resistance. AXL and Mer can reshape the tumor microenvironment to allow tumors to evade immune responses by increasing regulatory T cells, M2 macrophages, myeloid-derived suppressor cells , and suppressed antigen presentation. We have an AXL/Mer program.
We also have a PD-1 / CD137 program, a LAG-3, and a TIM-3 program, as well as what we'll go through today, the A2A / A2B program and CD73 program. I will now pass the call over to Patrick.
Thank you, Steven, good morning, everyone. I'd like to begin with a brief overview of the biology around adenosine-mediated immunosuppression in the tumor microenvironment. In normal tissues, the presence of extracellular ATP is exceedingly low. As is often seen in solid tumors, the event of cell destruction and other factors, including inflammation, hypoxia, and necrotic cell death, can release high levels of ATP into the extracellular environment. Under normal conditions, ATP is a pro-immunogenic stimuli.
Tumors have adapted to upregulate two ectonucleotidases, CD39, which hydrolyzes the conversion of ATP to ADP and AMP, and CD73, which subsequently converts AMP to adenosine. Due to its short half-life under physiologic conditions, adenosine can only exert its activity in the local environment where it's produced. Unlike ATP, adenosine's a potent immunosuppressive metabolite, which acts through a family of G protein-coupled receptors, A1, A2A, A2B, and A3.
A1 and A3 are primarily located in the central nervous system and cardiovascular system and have functions unrelated to immunity. As shown here, A2A and A2B are found on many immune cell populations, including T cells, dendritic cells, myeloid cells, and others. Binding of adenosine to A2A and A2B initiate the cascade of intracellular signaling, which results in the suppression of immune cell function through multiple mechanisms, including direct T cell suppression.
High levels of adenosine, as well as the expression of regulators of the adenosine pathway, have been shown to be prognostic indicators of poor outcome in cancer, including as response predictors to PD-1 and PD-L1 therapy. Turning to slide seven. At Incyte, our approach is to modulate this critical pathway through targeting it at multiple nodes in order to fully suppress adenosine formation and its subsequent action on immune cell function.
Through our own internal capabilities, we've developed a highly potent anti-CD73 antibody, which I'll refer to as INCA00186, as well as the selective and high potency small molecule dual antagonist of both the adenosine receptors A2A and A2B, which I'll refer to as INCB106385. These agents targeting the adenosine axis will be developed in combination with our anti-PD-1 antibody, retifanlimab, and we believe there's strong rationale for a combination approach involving these three agents for targeting tumors with high adenosine signaling.
Turning to slide eight. This is an example showing the survival of patients from a large trial of an anti-PD-L1 antagonist, which stratifies outcomes according to an RNA signature developed by Incyte, which identifies patients whose tumors have high levels of adenosine signaling. You can see from the Kaplan-Meier survival curve on the right, patients whose tumors had high adenosine gene signature fared significantly worse than those patients whose tumors had low adenosine gene signature.
Analysis from our other internal data sets at Incyte shows similar associations between outcomes to PD-1 targeted therapy and our adenosine pathway gene signature, including in head and neck cancer and non-small cell lung cancer. We believe this finding offers an opportunity to employ a precision medicine approach in order to enrich our trials for patients most likely to benefit from our adenosine pathway combination therapy. A large percentage of these patients are non-responsive to monotherapy checkpoint inhibition.
There's the potential that this triple combination therapy with 385, 186, and retifanlimab could show synergistic immune activation in these patients where there's a high unmet need. I'll now walk you through the characterization of our adenosine pathway targeted agents, INCB106385 and INCA00186. I'll begin with a description of our potent and selective dual A2A and A2B antagonist, INCB106385.
This is a high-affinity adenosine competitive inhibitor, as shown in the graph on the right, which potently inhibits adenosine-mediated signaling via the A2A and A2B receptors. INCB106385 has excellent drug-like properties resulting in high tumor penetration and exposures which provide maximal target coverage across the dosing interval. Additionally, the compound has low activity towards A3, thus limiting potential cardiovascular effects, and also has minimal brain penetration, thus avoiding A1 targeting and CNS complications.
