GRTS B. Riley Oncology Panel Transcript | Click here for the webcast
Unknown Speaker 0:01
Yes this morning for the second of three planned panels in the D Riley securities fall 2021 best ideas and oncology Webcast Series. My name is Justin Walsh. I’m a senior analyst at the Riley securities within oncology focused franchise. Before we get started, please keep the following disclosure in mind. In the normal course of business B Riley security seeks to perform investment banking and other services for companies and to receive compensation in connection for sub services. In addition, B Riley makes a market in most covered companies, please contact your B Reilly securities representative for specific disclosures. We appreciate our speakers spending time with us today. Their opinions are their own and do not necessarily reflect those of be Riley securities, and we ask them to avoid any disclosure of confidential nonpublic information. This panel is titled overcoming checkpoint resistance in solid tumors. We’ve invited and experienced Kol as well as representatives from Select companies with relevant exciting technologies to participate in the discussion. We have Dr. Michelle cross guard is our Kol. She’s an associate professor in the Department of Pathology at the NYU Grossman School of Medicine. We have Dr. Vera Fisker leap, president and chief operating officer of Compass therapeutics, Dr. Andrew Allen, co founder president and chief executive officer of gritstone bio, and Dr. Ian Walters, Chief Executive Officer and director of Portage biotech. Thank you all for taking the time today. to frame our discussion, it’s clear that checkpoint inhibitors have made a dramatic impact across various solid tumor indications. And the class includes multiple drugs that have achieved blockbuster status. However, not every patient responds to treatment, and many patients who do respond ultimately progress and require additional treatment. This has created new areas of unmet need and has attracted innovators across industry and academia. So clearly, this is a big topic and we won’t be able to address every indication or nuance. However, I do hope that we can highlight the complexities and some specific strategies that I believe are of particular interest. With that, Dr. crossguard, can you kick things off by providing an overview of the basic science behind checkpoint inhibitors? Yeah, thanks, Justin. I’m happy to do that. So we all know that the efficacy of checkpoint inhibition is a result of releasing T cells from the inhibitory effect of checkpoint blockade. So there are T cells in the tumor microenvironment. And then in response to various tumor microenvironment derived factors. There’s upregulation of checkpoint molecules such as PD, one, Pdl, one and cytotoxic T lymphocyte. Associated protein four also known as CTL, for T cells can also be epigenetically reprogrammed to be poised for expression of the checkpoint molecules, when they upregulate checkpoints and the subsequent like an interaction mediated downstream signaling then leads to suppression of effective T cells, signal transduction, proliferation, cytokine production and effector functions such as cytotoxicity. We want to go into the specifics. ligation of PD one and T cells with the Lykins PDL one, and PDL two leads to tyrosine phosphorylation of cytoplasmic domains of PD one which are referred to as immune receptor tyrosine based switch motifs. And this leads to then a recruitment of a Sark homology domain containing phosphatase two which is also known as ship two to the cytoplasmic tail of PD one which is responsible for the inhibitory function of PDL, one
Unknown Speaker 3:46
that leads to activation of SIP to that then leads to the phosphorylation of TCR proximal kinases, that leads to further inhibition of downstream signaling, and cytokine release proliferation cytotoxic activity, which also promotes apoptosis. So there’s PD one signaling on other immune cells and T cells such as B cells, dendritic cells, macrophages, NK cells, which I think we’re going to hear about today. And that’s also been shown to inhibit their function. So this all results in T cells existing in a state of energy where they’re unable to perform and to tumor effector functions. So what checkpoint inhibitors does is that they block these checkpoint molecules and that allows the adaptive immune system to respond to the tumors. Therefore, the presence of these existing tumor specific T cells, or employment of other modalities that generate tumor specific T cells are required for the efficacy of checkpoint inhibition.
Unknown Speaker 4:52
Got it? So what types of tumors or tumor cells seem to be the most sensitive or resistant to treatment with these drugs? Yeah, so
Unknown Speaker 5:00
So we know that human melanoma, renal cell carcinoma and non small cell lung cancer are the most sensitive to PD one Pdl, one therapy. And this is due to their association with very high immunogenic mutations that are on these tumors. So drugs like Kimbro or nivo, that target PDL one, they’ve shown very promising results in both melanoma and non small cell lung cancer. And we’ve seen objective response rates to up to 40 to 45%. In addition
Unknown Speaker 5:36
urethral bladder cancer patients that are treated with PD one and PDL, one inhibitors also show an increase in overall response rate, which is between 13 and 24%.
Unknown Speaker 5:50
In addition, Triple Negative Breast breast cancer has also shown to be responsive, although this response was moderate about 90%. And also Hodgkin’s lymphoma.
Unknown Speaker 6:03
We’ve seen that anti PD one therapy can result in objective response rates to up to 87%. So very successful with about 70% complete response. And this is all related to that these tumors are highly immunogenic and express a lot of mutations. There are also of course, poorly immunogenic tumors that generally slow lack of response to these checkpoint inhibitors, for example,
Unknown Speaker 6:34
pancreatic cancer, usually we see the checkpoint inhibitors are not very, in fact, effective as monotherapy except in a very small subset of patients that have Michmash repairs. And this is due to that this mismatch repair or microsatellite instability leads to an increased number of somatic mutations, which may be translated into new antigens that can be recognized by the immune system. And that will increase the responsiveness to checkpoint inhibitor monotherapies. So, in fact, anti PD one therapy has been used are approved for use in a subset of pancreatic cancer patients who has tumors that have high microsatellite instability. There’s also other cancer types that have very low frequency of response, such as breast cancer other than triple negative breast cancer, prostate and colon cancer. And there’s often heterogeneous responses that’s been seen between things, distinct tumors within the same patient.
