Okay, great. Thanks for joining the Oppenheimer Healthcare Conference on day 2 here. My name is François Brisebois. I'm one of the biotech analysts at the firm. The next presenting company here is Sensei. Sensei, the ticker is SNSE. We do cover the stock with an outperform rating. Very interesting oncology play with a differentiated approach here with a big year ahead of them. So what we'll do in terms of format is I'll let the company CEO, John Celebi, present the story for about 20 minutes, and then we'll have some Q&A afterwards. If you want to send questions in the chat, I can see those. If not, by email, it's francois.brisebois@opco.com, and I'm happy to ask them for you. Thank you again, the whole team here, for joining, and I'll let you take it away, and then I'll come back in for the Q&A.
Thank you so much, Frank, and welcome to everybody listening online today. We'll give you a little bit of an overview, and then the team here will be available for Q&A afterwards. As Frank said, we're an oncology company, specifically immuno-oncology, and we have a differentiated approach focused on conditionally active antibodies, and we'll talk about what that means. So I mentioned the team will be with us here today to answer questions. I just want to set it up with a little bit of background. We've got an approach that is really designed for the modern-day challenges in immuno-oncology, and that is that these antibodies are designed to harness a unique feature of the tumor microenvironment to create unique selectivity. And that's the acidity that's inherent in most tumors within the tumor microenvironment.
We'll talk a little bit about what creates that acidity and how we enable drug ability of promising targets by leveraging that acidity. But our most advanced asset is SNS-101 targeting VISTA, and VISTA is a very unique protein by virtue of the fact that itself has sensitivity to the acidic tumor microenvironment. As many published papers and prior efforts have shown, VISTA is a very important immune checkpoint, but it's also a very challenging immune checkpoint, again, as a result of the fact that it's near ubiquitous expression in the myeloid compartment throughout the body, and it's a critical regulator of T cell function. We're right now in phase 1 testing. We released some initial data in November of last year, and we're poised for an important data milestone in the Q2 of this year, which is our top line data for this program.
We also have several other early-stage drug candidates, but in the interest of time, we're going to focus you on our lead program today since it is really a proof of concept for this pH-sensitive approach and where we have clinical data. We're well financed. We have cash runway into the Q4 of 2025. That will get us through phase one and, in rough terms, about halfway through the phase two study that I'm going to talk to you about today. So with me here today are Erin Colgan, our Chief Financial Officer, Edward van der Horst, our CSO, and also Ron Weitzman, who's our Chief Medical Officer. We have a couple of other members of the team as well that are focused in business development and general counsel areas. I'm sure many of you are familiar with immuno-oncology.
I just want to highlight one aspect of it, which I think really speaks to the modern-day challenge, which is that despite the fact that immuno-oncology has been a transformative field in many ways for the oncology sector, it's also been challenging, and really a minority of patients receive benefit. Our entire corporate thesis is devoted to addressing that challenge, and we believe that there have been some challenges in immuno-oncology in the checkpoint field based on some really fundamental reasons. As you can see from the chart below, there really have only been three new classes of immune checkpoint drugs approved over the last decade plus. We believe that that is due to some very basic reasons, as outlined here on the left, and that is the fact that we're using really traditional approaches to develop antibodies toward these very important immune checkpoint targets.
A traditional antibody is great when you're dealing with a target that is restricted to the tumor microenvironment, but like many targets in the immune system, they're not. They're expressed rather frequently throughout the body, so a traditional antibody will bind that target regardless of whether it's expressed in the tumor or in the periphery. That has a couple of important downstream effects. One, it usually leads quite often to poor PK properties, a sink effect. That leads to a need for higher and more frequent dosing. When you have higher and more frequent dosing, quite often that increases your chance of running into dose-limiting toxicities. That, in turn, can limit the activity of your drug and perhaps even prevent you from reaching therapeutic dose levels. There's a very important case study in the context of VISTA that I'll focus on in just a moment.
Our approach, therefore, is really quite different. We are creating antibodies that are tuned to specifically recognize target regardless of expression, where it's expressed, but to bind only in the tumor microenvironment. To do that, again, we take advantage of the pH. That has a couple of downstream effects that allows us to really avoid the issues you see on the left. We avoid poor PK issues. That allows us to dose lower and less frequently. That gives us a better chance of avoiding toxicities we might otherwise see, and that, of course, also allows us to get to therapeutic dose levels in much broader terms. To give you a visual of the pH levels within the tumor and the periphery, pH in the periphery is very tightly buffered around 7.4. In the tumor microenvironment, it is not as tightly buffered. It usually is a range.