Turning to slide 11. We believe our dual A2A/A2B antagonist has an optimal profile and superior drug-like properties. With regards to potency, the most important measure is the ability to block adenosine receptor signaling in immune cells under human physiologic conditions, such as in human whole blood. As compared to some competitor compounds, as shown in the table, INCB106385 shows superior inhibition of adenosine receptor-mediated signaling in T cells, as measured by phospho-CREB downstream of the adenosine receptor.
This was measured in human whole blood. We believe this potency advantage will translate to an optimal inhibition profile in patients. Additionally, the emerging data has shown that adenosine-induced A2B activation serves an important role in increasing the immunosuppressive activity of myeloid cells. Therefore, dual targeting of both A2A and A2B can fully inhibit the immunosuppressive properties of adenosine on these cells within the tumor microenvironment.
Importantly, INCB106385 is one of only two clinical-stage adenosine receptor antagonists that we're aware of that potently inhibits A2B as well as A2A, thus maximizing the immune stimulatory activity in tumors. In addition, INCB106385 is able to achieve functional blockade at lower concentrations due to its much higher potency in human whole blood. Preclinical characterization of INCB106385 in mouse studies demonstrated there was good target coverage above IC90, which was achieved for greater than eight hours after a single administration of a 10 mg/kg dose.
BID dosing resulted in IC90 exposures for greater than 20 hours. This again indicates the excellent PK and exposure of this compound. Therefore, INCB106385 was tested at the 10 mg/kg BID dose in mouse tumor models, and as you can see on the right-hand side, it demonstrated significant antitumor activity as a monotherapy in a mouse CT26 colorectal tumor model. I'll switch now to a description of our internally developed anti-CD73 antibody, INCA186, which is a potent allosteric antagonist of CD73. INCA186 selectively binds to CD73 with picomolar affinity, and upon binding, it results in potent inhibition of AMP-mediated T cell suppression.
As shown in the graph on the right. As mentioned, INCA186 is an allosteric antagonist of CD73, as indicated by the binding model below, which demonstrates that the epitope for INCA186 is distal and distinct from the AMP substrate binding pocket. We believe that the non-competitive inhibitory mechanism is important and distinct from some other antibodies and the small molecules in that it allows for potent inhibition in the context of high levels of AMP, such as those that are found in the human solid tumor microenvironment.
Finally, we show that upon binding to CD73, INCA00186 induces downregulation of CD73 on the extracellular membrane cells, thus contributing to the antagonist function of the antibody. This mechanism may also be a key feature of the B-cell activating properties that have been observed with anti-CD73 antibodies. Characterization of INCA00186 in vivo demonstrates that this agent has an optimal pharmacodynamic profile in the tumor microenvironment. Dosing of INCA00186 resulted in a dose-dependent downregulation of CD73 on the surface of tumor cells.
As shown in the graph on the left, and of the remaining CD73 on the cell surface, INCA00186 bound to and occupied the receptors in a dose-dependent manner, up through the top dose of 10 milligrams per kilogram, which was tested.
Finally, the net effect of CD73 downregulation, the occupancy of the remaining CD73 allosteric site, led to the near complete inhibition of CD73 enzymatic function in the human A375 tumors. Transitioning now to the rationale supporting the combination of our two adenosine pathway targeted agents. As shown in the first bullet, there are very high levels of adenosine which have been reported in human solid tumors. Therefore, we aim to model preclinically these high adenosine conditions, which could recapitulate the human solid tumor microenvironment.
The left-hand graph illustrates an in vitro system where T cells were suppressed by high levels of AMP, as would be found in human solid tumors. What this data shows is that either INCA00186 or INCB106385 administered alone can overcome T cell suppression driven by high AMP, but only to a limited extent. However, the combination of both agents administered at the same concentration as used as monotherapy demonstrated the synergistic effect of the 186 plus 385 combination under these tumor-like high AMP conditions.