Unknown Speaker 7:45
So I think, you know, there are, of course, a lot of cancers that respond very well, but we still have a lot of cancers where we can improve these therapies. Got it? And we might have some conversation about whether how meaningful some of these these terms are. But we’ve heard about primary adaptive and acquired resistance to checkpoint therapy, how can can you sort of give us an idea about what those are and how our understanding of these have evolved over the years?
Unknown Speaker 8:15
Yeah, so so that there’s, you know, there’s many facets to this question.
Unknown Speaker 8:21
You know, there are, even though we’ve been very successful with these types of therapies, there are fortunately, the majority of the patients that do not benefit from the treatment, who develop what we call primary resistance, and then there’s some that respond, but relapse after a period of response and we turn that acquired resistance. So, these mechanisms might exist at the time of initial presentation,
Unknown Speaker 8:49
which highlights primary resistant mechanisms, or they evolved later, which is what we call the adaptive resistant mechanisms. So when we look at resistance mechanisms, we can divide it up to into tumor intrinsic and tumor extrinsic mechanisms, and that means it’s either occurring inside the tumor or in in cells that are outside. So, the intrinsic mechanisms have been identified and they can include things such as signaling through the MAP kinase pathway or loss of P 10 expression, which enhances pi three kinase signaling, it could be due to expression of the wind, beta carotene and signaling pathway or loss of interferon gamma signaling pathways or it could also be due to lack of T cell responses due to loss of tumor antigen expression because the tumor downregulates antigen expression
Unknown Speaker 9:50
for the tumor extrinsic mechanisms that lead to primary and adaptive resistance. It can involve components other than
Unknown Speaker 10:00
tumor cells within the tumor microenvironment. And that could be related to regulatory T cells, myeloid derived suppressor cells, macrophages, or other inhibitory immune checkpoints. And those all contribute to inhibition of anti tumor response.
Unknown Speaker 10:20
So that adaptive resistance refers to patients that respond to for a period of time, then they progress. And then we term it acquired resistance and that increases. And it has become clear that approximately 1/4 of to 1/3 of the patients with metastatic melanoma, who have objective response to checkpoint blockade therapy with anti CTLA four or anti PD one, they will relapse over time, even though they receive continued therapy. And some of the mechanisms I already mentioned, they include loss of T cell function, lack of T cell recognition or down regulation of tumor antigen presentation, or development of escape mutation variants in the cancer.
Unknown Speaker 11:09
So it’s there’s evidence that these mechanisms can lead to acquired resistance to checkpoint inhibitor or even adoptive cell therapy. So it’s not completely clear how this dysfunction persists despite PD one blockade. But it might involve commitment to cell death, epigenetic inflexibility, or contribution of other immune inhibitory receptors. I think it’s important when we consider their resistant mechanisms to immune based therapies, that we have to remember that the immune response is very dynamic and constantly involving in each patient, other as a result of the patient’s own environmental and genetic factors, or as a result of treatment interventions, including surgery, chemotherapy, radiation therapy and immunotherapy that many of these patients undergo. It’s also important to consider that anti tumor responses are ongoing during the course of the patient’s disease. And that might be affected by many of these factors. And therefore they’re established and establishment of resistance mechanisms relevant to immunotherapy failure may predate the time where the patient actually received immunotherapy.
Unknown Speaker 12:28
Got it. Thank you. That’s a great way to frame our start here. So maybe the last question for you before we move on to the companies. Are there any specific avenues of inquiry that you believe are most promising for overcoming these challenges and improving outcomes in the post checkpoint setting?
Unknown Speaker 12:47
Excuse me. Yeah, no problem. Hold on one sec.
Unknown Speaker 12:54
Sorry, I have a cough.
Unknown Speaker 12:59
Yeah, I think you know, one of the prime examples that we have is combination therapy, which is, of course, the combined therapy of blocking antibodies against, for instance, two different immune checkpoints such as CTLA, four and PD one. And we’ve seen that that increases the response rate to therapy and also leads to improve survival in patients with at least in melanoma.
Unknown Speaker 13:23
So the rationale for combining these checkpoint therapies are, there are many different reasons but blocking several checkpoints on energized tumor specific T cells
Unknown Speaker 13:37
could lead to more efficient blockade or
Unknown Speaker 13:41
even convert the tumor environment from cold from cold to hot. One issue with these combined therapies is often an increase in toxicity which of course we want to avoid. Other combination therapies that have strong clinical and preclinical rationale, could be the use of molecularly targeted therapies in combination with immunotherapy. And I think one of the illustrious, most illustrative examples of that is oncogenic, BRAF in melanoma, and so through treatment with B RAF targeted therapy
Unknown Speaker 14:19
along you, you provide limited durable disease control, but it’s associated with fair, very fair favorable effects in the tumor microenvironment where it increases the antigen and HLA expression, it increased T cell infiltrate, and it reduces immune suppressive cytokines to increase the T cell function. So when you combine these targeted therapies, with checkpoint inhibitors, you might in convert a cold microenvironment to hot one. And that results in increased expression of PDL one, which could then lead to a better response with immune checkpoint blockade.
Unknown Speaker 15:01
There are also other strategies that I’ve seen that seems very promising, that are based on on the novel insights that we have into T cell and overall immune function. Some Examples could include metabolic reprogramming of T cells to enhance therapeutic response. We can add chemotherapy, which increases antigen expression and modulate cytokine environment.
Unknown Speaker 15:29
Unknown Speaker 15:30
perform epigenetic modifications, inhibit macrophages, which has an inhibitory function on the T cells. You could give immune modulators such as chemo kinds, you can combine immune checkpoint with adoptive T cell therapy, NK cell therapy or activation.