As you can see here, we depicted around 6.0, but you could see something in the 5.8-6.4 range, for example. This gives you a sense of what we're dealing with with the tumor microenvironment. The acidity within the tumor microenvironment is really driven by what's called the Warburg effect. This was described by Otto Warburg over 100 years ago, and it's the result of the altered metabolism of rapidly dividing cells. So I'll take you through our lead program. As I mentioned, that's SNS-101. We have a couple of important collaborations I should mention here for SNS-101. One is with Regeneron. They're our PD-1 supply partner and a great collaborator for us. We also have a CRADA with the NCI that's focused on preclinical and clinical work with the VISTA program as well.
Other pH-sensitive programs targeting VSIG-4 and CD39 are still preclinical, and last year we announced our first pH-sensitive bispecific antibody, which we're very excited about. So I'll focus on SNS-101 here. 101, as I mentioned, is targeting VISTA. VISTA itself is a B7 family member. That's the same family as PD-1. It is an immunosuppressive checkpoint, and it's believed to be mediated by its receptor on T cells, PSGL-1. It plays an important role in the tumor microenvironment, but importantly, that role itself is pH-sensitive. So as you can see here from the right, there's a crystallographic representation of VISTA in the lower panel interacting with its receptor, PSGL-1, and you can see three amino acid residues. These are histidines circled. Histidines are uniquely sensitive to pH. When the acidity is low enough, histidines become positively charged, and that's what allows VISTA's interaction with PSGL-1 to occur.
Now, when we disrupt that interaction with an antibody, you avoid the suppression that VISTA brings, and you allow for T cell proliferation and activation. The trick, however, is to do that selectively. Otherwise, you create a situation in the periphery, and that's why we developed SNS-101 as a pH-sensitive antibody. So as you can see here on the left, we've got the KDs for SNS-101 binding to VISTA, both at pH 6 and 7.4. And as you can see, there's a roughly 500-fold selectivity for VISTA at pH 6 versus pH 7.4. It's also an IgG1. It's got an active Fc. That's very important for many immune checkpoints, including VISTA. It's got a 7 nanomolar IC50 for blocking PSGL-1 interaction, and we recently resolved the crystallographic structure of SNS-101 binding to VISTA.
So there were prior efforts to target VISTA, and I think I'll focus here for a minute because the difficulty that companies have had in the past has really raised some question marks about whether VISTA is an important checkpoint target or not. We believe it is, and we believe we'll be the first to really test VISTA at therapeutic dose levels and validate it. This data that you're seeing here was developed by J&J back in the 2015-2016 time frame. They ran a phase 1 study, and almost immediately out of the gate, they ran into toxicity, grade 3 CRS at 0.3 mg/kg. Not only that, but as you can see here from the PK profile on the right, the PK is nonlinear. There's clearly target-mediated drug disposition that's occurring, and as you can see from the x-axis, the antibody is eliminated rapidly from circulation.
So this makes drug development very challenging, let alone reaching therapeutic dose levels. And in fact, J&J terminated this study after treating roughly a dozen patients. So this really raised some question marks, as I said, and when we decided to develop a new VISTA antibody, we knew we had to take a very different approach, and I think that's exactly what we did. So we designed an IgG1 FC active antibody to lock VISTA selectively in the tumor microenvironment. As I'll show you, that has some important downstream effects that allows us to avoid the issues that J&J ran into. We're enrolling our phase one study now. We announced data back in November where we did not observe CRS or dose-limiting toxicities. Talk a little bit about that.
We believe this is the first VISTA-blocking antibody to be administered at doses anticipated to be therapeutically relevant, and we have several milestones ahead, which I'll also touch on in more detail as we move through the presentation. I've used the word differentiated a lot. I think this slide kind of says it all. There are several competitors in the field. We believe there are 3 really critical properties for a successful VISTA-blocking antibody. 1, it has to disrupt PSGL-1 binding. 2, pH sensitivity is important, and it has to have an active FC. And as you can see here, Sensei's antibody is the only one that achieves all three of these criteria. Interestingly, there is one other pH-sensitive antibody in development, or at least that's been published on, and that's from BMS. Okay, so I'm going to focus here a little bit on our phase 1/2 study design.
I'll move pretty quickly through it since I know our CMO will answer some questions on this later on as well. Right now, we are in the combination dose escalation, as you see here on the left. We announced that we've completed the first cohort for the combination, and we've already completed all the cohorts for the monotherapy dose escalation getting through the DLT period. Once we complete combination dose escalation, we'll start our dose expansion and the combo. As you can see here, what we've done is we've moved from an all-comers design in phase one to gradually narrowing the focus. So you can see in the combination, we're taking a basket approach in colorectal cancer, non-small cell lung cancer, head and neck cancer, and melanoma. Ron will expand later on why we selected these indications and what our approach is.