Likewise, as shown in the graph on the right, utilize the human breast carcinoma tumor model with very high levels of CD73 expression and adenosine signaling to test the effect of either single agents or the combination of these adenosine pathway targeted therapies. Similarly, the combination of 186 plus 385 resulted in a synergistic effect on tumor growth inhibition, whereas the single agents had a lower anti-tumor response. These data demonstrate the necessity of targeting multiple nodes of the adenosine pathway in conditions where there are levels of adenosine are very high, such as in the human solid tumor microenvironment.
Finally, using the same high level of adenosine as shown in the prior slide, we show on the graph on the left in vitro data demonstrating that high levels of adenosine result in significant inhibition of anti-PD-1 activity on T cells. The addition of the combination of 186 plus 385 was able to fully overcome the adenosine-mediated suppression of anti-PD-1 activity. Using the high CD73-expressing human breast carcinoma tumor model in mice, treatment with retifanlimab alone had very little anti-tumor activity.
When dosed in combination with 186 and 385, we see a significant anti-tumor response, including multiple mice with complete tumor regression. In summary, we've demonstrated that high levels of adenosine, such as those found in the human solid tumor microenvironment, creates an immunosuppressive checkpoint which limits the activity of anti-PD-1 targeted therapy. Incyte has developed INCB106385, which we believe is a best-in-class A2A/A2B dual receptor antagonist, as well as INCA00186, which is a potent allosteric CD73 antagonist antibody.
Our preclinical studies demonstrate that under conditions of high adenosine signaling, such as those found in the human solid tumor microenvironment, the triple combination of 385, 186, and retifanlimab overcomes adenosine-mediated PD-1 suppression. These data provide compelling rationale to further develop the 385/186 retifanlimab combination as an immunotherapy for cancer patients. Now I'll pass the call back to Steven for the clinical development plan.
Thank you, Patrick. As you can see on this slide, we will be utilizing, as Patrick said, our proprietary adenosine gene signature and our biomarker strategy to guide development. INCB106385 is already in the clinic in the dose escalation and expansion study illustrated on the left. We will also, as soon as the IND clears, do the same thing with INCA00186, the CD73 antibody. We will go on as soon as we achieve a safe monotherapy dose to test the A2A/A2B combination of retifanlimab and then the CD73 combination, both with PD-1 and with A2A/A2B, eventually going on to the triplet once we establish safe doses and schedules for all of them.
With that, operator, please give your instructions and open the line for Q&A.
Thank you. We'll now be conducting a question- and- answer session. We ask that you please ask one question and one follow-up, then return to the queue. If you'd like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. Once again, that's star one to be placed into question queue, and we do ask that you ask one question, one follow-up, then please return to the queue. Our first question today is coming from Salveen Richter from Goldman Sachs. Your line is now live.
Hi. Thank you so much for taking our call. This is Sonia on for Salveen. How are you thinking about the potential utility for these agents as monotherapy versus in a doublet or versus in the triplet?
Yeah. Sonia, it's Steven. I'll start. Thank you for your question. Based on what we have with our own preclinical data, which Patrick walked you through, it looks like at least preclinically, that there is synergy. Firstly, you have monotherapy activity that's modest. When you go to the doublets, you see increased activity, and as soon as you add in the checkpoint blockade, you see that in a relatively dramatic preclinical data, including, as Patrick said, some animals with complete tumor regression. The preclinical data would point to the need, potentially to do the doublet and the triplet.
Obviously there are competitors with slightly different approaches, in the clinic at the moment, that may guide some of the choices related to, for example, combinations as we saw at AACR this weekend with chemotherapy, with A2A/A2B blockade. The short answer is we'll see. The longer answer is based on our preclinical data, it looks like we'll need the doublet and potentially the triplet to get the maximum clinical effect. That's why, as I outlined on the clinical development program, the intent is to get pretty quickly to the combination safety dose and schedule, because that's what we'll intend to use. Thanks.
This is Patrick.
Thank you.