Unknown Speaker 15:52
You can combine it with Oncolytic viruses or even modulate the gut microbiome to respond or to augment these responses in cancer immunotherapy. So I think there’s a lot of promising
Unknown Speaker 16:09
approaches. Of course, what we’ve so far, mostly been focusing on our approved therapies. So the combination therapies,
Unknown Speaker 16:18
but I think there’s a lot of promise in new avenues. And I think we’re going to hear about some of those today. Some excited about that. Yeah. And that that’s a good, good transition there. So Ian, can you provide a brief introduction to Portage is intp agonist approach?
Unknown Speaker 16:36
Let me just to highlight a little bit about Portage. So we’re a bunch of former BMS drug developers, scientists, business guys who participated and helped develop PD one and CTLA, four antibodies. I learned a lot during that process about to Michelle’s
Unknown Speaker 16:56
intro about why they’re not responding. And what we have done is we’ve gone out and we put together a pipeline about 10 products that address almost every mechanism that you just heard about improved antigen recognition, turning cold tumors to hot,
Unknown Speaker 17:11
you know, correcting the tumor microenvironment, and so on. So, three of the products that we have started developing our own clinical trial. So I’ll tell you a little bit about IITs because people often get confused. It’s not an NK cell. It’s not a T cell. It’s an interesting, hybrid cell in very natural killer T cell that bridges the innate and the adaptive arms of the immune system. And what we’ve shown and we licensed technology from 20 years of research and Oxford University on this, and we have five small molecule agonists, my NK ds, and what these agonists do, is they,
Unknown Speaker 17:52
you know, completely reprogram the immune microenvironment. So we’ve shown that they can activate NK cells, we’ve shown that they can activate a dendritic cell.
Unknown Speaker 18:03
We’ve shown that that leads to a B cell response. We’ve shown that this also can activate antigens specific CDA T cell response. So you’re really getting a broad attack on on multiple different cell populations that contribute to an anti tumor response. We’ve shown because ndscs and TAMMS, as we just heard, are important in the tumor microenvironment that they have CD one D molecules on their surface and we can down modulate the mdscs and tumor associated macrophages so we can help correct the tumor microenvironment which can let these CDA T cells come and do their job as well as the NK T’s and B cells. We’ve also shown that exposure to ATS and these agonists, does impact the cancer cell directly by up regulating Pdl, one on the surface of the cancer cell and some of the immune cells. So in essence, we’re converting a Pdl, one negative tumor to a PDL one positive tumor.
Unknown Speaker 19:01
We’ve shown preclinically, that our drug as a monotherapy has activity even in PD one resistant models. And then when you give the combination of our drug with a PD, one antibody that we can restore sensitivity to PD one. So it’s really a novel approach. I mean, I think our approach at Portage is to try to make sure that in each patient, we are augmenting all three of the kind of key mechanisms to get an anti tumor response, which is potentially relieving a checkpoint signal, improving immune priming and boosting even in immunologically cold tumors, and addressing the tumor microenvironment and antigen recognition. So it’s really interesting the way we’re developing these drugs. So I NK T agonists are in a clinical trial right now.
Unknown Speaker 19:51
Where we’re looking to, you know, in phase one, obviously to establish the safe dose either monotherapy or in combination with PD one and then we go directly
Unknown Speaker 20:00
into randomized phase two, where we’re comparing a PD one antibody alone versus our NK T alone versus the combination of the two, which was will give you a lot of information about the utility of these drugs either as a monotherapy, or in combination in patients who either have failed the PD one, and we’re trying to overcome that acquired resistance, or patients who are naive to PD one, and we’re trying to avoid some of the mechanisms of resistance, either primary or acquire that yeah, that’s a great lead into the the next question. So you highlighted some of these details here. But are there any what like key pieces of information? Do you expect to be able to learn from this the Oxford University trial, I know that you have some biopsies you’re doing and you highlight some of the trial design? What are you hoping to learn in this this earlier stage trial? You’re? Sure. So you know, part of our process when we take on development of a compound is to talk to the pharma companies that could be acquires of our technology. So we have a pretty good understanding of what people are looking for. And I think the challenge we have as an industry, there’s a lot of companies go directly to combo studies. And they haven’t really delineated the contribution of the parts, and they don’t really have comparative data to understand, does that drive really add benefit on top of PD one. So in this particular trial, we’ve chosen to focus on two tumor types that are already sensitive to checkpoint inhibition. So we’re doing this in melanoma, and we’re doing it in non small cell lung cancer. And the randomized arms are somewhat different for each tumor type. So in melanoma, again, we’re going to compare a PD one alone, to the combo to our drug alone. So we’ll very clearly be able to do any eight the contribution of parts, and we have a strong correlative component where we’re looking at blood and and tumors to understand, you know, what’s going on in the tumor microenvironment, what’s going on with T cells? Are we getting more activation when we had an intp agonist to PD one, or we can, you know, increasing Pdl, one expression, and so on and so forth. And we’re also trying to look at
Unknown Speaker 22:16
things that could help us predict which patients are more susceptible to treatment. So if you study and you know a lot about diabetes, you know, it’s a relatively rare patient, you know, cell population. So we’re looking at the level of I NK T cells at baseline to understand if that’s a predictor of benefit from this particular treatment, obviously, and it’s really interesting because the levels of I NK T cells at baseline has been shown to be a prognostic marker, a negative prognostic marker in a variety of tumor types. So if you don’t have a lot of these cells, you tend to do worse. If you have a lot of cells, you tend to have better overall survival. So that’s what we’re looking at in melanoma. Now in non small cell lung, it’s a little bit different story. And treatment, particularly in the UK, where we’re doing the study is highly