In the monotherapy, we're really focused on CRC, and in particular, primarily microsatellite stable CRC. Following dose expansion, we'll then move into a phase 1 single-arm Simon two-stage design, either with or without Libtayo and indications that will be determined. Here's the data that we announced back in November. This is a data cutoff date of October 3rd, 2023. As you can see from this table, SNS-101 has a favorable safety tolerability profile. I'd just note for you all that there were no CRS events. Again, as a reminder, this is really what ended the development of J&J's drug. Through 3 mg/kg, we have not seen any CRS and also no DLTs. No drug is without some side effects.
As you can see here, there was one SAE here and also one treatment-emergent adverse event that led to discontinuation, but by and large, a very well-tolerated profile here through 3 milligrams per kilogram. This is just monotherapy. Not only did we not see CRS in that dataset, there was also really no hint of sort of treatment-emergent CRS. What you're looking at here is whether there are any changes in key inflammatory cytokines. As you can see, from start, pre-dose, through the end of treatment, these cytokine levels remain remarkably stable. We feel pretty good about this drug's ability to maintain good parameters for cytokines. As predicted from our preclinical data, we've got really nice safety, sorry, PK profile here. You'll notice that this is dose proportional. There's no evidence of target-mediated drug disposition.
In contrast to the PK profile I showed you from an earlier study, the x-axis here goes over hundreds of hours, not dozens. So this is really the first opportunity, I think, we'll have to develop an anti-VISTA antibody that is dosed once every three weeks, which is what we intend to do. Having said all of that, we are now in a place where we've, I think, met two of the three really important criteria for success in the VISTA field. A potentially best-in-class PK profile, as I've shown you, safety parameters on track. Of course, the next big hurdle is anti-tumor activity, and we have our first efficacy data that we're planning to share in Q2 of this year. We're now at a dose that's 50-fold higher than J&J was able to achieve.
So as I said earlier, we think we're going to be the first company to be able to test VISTA at therapeutic dose levels, which should enable us to uncover anti-tumor activity. So in terms of milestones here, we're going to announce some additional safety and PK data in the Q1. I've already touched on the big Q2 milestone for the company. That's the dose escalation data for phase 1. There'll be more coming in Q3. And then in Q4, we do intend to announce additional data for the dose expansion that I highlighted, as well as have an end-of-phase 1 meeting with the FDA as we prepare for our phase 2 study. So that's what I wanted to touch on here today. I can turn it back over to Frank here, and we can allow some time for Q&A.
Okay, thank you, John. That's a great overview of the company. And like we talked about, this is a, if you just keep this slide up here, it's pretty obvious that this year is a big year. In terms of the, if we just go in order a little bit here on these milestones, obviously, you talked about so far, the safety has been great. The PK has been consistent preclinically and clinically, what you've shown. But so if we look at Q2, the efficacy, you talked about anti-tumor activity. Can you just go through a little bit more about expectations, what you intend to show? And VISTA, has anyone ever pushed it to a dose where the toxicity allowed, or is this really, no one's really, like you mentioned, been able to test VISTA at therapeutic doses here?
Yeah, thank you, Frank. That's a great question. I've done a lot of talking. This is a perfect opportunity for me to hand it off to Ron here to answer that question.
Sure. Hey, Frank. Yeah, so where we see ourselves right now is certainly, we have competitors in this area, but the most exhaustive effort that's occurred and is publicly known is that of J&J's. And as you just heard from John, they failed at a dose of 0.3 mg/kg. We've already reached a dose, at least with the monotherapy, that's 50-fold higher than that and not seen the issues that they've seen. So while VISTA, it's an exciting, I believe, very promising I/O target, it's not yet clinically validated. So we're now sort of—I kind of feel like a kid in a candy shop as a drug developer, sort of the front-row vantage point to see, does this target behave as advertised? And I think it will, but we need to do the clinical experiment to know.
In terms of the first part of your question, what are our expectations around efficacy? Let me just back up. The patient population that we're enrolling, and I'm mentioning this because you have to understand the patient population in this study for me to speak to your question. We're enrolling two categories of solid tumor patients here. It's technically an all-comers population, at least in dose escalation, which includes one subset, which are cold tumors or unresponsive tumors to immunotherapy. That would typically mean microsatellite stable colon cancer, tumors like prostate cancer, etc. They shouldn't have received a checkpoint inhibitor because they don't respond to them. Maybe they received it in the past while on a clinical trial, but regardless. And then the other subset are patients with classically more responsive tumor types or hot tumors. And that includes tumors like lung cancer, head and neck cancer, melanoma, etc.