If I can just add a couple of things to Steven's comments, which are spot on. I would also add that in the design of these molecules, our intent has always been to develop these as combination agents. As the data showed, that's where we see the best activity preclinically, and it's consistent with what other people have also reported. The design, particularly the small molecules here, is important in the sense that by blockading both A2A/A2B while sparing the other receptors, it gives us the opportunity to explore combinations rapidly and in a safer way.
We think, going forward. It's correct to assume that these are always intended to be developed as combination agents.
Thank you so much. Just a quick follow-up. Could you provide some initial thoughts on where the triplet would make most sense? The adenosine receptor antagonist CD73 and anti-PD-1.
Yeah. It's Steven again. Thank you, and Patrick and Dash may want to add something. I think it's probably too early to comment in detail on your question. We have a gene signature, which we hope, based on the data we have, will guide a program in an enriched manner. I don't think we're ready to lean into which particular histologies may lend itself to the signature, unless Patrick wants to add anything.
I think that's right, Steven. I think a combination of the gene signature, we know that many tumors highly overexpress CD73 as well. Some of the tumor types we indicated in the early response prediction to PD-1 obviously would be in scope, a number of others as well.
Thank you. Our next question is coming from Evan Seigerman from Credit Suisse. Your line is now live.
Hey, guys. Thank you so much for taking the question and providing the update today. My first question on the clinical development plan, are there any tumor types that you think will be best suited for the doublet or even the triplet? I know you had mentioned head and neck cancer and lung cancer up front, but I'm just trying to better understand where this may be most useful, and then I have a follow-up question.
Yeah, Evan, I'll start off. Thanks for the question. Again, as Patrick just said, if you look at patients which may benefit that have potential with the gene signature. We said broadly that approximately half of non-small cell lung cancer and about a little over half, maybe 60% of head and neck cancer may have it. If you couple that with CD73 expression, it may lend itself to those same tumor types and others. It's just hard at this very early juncture to give more granularity on where we may head.
It's very encouraging from a clinical development point of view to have from the get-go, a biomarker translational plan that'll help us enrich as opposed to an all-comer plan. It really helps early on to guide the program. That's as sort of broad I can be at the moment.
No, that's fair. Then just my follow-up, thinking ahead, maybe a little premature, but when you look at the triplet, how do we think through any potential tox issues? If you see a tox issue with the triplet, would there be any read-through or derailment to the doublet programs?
Yeah. I'll start, and again, my colleagues may want to add. As Patrick said, the compounds were designed to try and avoid the known areas where we may run into trouble, for example, in the cardiovascular system, we've engineered out the A3 receptor blockade there, so that hopefully shouldn't happen. In terms of CNS, remember, these drugs were developed years ago for potentially diseases of the central nervous system. We try to engineer that out with lack of brain penetration to try and limit or get rid of CNS effects.
As I said up front, 385, it's early days, is already in the clinic, and thus far has been well-tolerated. Obviously, we have a way to go. Obviously, we never want to see toxicity, and we've tried to, based on what we know of the pathophysiology of the receptors and pathways, to make sure that doesn't happen.
This is Dash again. I'll go back to my earlier answer regarding the design of these molecules exactly as was laid out. These were designed not to have some of the liabilities of the sort of first generation, second generation molecules even around those. In addition, I'll say, of course, the potency of these molecules is also very high, which means the clinical doses we anticipate will be relatively low. The final piece of that really is around our preclinical characterization, obviously in safety studies, for all of these molecules where we did not see any sort of relevant toxicities that might preclude combinations, et c.
They look like pretty decent, pretty good molecules and clinically, we don't anticipate many issues. Of course, as Steven said, we have to do the experiment.
Thank you. Our next question today is coming from Leonid Timashev from RBC Capital Markets. Your line is now live.
Hi. Yeah, it's Leo on for Brian. Thanks for taking my question. I was curious if you can maybe talk about some of the potential I guess I realize that you're dosing currently in phase I, and curious how recruiting there is progressing, if you can speak high level, if you're encouraged by the safety and efficacy that you're seeing. You're also developing oral PD-L1 inhibitors, and I'm curious if you're thinking of combining your adenosine programs with some of those molecules as well, in addition to retifanlimab. Thanks.