Unknown Speaker 23:07
dictated by expression of PDL one. So if you are Pdl, one negative lung cancer in the UK, you don’t get a checkpoint inhibitor. So we look at that as a real opportunity. Since we’ve shown we can convert a PDL one negative to positive in the lab, we’re going to take a long patient has been one negative we’re going to get a fresh lung biopsy, we’re going to give them our NK T agonist, just one treatment, and then re biopsy a few weeks later. So we’ll be able to prove whether or not we converted that PDL one negative killer, the PDL one positive, then they go on the combo with the PD, one antibody and we take another biopsy. So that’s a nice kind of proof of concept. Kind of study with you know, biomarkers that show whether or not we’re converting a Pdl, one negative to a PDL one positive in the patients that are PDL one positive already we’re taking PD one naive kind of first line patients and randomizing them to get Pdl, one PD one antibody alone versus the Tomba. So that’s a nice kind of proof of concept
Unknown Speaker 24:08
trial to to understand, does this combination really add benefits and OBD one, and there’s even like a third arm there, which is the PD one alone control arm at the time of progression, those patients get to crossover and get our NK T agonist as well. So all patients get our drug at some point. So we’ll be you know we’re really looking to see multiple mechanisms can we you know, overcome the acquired resistance that we talked about to PD one therapy can we avoid b you know, improve the primary resistance as well by giving the combination of front and all these arms have a strong correlate of science component where we’re looking at you know, T cell activation I NK T levels and how that correlates with results. So really excited about this novel trial and, you know, somewhat unprecedented to do a six arm randomized study as your first few
Unknown Speaker 25:00
But I think that you know, reflects our understanding of the market and what the market wants to see, and what we need to understand to be able to advance this forward for cancer patients. Got it. So I’ll give you one more question before we move on to the next panelist. So what are the next steps for these for port two and port three? And when can we expect these data readouts? Because it it seems like we’ll we’ll be able to get a much better sense of, of where these drugs could see their best use based on on the the current trials that you’re running? Sure. So what I just told you, that was all part two, that’s our ion Katie agonist, the liposome formulation just mentioned, point. 3.3 is a very interesting compound where we took tumor antigens, and our ion Katie agonist and CO formulated that nanoparticle. And what we’ve seen is the CO delivery is the key ingredient here. So when we combine these two drugs in a particle, they’re fivefold more important potent at killing cancer, as well as generating antigen specific CDA T cell response as the two drugs given individually. So it’s very interesting concept. And it really relates to how do we get the immune system primed. And when you they’re both in a particle, they’re going to be both taken up by an APC and the same endosomes at exactly the same time. And that creates a huge degree of synergy that you don’t see when these are given individually.
Unknown Speaker 26:30
So we’re really excited about that one that’s also in a randomized trial, hybrid phase one phase two trial where we’re going to be looking at combinations with PD one, and a randomized trial. So PD one alone versus the combo. So both these trials started early this year. So we’re really trying to establish a safe dose to proceed to phase two, you know, there’s no expectation that there’s going to be overlapping toxicity, because they’re quite different mechanisms. So we should get some of that safety information this year looking to go into the randomized phase two portions next year, but we’ll be getting this biopsy data and response data and mechanism based data, you know, next year, so we’re excited that these trials are ongoing, despite COVID challenges, and that we’re hoping to have be able to report on efficacy next year, and I agree with you is will be critical to do these comparisons versus the appropriate controls to really understand is there merit in this approach? And what’s the magnitude of that of that benefit? Great. Thank you for that introduction. So let’s turn to Andrew. So what is grit stones approach to immunotherapy? And how do you believe that it’s differentiated from what others are doing in the space?
Unknown Speaker 27:44
But thanks for the question, Justin, thanks for having us on the panel. The centerpiece of the adaptive immune response to tumors as you heard a moment ago from Dr. Crows guard is CDA T cell recognition of class one HLA presented Neo antigens. So that kind of lies right at the heart of much of what we’re seeing as claim in terms of effective immune responses against tumors leading to clinical benefit. And as you’ve also heard, unfortunately, the majority of patients with the common solid tumors do not have evidence of tumor infiltrating CDA T cells and baseline. They don’t respond to PD one antibodies, the tumors are cold. And the therapeutic hypothesis that sits right there is that these patients tumors have successfully evaded the adaptive immune response. In other words, the patient remains immunologically ignorant of the existence of their tumors of the tumor Neo antigens. And therefore, treating these patients with nonspecific immune stimulants, perhaps is unlikely to lead to clinical benefit because the substrate is not there. There are no Neo antigen reactive T cells in these patients, there is nothing to stimulate. And so that’s the hypothesis that we articulated when we formed our company six years ago now.
Unknown Speaker 29:02
And what we’re seeking to do is to generate prime if you like, the adaptive immune response against the new antigens present in that the patient’s tumor. And then once you’ve created new engine specific CD aids, then the checkpoints may be able to be effective by maintaining the functional active activity of those T cells. So that was the basic idea. And there are two key challenges to doing this. Number one, how do I identify the relevant new antigens in the patient? And then number two, how do I administer those to a patient to drive a CDA T cell response? And you’ll hear me keep referring to CDH because again, most epithelial tumor cells express class one actually, they don’t express class two, CD fours recognized class two. And so while CD fours perhaps very important for the generation of immune responses, they’re probably not the common final effectors killing of epithelial tissue
Unknown Speaker 30:00
muscles is likely to be all through class one new antigen recognition.
Unknown Speaker 30:06
Making CDs in humans is not easy. Most vaccines are pretty good at making CD fours and making good antibody titers tired to make CDs. So those were the two challenges. And we built a machine learning model to take a routine core needle biopsy and predict just from sequence data, which of the mutations in the tumor are likely to be true Neo antigens. And we tested this using orthogonal data from Steve Rosenberg still work. We publish all of this in nature biotech a couple of years ago. And so now we’re predicting new antigens with 75 to 80%, positive predictive value. And then we take the new antigens and plug them into our vaccine vectors. And when we use two vectors, we use an adenovirus to prime the CDH immune response. And then we expand and boost using a self amplifying mRNA vaccine. So somewhat similar to the Madonna and biontech COVID vaccines, but it’s using a slightly different construct self amplifying mRNA, which does have some potential benefits over simple mRNA, particularly in terms of CDA immune response. So that’s the platform that we built. And then we’ve been testing it in fairly standard phase one to study and advanced solid tumors. And we’ve seen data that have been extremely encouraging, such that we’re now launching a randomized pair of phase two studies. In earlier stage metastatic, microsatellite, stable colorectal cancer, which is one of those archetypal cold tumors, where there’s huge unmet need, where checkpoints really don’t do anything. And there’s a huge opportunity to to affect change and transform the outcome for those patients. Because sadly, once you have a diagnosis of metastatic colorectal cancer, MSS, microsatellite, stable, then all therapy is essentially palliative at that point, and you’re likely to succumb to your disease in around two years from time of diagnosis. We’re looking to change that statistic.
Unknown Speaker 32:09
Got it? So speaking to that, and you can clarify the these exact which each of these programs are but how do you anticipate the granite versus the sleep programs working to improve the IO outcomes for patients? And beyond the safety and clinical response? Are there specific signals that you’re looking for to indicate that the therapeutics are working as intended.
Unknown Speaker 32:33
So based off of the technologies I described, we’ve built two product concepts. The first is a fully personalized, new antigen based immunotherapy. And that’s called granite. We take the biopsy from the patient, sequence it, plug all of the mutations into our prediction model, pick the top 20 with the highest probability of being new antigens, and put those into the vaccines that are unique for that patient. And we administer those on a monthly intramuscular basis, together with checkpoints. And then there’s an off the shelf product called slate. And at the moment there, that product of the first version of slate is centered on K RAS mutations. K RAs, of course, is a very common driver mutation found in large numbers of patients with lung cancer and colorectal cancer, and pancreatic cancer.
Unknown Speaker 33:21
And some of those care as mutations can be processed and presented as new antigens by certain HLA class one molecules. And so we select patients who have the right care as and the right HLA. And then those patients can receive our off the shelf sleep therapy. So the opportunity set for Slate is a little narrower, because somewhere between 10 and 15% of lung and colorectal cancer patients will be candidates for that therapy. Whereas for granted, the majority the vast majority of lung cancer patients will be candidates, and around 60% of colorectal cancer patients will be candidates for the personalized immunotherapy approach. So there are some differences in terms of population addressable population. And perhaps, granted has some benefit, because there are likely to be multiple Neo antigens for each patient, a multiplicity of targets that may protect against acquired resistance, whereas with slaid, for most patients, they will just be the 1k RAS Neo antigen, and therefore, it’s a single antigen focused. And of course, that doesn’t mean it can’t work. But it does mean that quite resistance perhaps might be a little more likely we shall see.
Unknown Speaker 34:35
So those are the differences. Now, as we’ve gotten into the clinic, not knowing what to expect, because no one’s really done this before. We were pretty broad in terms of efficacy, biomarkers. And what we’re starting to learn, I think, as a population and the panel may have some perspectives on this is that recessed response is appears to be an unreliable biomarker for some forms of novel immunotherapy. And I think the clearest data
Unknown Speaker 35:00
to come from immuno core, who showed that in a randomized phase three trial in a subset of melanoma comparing there, essentially it’s a bi specific T cell engager with Pember lism AB, the Rhesus response rates were low, single digit, it was 5% in the pen bro arm 9% for the patients receiving their molecule. But overall survival, the hazard ratio in favor of their drug was 0.5. So a very strong effect that you would completely miss if you relied on traditional recessed radiology. And they published some very nice data Erasmo a month ago, showing that circulating tumor DNA and genetic molecular response was a much much better biomarker that correlated remarkably consistently and strongly with overall survival benefit. Because, of course, the FDA and patients care about true clinical endpoints. Living Longer is of course number one overall survival, feeling better and functioning better. Patients don’t care about radiology, it has been a useful tool to assess whether an a therapy is likely to be effective or not. But now, it appears to be losing its utility, at least with some forms of immunotherapy. And the good news is we appear to have a better alternative, which is CT DNA.
Unknown Speaker 36:20
So we looked at both of these, and we’ve certainly seen evidence that we have molecular responses in colorectal cancer patients in nearly half of them. In small numbers. Obviously, this is phase one, two, but we see molecular responses and multiple patients defined as at least a 50% reduction in CtDNA titer, from baseline. And that correlates with extended survival. Because in third line colorectal, which is where we’ve been working, median survival is a remarkably consistent and depressing six months. And we had again, in small numbers of patients non randomized study, let’s be clear, but what we saw was that half our patients roughly did not exhibit a molecular response. And they progressed and died at the expected rate with a median survival of six or seven months. And then the other patients who had molecular responses, none of them died of tumor progression, up to 80 weeks eight zero, obviously significantly longer than the expected six or seven months, there was one death and that was actually related to irinotecan induced febrile neutropenia and sepsis. The physician was a little nervous stopping all chemo, even though the patient progressed on chemo. And so sadly, actually, the patients had come from a from a drug induced toxicity.