Yeah, Leo, it's Steven. Thank you for your question. It is early days on the A2A/A2B program in phase I, thus far, it's well-tolerated, you always have to caveat that you have a way to go. Nothing unexpected based on the engineering. We're very comfortable with what we've seen to date, obviously we want to get the CD73 into the clinic, get the monotherapy data, and start combination there as well. Just to segue to your second part, you're right, our oral PD-L1 is a program. There's more than one compound in the clinic.
We've always said on various calls, including our earnings call, that the intent would be to use combinations there as well, would obviously lend itself, given its oral to oral combinations, in certain settings would be really relevant, and obviously we have ones within our own pipeline we've been interested in, including outside our pipeline with VEGF inhibitors, for example. It's certainly in scope when ready to do so because of the data we have with checkpoint inhibition in combination with adenosine inhibition.
Got it. Thanks.
Thanks.
Thank you. Our next question is coming from Mara Goldstein from Mizuho. Your line is now live.
Great. Thanks so much for taking the question. I just had a question on adenosine signature. There obviously are a couple of companies that have been developing adenosine molecules as well as anti-CD73. As it relates to the adenosine signature and the use of a diagnostic tool, can you share with us your thoughts on where this is kind of with the FDA from a regulatory perspective or rather clinical development perspective as a tool for the clinical trial, and from a proprietariness, what we should be looking for your adenosine signature as it relates to your molecule relative to what others are using.
Hi, this is Patrick. I can start and then pass to Dash for additional comment. It's still in its laboratory stage. This was derived in-house through one of our internal data sets. It identifies tumors that have high adenosine signaling. We still obviously need to better understand what a cut point would look like clinically. I think we'll take this into the clinic in the phase I setting and look at tumors, and then once we have the data, make some decisions about how to progress that as more of a prognostic indicator, something that we can enroll patients based upon.
Just to add a little bit to that, this is Dash again. Just to add a little bit more to Patrick's description there. Clearly, it's early days to see how well this signature will play out in the clinic. We're pretty confident based on the data sets we've looked at, both our internal data sets as well as publicly available data sets that you saw on one of the slides, that the signature looks suitable for guiding clinical development.
Clearly, because it's adenosine-driven, there are some similarities to other signatures that have been reported externally, but there are also some unique insights that we've generated, looking at the data ourselves with our history and our data sets. Yes, there are some similarities, as you might expect, given it's the same sort of pathway modulation. There are unique differences that we feel give us a deeper sense or a different sense of where to take this, and we'll see how it pans out as we go into the clinic.
Okay. If I could just ask a follow-up, and that is just on combinations. The totality of the data so far that we've seen from competitors, so these are obviously not your molecules. Suggest that the strongest data thus far has really been in chemo combination, so I'm curious about, I know we've talked about various different combinations, but the thought process around a doublet or a triplet, adenosine anti CD73 PD-L1 strategy versus a chemo combination.
Yeah. Steven, I can start. I think it's context, and tumor dependent, right? In terms of what's practical that you can use at certain junctures. For example, the data you saw this weekend in colorectal cancer and in the third line, chemotherapy combinations there are a care standard. You saw the addition of adenosine-directed therapy to that, taking advantage of that particular milieu or context. I think when you're in settings where IO therapy is an established standard of care, then you can build on that, as opposed to using a chemotherapy combination.
Then again, going to our preclinical data in that particular model, obviously there was no chemotherapy used there. It was all adenosine-directed therapy and then the addition of checkpoint blockade. I think it'll ultimately depend on the context and where you test it, and with the idea being potentially to try eliminate the need for cytotoxic therapy where you can to avoid those side effects.
All right. Thank you so much.
Thank you. Our next question today is coming from Matt Phipps from William Blair. Your line is now live.
I want to thank you for taking my questions. Just quickly, you mentioned downregulation of cell surface CD73 with your antibody. Do you know if that's internalization or shedding, and do you think there's any biological difference? One follow-up.