Unknown Speaker 37:33
So it’s a signal. It’s an Ian made the point that if you look in hot tumors, where checkpoints work, it’s very hard to discern signals in small and uncontrolled phase one, two studies. That’s one of the reasons we chose colorectal because we know the checkpoints really don’t do anything in MSS, colorectal, the response rate is maybe 1%. And there’s been consistently good evidence that there’s no effect on PFS or iOS. And so here, when we see, you know, molecular responses and half of subjects, you cannot attribute that to checkpoints, that has to be the therapy, when that then associate strongly with extended survival, then this starts to look very compelling. And obviously, that’s why we’re following the signal into earlier stage randomized trials to show definitive efficacy. Yes, that sounds very interesting. And
Unknown Speaker 38:23
to to make sure we have enough time for some cross panel questions, we can move on and turn to verad and compass so varied. Can you explain the company’s broad approach to to drug discovery and how that might lend itself to addressing complex questions around prior treatment resistance, including with checkpoints and and how does the company’s technology platform come into play here? Sure. So companies realize early on that the future treatment paradigm in oncology are going to be combination regimens. And therefore, we build our platform such that it can test a lot of those proposed combinations and an empirical broad approach. And out of those experiments, we select the ones it looks to be the most promising one based on scientific evidence and data, and not by sort of guessing based on the biology alone. So the way that it came into play is we are also combining novel and existing checkpoint blockers in our experiments, but we also push the boundaries and look for novel mechanisms. Our third program is a bi specific antibody targeting PD one and PDL one and that came out of that platform for example.
Unknown Speaker 39:44
Got it. So it looks like you you have plans to test your lead assets CTS 009 in combination with PDL one inhibitors, but are currently focusing on monotherapy and chemo combos in gland Geopark
Unknown Speaker 40:00
Colorectal cancer and ovarian cancer. What’s the thinking behind why a potential PDL? One combo would be worth pursuing for this asset? Sure. So RDL for VEGF by specific antibody has been studied in many of the so called Cold tumors and has shown and demonstrated activity as a monotherapy. Already in colorectal and in gastric cancer. And in combination with chemotherapy, that’s shown also promising activity in colon Jia Christina, and in pancreatic cancer, and because it has already demonstrated compelling activity and all of those indications we plan on exploring those indications further in a controlled studies in phase two larger studies etc. Now, why do we want to go the pathway of combining that with a PD one blocker also why are we exploring that because we have seen a study that Roche has done with a teaser Liza Mab combining that with
Unknown Speaker 41:07
Unknown Speaker 41:09
Bevacizumab with with basically with Avastin and they did something very courageous. They tested that in frontline hypothesis cellular carcinoma against Serafina against the standard of care in front line, and that Teza plus Bevacizumab has been superior and is now taking over standard of care and first line HCC. So we figured you know, we have a deal for VEGF by specific that has demonstrated stronger activity than Bevacizumab in preclinical studies with the mechanism make a lot of sense.
Unknown Speaker 41:44
There is scientific evidence so so from all those reasons, it makes a lot of sense to test the combination. Got it your second asset, so CTS 471, is being tested in in post PDL? One setting and you’re already looking to combine it with Pdl, one inhibitors and in various lines of therapy. Have you believe this drug works to potentially benefit post PDL one patients and or demonstrate synergy with drugs that target PDL? One?
Unknown Speaker 42:14
Sure, so our second drug is a CD 137 agonistic antibody, which is a non overlapping mechanism with PD one or PDL? One. So we’re targeting on not only T cells, but also NK cell with with his approach with this CO stimulatory molecule. So, so that’s to begin with. And then in terms of the mechanism, and then in terms of the evidence, the clinical evidence we have gone after those patients who have secondary resistance or developed resistance over time initially responded to PD one or PDL one and then progressed. And what we’ve seen in our phase one study in this patient population is we’ve seen a lot of long, durable, stable diseases and some tumor shrinkage is impatient inpatients and then we have followed as with a phase one, B. And in the phase one B, we have already seen response in a patient with a small cell lung cancer, and we’re getting more and more data from that study. So we’re very pleased to see that our
Unknown Speaker 43:21
monoclonal antibody appears to work in those patients that have progressed and PD one or PDL. One, which is a very, it’s an area of very high unmet medical needs. Do we have a sense of when the data readouts could be for the for these first two assets? So we have recently released data at the triple meeting. We were we had a plenary talk about CDs 009. And we’re getting data from the ongoing studies of 009 and 471 on an ongoing basis, and we’re probably gonna release data in the next two weeks additional data. Got it?
Unknown Speaker 44:00
And so maybe the last question for you before we go on to the the cross panel questions here. So you mentioned that that PD one Pdl, one by specific targeting post PDL one patients that you’re you’re preparing at least for a potential ind next year.
Unknown Speaker 44:15
Why do you believe that patients who are relapsed refractory to PDL? One therapy could benefit from PD one PDL? One by specific if then I saw a question because it’s not counterintuitive that patients that have progressed on PD one or Pdl, one would respond to a dual
Unknown Speaker 44:32
PD one PDL one blocker, the reason we think that or we believe and we don’t only believe we have data to substantial substantiate our beliefs. So the reason that we’re going after that patient population is that our BI specific does not only block PD one or PDL. One we have done extensive studies around the mechanism of action of that by specific and we figure that he works through additional mechanisms. For example, it
Unknown Speaker 45:00
cleaves off the extracellular domain of PDL, one from the surface of effector cell, making them completely, completely immune, if you will to, to being inhibited by the immune system. It also serve as an indirect agonist of CD 28, which in and by itself is a really interesting mechanism. So, so it’s not only doing the blockade that PD one or Pdl, one is doing. It has some additional activities. And because of those additional activities, we believe that’s the reason why we’ve seen in preclinical testing and in vivo models of colorectal cancer and other cancers we’ve seen enhanced activity over Keytruda or a tease Elisa Mab or best in class. Other PD one Pdl, one blockers, so so that’s the reason we’re taking it forward into the clinic.
Unknown Speaker 45:55
Got it. That sounds very interesting. Looking forward to that. So with our remaining time, I’d love to throw some general questions out there and see if any of our panelists would like to, to weigh in on them. So to the panelists, what do you believe are the greatest challenges to improving checkpoint inhibitor outcomes and solid tumor patients today?
Unknown Speaker 46:21
I’ll start I mean, I think, to me, the biggest challenge is availability of patients. You know, there’s a lot of interesting science out there that are designed to test different mechanisms. And we probably don’t have enough patience to test everything. And you know, in the past, there’s been sort of a shotgun approach, I’m sure you’ve seen some of the figures of all the different PD one combo studies and, and people are throwing a lot of resources at this at these problems. And some of them have better rationale than others. But the challenge, and to me, the Raven receptors, availability of patients. That being said, you know, the other challenge is also,
Unknown Speaker 47:06
which my panelists and angio and others have experienced is how do you access benefit, I would say today in the current environment, everyone’s expecting your phase one study in oncology is going to show you no responses and CRS. And if you don’t show that, you know, people start to lose interest. And I think that’s a mistake, right? Because these drugs are working in different mechanisms. And sometimes radiologic response may not be the best measure of success. And then if you have to go look at something like overall survival, that’s something that takes a long time. And you can compare it to historical data, which is sometimes good, sometimes bad. But it’s really hard to tell if you have a signal early on in these and you have to sort of take a leap of faith and go into bigger studies, I could tell you, you know, our experience, you know, we had one project where we were not seeing clinical responses, but we were seeing survival. And, you know, we moved it into, you know, moving into a phase three program. But it’s a big commitment to go into big randomized phase three with survival implant based on some surrogate endpoints or some suggestion of survival from an early stage trial. So I think that’s the challenge misses is how do you get confidence in your programs early on to you know, take them forward? If you’re not seeing response? Of course, we all like to see response. And I think the expectation from the financial community is that you’re going to see responses even in your phase one. And that’s not always the case, with the way we are testing our drugs. So to me, that’s those are the challenges that I experienced in my company.
Unknown Speaker 48:51
Thanks. And let me let me pick up on that. I agree the obviously on on your first point. And I strongly agree with you on the second point, I think people use the term radiology and radiology response as a synonym with clinical response. And of course, they’re not.
Unknown Speaker 49:07
They’re very different. They can be similar, but they can also be very different. And I think we just have to be more thoughtful here. Radiologists served us? Well, it was developed for chemotherapy, which obviously just kills tumors. And so shrinkage of lesions became this proxy. And it worked well with targeted therapy. It stopped working as well with checkpoints. First of all, we had to acknowledge the existence of pseudo progression and the development of things like aI resist, but that doesn’t really solve the problem. I think fundamentally, radiology is just not a very good tool, because we’re looking to drive T cell proliferation in lesions. Therefore, measuring lesion size does no longer tell us what’s going on. When we had the simple model that the lesion was all tumors and therefore less is good, fine. That’s not the model we’re in now with with immunotherapy, we’ve got a tumor that contains at least two cell types of course in reality many more
Unknown Speaker 50:00
You got tumors, the bad guys and T cells, the good guys, if the T cells are proliferating, I don’t really know what is going on in that lesion, it might get bigger, it might stay the same, it might shrink, shrinkage is probably always good, I think we can all accept that. But lack of shrinkage doesn’t mean that not good things are happening. Excuse the double negative
Unknown Speaker 50:20
AstraZeneca just showed some really nice data and asthma, making the point that in their retrospective analysis of the mystic study, which was a big Durva tremie versus chemo, frontline lung cancer trial.
Unknown Speaker 50:35
Of course, responses are good. But stable disease per resist has really lost its value doesn’t mean anything.
Unknown Speaker 50:43
It because some patients are going to do terribly, and some patients actually do very well. And again, the good news is CtDNA. And this was the point of their publication splits this so called stable disease population into two much more meaningful categories CtDNA responder, and CtDNA progresser. And so I think radiology really does need to be moved into the retirement home at this point for novel immunotherapy still has utility for many classes of drugs, don’t get me wrong, but for what we’re doing, I don’t think it’s very helpful. Molecular response looks to be a much more useful biomarker for survival. And of course, it’s survival that we ultimately care about. And there’s a lot of work ongoing, trying to validate various CtDNA metrics in different contexts with different drugs as a useful surrogate endpoint. So that, to me is the big focus right now, for many of us across this sector of the industry.
Unknown Speaker 51:39
I would like to make a comment also, you know, I think what it really comes down to is the T cells, right? Like, if we don’t have T cells in the tumor, nothing is really going to happen. And you know, we have to find ways of overcoming these very
Unknown Speaker 51:56
immunological, suppressed tumors, like pancreatic cancer is the excellent example. Lots of inhibitory cells, very difficult stroma many different things.
Unknown Speaker 52:10
So I think until we actually can get the T cells in there, you know, it’s nothing is going to happen, it doesn’t matter what we measure, it doesn’t matter what, you know, other things that we do. So I think we have to focus on these solid tumors that have these extremely suppressive environments.
Unknown Speaker 52:30
And you know, even though we boost a very effective T cell response in the periphery, if they don’t get into the tumor, are never going to see an effect.
Unknown Speaker 52:40
So I think that’s, that’s the main roadblock, two to getting them into, you know, getting solid tumor patients with very complex tumors to respond. And then of course, antigen expression.