It's a good question. Thank you. I think it's potentially a combination of both. We know internalization does occur. We can't rule out the fact that it might be shed as well. I think at the end of the day, the shedding, I think biologically we're not sure of the relevance there, right? The ATP, as I said, when converted to adenosine, it's a short-lived metabolite, so it acts really in that local environment right where it's produced. We believe in the tumor microenvironment, the studies we've run, the cell surface levels seem to be predictive of the effect that we're seeing.
That's what we've developed assays in order to measure. That's how we've developed the anti-CD73 antibody, and that's what we'll be following is the tumor-based CD73 expression that's found primarily on the cell surface.
Okay, thanks. Just a quick one on the gene signature. You're obviously looking at specific tumor types. I'm wondering if it's almost more what types of treatments are used in those tumors. Something like cisplatin in head, neck, and lung cancer may be just driving more apoptosis, leading to spillage of ATP and kind of starting that pathway off. Is that something you're considering?
Yeah. I think that's a good point, right? You can sort of divide this up into sort of intrinsically immunosuppressed tumors, for the reasons that you mentioned, and others where adenosine plays that role due to cell death, etc . There are a couple of reasons you could do this and different ways of looking at it. At the end of the day, our gene signature is somewhat agnostic in how it picks it out, so it shouldn't really matter whether you're coming in from either angle. Patrick can add to that.
I think you're right. I think some chemotherapies in particular lead to the higher release of ATP, and I think we can look at this. Obviously, the triple combination we described would serve as the immunotherapy backbone, but that could then be explored with other standard of care chemotherapies that we think at least some of those are going to have a high propensity towards the release of ATP into the environment upon cell death. I think that makes good rational sense for why you would want to combine with this immunotherapy backbone.
Okay, thanks.
Thank you. Our next question today is coming from Jay Olson from Oppenheimer. Your line is now live.
Hi. Thanks for taking the question. Can you talk about how the adenosine gene signature is associated with the patient's prognosis?
Yeah. Thanks, Jay. Thanks for the question. Again, as I said in my earlier reply here, when we looked at the data sets that we have accessible both internally and externally, this was a full sort of analysis based on looking at transcriptional profiles in vitro with some of our agents that target a pathway, and then using that as a basis for looking at clinical data sets, either published, as I said, or in-house, to sort of dissect out what are the features that associate with outcomes, et c.
The idea is then to use that as a prognostic, potentially anyway, in the clinic to figure out which patients may respond best to this. I have to say, it is still early days, and none of the signatures that have been reported fully explain all of those data sets. We think we're making progress.
I think to the point, I think it's unlikely that it's identifying just a subset of patients that are going to fare worse. It actually associates quite well with immune cell infiltration in the tumors, which would otherwise be, I think, a positive predictor. Really, I think the correlate there is the poor predictive value to a response to a PD-1 checkpoint. That was what the data showed us, and I think it's independent of PD-1, perhaps, you don't see that same association.
Okay, great. As a follow-up, can you talk about possible resistance mechanisms to the adenosine pathway?
Yeah. This is Dash again. I'll try and address that one. First of all, we fully expect some sort of resistance pathways to check in. Pre-clinically, we haven't done a lot of work yet to identify resistance pathways. Fully expect that there will be some. We can speculate about how those may come about, whether it's upregulation, downregulation of specific adenosine associated proteins in the TME or whether there are additional pathways that kick in once you've released a breakthrough through adenosine.
A little bit too early to say exactly. We can certainly speculate. I know Patrick want to add to that.
No, I think that's right. I think just one thing, an observation about the class generally is that we know that there's very high levels of these metabolites in tumors, AMP, adenosine, and I think one of the potential resistance mechanisms to this first generation of clinical stage inhibitors is just the presence of these high amounts, and this is the reason for the combination approach from the get-go. It was the reason for targeting both A2A and A2B to kind of fully target all the immunosuppressive properties of adenosine in that environment.
As we showed in the preclinical models, in these situations where there are high levels of adenosine, you really need the combination to overcome these levels of adenosine presence. I think one potential resistance mechanism is just the upregulation of adenosine upon tumor cell kill. That might be kind of an adaptive mechanism to get around the blockade. I think through this combination approach, we could circumvent that.