Unknown Speaker 52:54
On it, yeah. A couple of points, I think that you guys made speaks to this next question. Specifically, what Andrew said, looking at the potentially the circulating the CtDNA. And the comments about resist that resist not really being the the best measure. But with so many players trying to solve these problems and so much money at stake, what do you think investors should be looking for in a novel IO approach? And at various stages of clinical development? How can they tell? So response might not be the best survival takes a long time to get to? So how can they tell if a drug is, is working at an earlier stage? Or Or do they have to wait, well, what are your thoughts on that front?
Unknown Speaker 53:46
So I like to take a shot at questions, I think, at the preclinical stage even before you get to the clinic investor in need to look at whether the therapy is working across various immuno immunological tumors and models in vivo models, basically, and look at those models as models of the immune system. Not necessarily tumor models, but it’s well known today’s ct 26. And MC 38, may not represent exactly colorectal cancer, but more of the immune system. So I think activity across multiple models is really important as a monotherapy for those agents that are advancing to the clinic. And then at the clinical stage. I think that at the early clinical stage, we at Compass have this rule and I think a lot of companies do as well, that you want to see the minimum monotherapy activity of your agent. I don’t buy those things that are only work in combination with PD one PDL one we all know that PD one and PDL one work. So if your acid are your molecule does not work in and by itself only when you combine it, it’s really hard to tease out what’s the contribution of that that other agent to to the combination unless
Unknown Speaker 55:00
You have an extremely enhanced activity in combination with PD one or PDL. One, but most companies do not have that. So I think at the early clinical stage, you need to see really monotherapy activity of your agents. And then at the later stage, you obviously need to have better activity than the standard of care in each tumor type. And in each tumor type, the bar is different. There are all those immune sensitive tumors that Dr. Grossberg mentioned, you know, melanoma and renal cells, where the bar is pretty high. And then there are the so called Cold tumors, like pancreatic, colorectal or gastric where efficacy bar is still pretty low, because the immune oncology agents have shown
Unknown Speaker 55:48
either single digit or double digit, low double digit activity. So there, you really need to be better than the standard of care.
Unknown Speaker 56:01
Got it. And I think that the
Unknown Speaker 56:06
from, from my perspective, I appreciate the the trial design, early trial design, thoughtful trial design approach that that Portage has took to get some of those signals. And I imagine that
Unknown Speaker 56:22
maybe biopsies could also play a role and just indications that the drug is working as
Unknown Speaker 56:32
as it’s as it’s supposed to.
Unknown Speaker 56:36
Unknown Speaker 56:38
maybe we can go on to the next question here.
Unknown Speaker 56:42
So what are your thoughts on making use of potentially complementary approaches to improve outcomes during or post PDL? One therapy versus seeking novel checkpoint inhibitor pathways? That is, do you think that the key to overcoming checkpoint resistance will be found in targets like LaGG? Three and tigit? Or in novel non checkpoint combination approaches?
Unknown Speaker 57:10
Unknown Speaker 57:14
know, I just wanted to say that, you know, the most common checkpoints that we had looked at, you know, there is an improvement, but it’s not very significant, right. But there are many other checkpoints that are present on the cell surface. And I think we need to understand more about how what is the combinate combinatorially effect of these checkpoints, a lot of them signals through the same pathways, right, so we can identify particular molecules to target common pathways. So we can basically knock all these different checkpoints out at the same time, I think we have a much better chance. So I think
Unknown Speaker 57:52
we all seem to focus on like three CTLA, four PD, one Tegid. There are many other checkpoints and novel checkpoints that’s been discovered. And I think we need to understand more about their downstream signaling and, and how they actually work in concert. Before we can, we can start designing better combination therapies, I think there’s, you know, is this, of course, coming from a basic sciences, but I think there’s too little understanding on how these molecules work, you don’t really know much about how they work. It’s, it’s very recent, that, you know, some of the signaling pathways for PD one was was figured out, right. So, you know, I think there just has to be more understanding of how the model called signal signal and, you know, what are their structural basis? And how can we best design these inhibitors? Like one example, for instance, like is
Unknown Speaker 58:47
either either one, right, that I that looked very promising in preclinical studies, but, you know, once we got to the phase three, there’s not really any good outcome there. But if we understand more about how these molecules work, and we can potentially design more effective inhibitors and, and maybe target, you know, different pathways than has been done in the past, then, you know, I think we have a much better chance of improving it, then, instead of just taking the antibodies we have and just combine them. That’s how I think about it.
Unknown Speaker 59:23
Unknown Speaker 59:24
Good. You know, for us, it’s, you know, we talked about all the mechanisms of resistance, right. And, you know, my belief is that, you know, tumors are not responding to checkpoints, perhaps because they’re cold or there’s no T cells or they have a suppressive microenvironment. So doing more checkpoints, in those particular patients may not get you too far. What might be better, as you know, increasing antigen presentation trying to recruit T cells, correcting the tumor microenvironment, and so on. So our approach is really more patient specific and trying to understand in which settings what
Unknown Speaker 1:00:00
have the key mechanisms that are potentially contributing to a resistance pathway and then trying to address all of them in the single patient. And, you know, unfortunately, a lot of the combos of checkpoint inhibitors
Unknown Speaker 1:00:14
that you just keep adding more checkpoints have not really panned out as being that much better. It’s like if you’re taking your foot off the brake penalty taken a little bit off or a lot off, you’re not really going to affect the speed as much as it is pushing on the gas or doing other mechanisms to make the car go faster.
Unknown Speaker 1:00:34
Got it. Unfortunately, we’re out of time. Thank you. On behalf of B Riley and myself, I’d like to thank our panel participants, as well as anyone who is able to tune in. Have a great day, everyone. Thank you. Thank you