Thank you. Our next question is coming from Eva Privitera from Cowen. Your line is now live.
Hi. Thank you for taking the questions. There's been a few adenosine CD73-directed programs before, and it seems like they haven't reported great clinical data. Can you compare and contrast the molecule, as well as the development plan to help us understand how this program is differentiated?
If we can start with CD73, as I mentioned, this is an allosteric CD73 antagonist. There's a lot of specific requirements for a CD73 antagonist. We believe the allosteric nature of this one is ideal because it allows for blockade even in the context of high AMP conditions, as was mentioned. The mechanism is one. I think the combination approach with A2A and A2B is another. Having both parts of these together within the same combination regimen, we think, is going to be important as well.
The intracellular or the, excuse me, the internalization of CD73 from the cell surface, we also think is going to be a valuable feature of the anti-CD73 antagonist we've identified. Really, all of these features have been developed in order to optimize the function of the CD73 antibody in a tumor microenvironment, where we think adenosine levels are going to be most important. That's where we focused in terms of readouts pre-clinically, that's the profile of the molecule we've selected as a result.
I think in terms of overcoming and how it differentiates from competitors, we know that at least some of the monoclonal antibodies in development are competitive inhibitors of the AMP substrate binding pocket. Obviously, the small molecules are the same. Then in terms of distinctions around the other allosteric inhibitors, it's really going to come down to their ability to internalize the potency of those molecules. I think all of these things are going to factor in ultimately to how these things perform clinically.
Thank you so much.
Thank you. Our next question today is coming from Tazeen Ahmad from Bank of America. Your line is now live.
Hi. Good morning. Thanks for taking my question. Just a point of clarification. Earlier on, you talked about the potency of your adenosine receptor blockers, and in a competitive landscape, is it going to be important to be able to have, let's say, for example, a lower dose than a competitor? Obviously, we're waiting still to see what the safety profile ends up being. Then the second question is, in each of the indications that you plan to pursue.
I guess, how easy is it to find patients that would be amenable to treatment? Thanks.
I can take the first one. This is Dash, and maybe Steven can take the second one. In terms of the potency, clearly given the differences that we've talked about and the clinical doses we're talking about, the intent was really to say that the higher the potency, and the greater the potency, particularly in a physiologically relevant system, the lower the pill burden at the end of the day. Whether that turns out to be significantly different as we get further into the clinic remains to be seen.
We note that competitor molecules certainly currently are being dosed at higher levels, seem to be tolerated. We'll see how that progresses. In general, particularly with small molecule drugs, the lower the pill burden, generally better, and you sort of limit off-target pharmacology with lower doses. Over to Steven.
Yeah. Steven, in terms of the ease of executing a clinical development plan, there's been some COVID impact on phase I programs across the globe in general. For the most part, we've been fortunate in keeping all our clinical activity open and then flexing appropriately around the world to needs as things change with the pandemic and being able to execute our programs. We're very happy we've been able to do that, and we expect the same here. If you're asking, does the use of a signature limit you in an enrichment play?
I don't think it's the case here, because in terms of the data we have, and it was on one of Patrick's slides, when you have literally half or more of a tumor type having the signature, you're not having a lot of screen failures even when you're enriching. We don't expect that to be problematic in any way either. I expect the program to move along pretty well given those two areas of interest. Thanks.
Okay. Maybe just a follow-up, when would be the next time we should expect to see a data update from this program?
Given that A2A, A2B is in the clinic, that CD73 will go in its IND the first half of this year and clear and start thereafter, I don't think you should expect anything until 2022, when we'll be able to show clinical data on the tolerability profiles and then potentially some efficacy signals. It's really next year.
Thank you. Our next question is coming from Michael Schmidt from Guggenheim. Your line is now live.
Hey, this is Kelsey on for Michael, thanks for taking our questions. Just kind of thinking about the pathway, was there any interest in pursuing CD39? Separately, I guess, do you see any opportunity to develop an oral CD73 versus the antibody construct you're advancing? That's it. Thank you.
I can start with the CD39 question. I think it's an interesting target, and we think it's an interesting target, and obviously could provide potential immunomodulatory benefit. I think in terms of limiting adenosine production, we think the approach we have with inhibiting CD73 and A2A and A2B really maximizes the effect on adenosine. I think potentially what CD39 could buy you in addition to that is this backup or the accumulation of ATP, which as I said earlier, is actually an immunostimulatory metabolite within the microenvironment.
I think in thinking about CD39, it could add that benefit in addition to the inhibition of adenosine. What we don't know is whether inhibition of CD73 can have similar effects. Obviously, we believe it's a rate-limiting enzyme within that process. Via the inhibition of CD73, would we get the same backlog of, or the backup or accumulation of ATP, which could be beneficial within the microenvironment? It's something we're exploring, and we'll see whether in patient tumors, whether this is true of CD73 as well. I'll maybe pass it to Dash for the second part of your question.
Yes, that was really around the potential for an oral CD73. As you mentioned, there are molecules already out there that are pursuing that path. The issue with CD73, at least some of the molecules that are out there, obviously, CD73 processes, as was shown, AMP. Most of the substrate-directed inhibitors tend to require very high potencies. You're seeing these in the low picomolar range. That's largely because the zinc-based enzyme binds to the very polar phosphate group, which then means the substrate-based inhibitors need to compete for that.
In a high AMP environment, you require that high potency. The problem with having that requirement means that oral drugs, which are not very cell permeable with that sort of motif, tend to have low oral bioavailability. You've seen some of the competitor molecules advancing to the clinics, or molecules anyway, being dosed intravenously in that first round. There are cases out there of orally bioavailable CD73s reported, but I think most of them are pretty early still.
Interestingly, there is a recent entry, I think, into the pipelines where people are going after CD73 in a different way, looking at allosteric inhibitor potentially, which may be more fruitful.
Got it. Okay. Thank you so much.
Thank you. Our next question is coming from Stephen Willey from Stifel. Your line is now live.
Yeah, good morning. Thanks for taking the question. I know that you're engaging a distal epitope on the CD73 receptor, which I'm presuming is preserved in the cleaved or soluble form of CD73. Just wondering if you've done any work to understand the differential binding between membrane-bound and soluble CD73, and whether there's a scenario where too much soluble antigen represents a competitive sink. Thanks.
Thanks for the question. Correct, the distal epitope is in kind of a domain that's on the arms of CD73, if you will, and this is preserved on the soluble variant as well. We've shown equivalent binding to the soluble variant as to the cell membrane-bound variant. In reference to, I think, the ability to inhibit that soluble pool of CD73, I think this has been an area of focus for the CD73 antibody class generally. We do have data indicating that we do inhibit soluble CD73.
The kinetics are somewhat different than cell surface CD73, and we can follow that. Maybe the dosing necessary in order to achieve blockade may be different between that soluble fraction and the cell membrane fraction.
The data from our monkey studies and the data from all the preclinical experiments we've done indicate that the levels of soluble CD73, even upon dosing, are going to be much lower than levels that would be necessary to provide a sink, if you will, for preventing antibody function. At the end of the day, the soluble CD73, we believe, is really not what should be followed. It's the role of CD73 within the tumor microenvironment. As I said, there's exceedingly low levels of ATP which are found outside the tumor microenvironment.
From an enzymatic standpoint, CD73 is going to be of little relevance in the systemic tissues. We believe that there's actually potential benefit by not inhibiting fully at least, that CD73 outside of the tumor microenvironment. They actually avoid or dampen some of the PD-1 mediated systemic immune-related adverse events that we see there. It's something that we'll follow clearly in the clinic and see, but we really think the action is in the tumor microenvironment, the way the molecule's been developed, and that's what our assays will aim on measuring in patients.
Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to Christine for any further closing comments.
Thank you all for your time today and for your questions. We look forward to seeing you at upcoming investor and medical conferences. For now, we thank you again for your participation in the call today. Thank you and goodbye.
Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.