Any of those patients that come onto our phase 1 first-in-human study will have received a prior checkpoint inhibitor and failed them, okay? So basically, if we see any kind of response or tumor shrinkage, short of a response or meaningful stable disease, prolonged stable disease, I think we'll be in a position to say that this, in some part, reflects the activity or the contribution of 101, SNS-101, certainly if we see it as a monotherapy and even in combination with Libtayo. Re-exposure to just Libtayo in these 2 subsets shouldn't be generating favorable outcomes just for the reasons that I mentioned, and I know the audience knows. So basically, responses, meaningful tumor regression, stable disease in any of these settings, I think, will be good news.
Okay, so response. Are we looking for p-values here or?
No, in phase 1, you wouldn't apply a statistical test. This is sort of a totality of evidence kind of picture.
Okay, perfect. And just to make that clear to people, and then you talked about the N number here on this slide from mono to combo. Why did we come to, how did we get to 10 and 30 in the combo arm? And is that just a question of maybe there's more indications or more people? What was the thought process there?
Sure. So for mono, first of all, we have preclinical data, and our knowledge of the target suggests that VISTA is not only an agent that is—it's not only a target that can help when targeted—can help overcome acquired resistance to checkpoint inhibitor therapy, but also as a single agent, we have reason to believe that there's a reasonable likelihood that it could be active even in the coldest tumor settings like MSS colorectal cancer, even as a monotherapy. Why did we pick 10 and 30? Somewhat arbitrary. I have to—we're being pragmatic and practical here. There's only so big a sample size you can go for in a phase 1b study. That's part of it. The other part of it is with the monotherapy, we're homogenizing the population. We decided to place our first bet on a cold, uniformly cold tumor setting, which is MSS colorectal cancer.
I don't think you could expose more than 10 patients to an agent like this without some kind of a futility analysis. So you can't go to 20 or 30 patients without showing some indication of activity in, say, the first seven or 10 patients. So that's just a practical reason for 10. If we see interesting activity in that setting, we'd probably keep going in one capacity or another, either in that cohort or in phase 2. We'd get more information and go beyond 10. But it's a pilot way to get more safety data, more PK data, more PD data, and some preliminary activity in 10 patients. Why did we increase that to 30 patients in the combo? Well, that's a basket approach. In other words, we include a variety of different tumor histologies.
I don't think 10 patients would be anywhere near enough to sort of get a more meaningful sense of activity in combination with Libtayo. If you divided 10 patients into 4 different tumor types, you're really diluting your experience. We decided to go up to 30 there, which is probably near the maximum of what would be permitted or allowed in this kind of a phase 1b setting. Hope that answers your question.
Nope, totally doesn't. Do you guys, if there were a low-hanging fruit here, would it be mono or combo? Which one is more important to the company, or which one do you expect should be easier to see signs of efficacy?
Well, definitely with monotherapy, despite everything I said, I don't think anyone would disagree that if you see monotherapy activity, bona fide monotherapy activity, that's about as unambiguous a signal and as easy to interpret a signal as you could hope to have. That's a higher biological hurdle. Yes, we have preclinical data to suggest there's certainly a possibility there. But to be candid, if we were to probabilize the probability of technical success and sort of hierarchically rank where we think we're most likely to see activity, I would say the majority of our data suggests in the combination setting, overcoming resistance to checkpoint inhibitor therapy. And so if I were to rank order where we think we'd see stuff or see meaningful activity, it's in the combo setting.
But we do need to test the mono because we do have preclinical data to suggest a reasonable possibility of activity there.
You push the dose to multiple, you mentioned 50-fold what J&J was able to show. Why does 50-fold matter? Why do you feel comfortable or confident that that is therapeutically active versus 100, 1,000, 20? How do you come to that maybe modeling assumption there?
Well, I'm going to let Edward comment on that. Before I do that, I'll just say, for better or for worse, almost any biotech company with a monoclonal antibody has some kind of ceiling dose that they go to. And so for practical reasons, there certainly is a limit that we set out. But we didn't just sort of stare up at the ceiling and pick 50. There's a basis for why we went as high as we did. And maybe I'll let Edward speak to sort of the pharmacological range of activity that we expect to see based on our preclinical data. Edward, I'll hand it to you.
Oh, yeah, absolutely. So we did a lot of PK/PD modeling preclinically and projected how that would relate to human doses. So long story short, above 3 mgs per kg of 101, so 3 mgs would be the lower end. It's always about a range. Above 3 mgs or at around 3 mgs and above is where we would anticipate to be in the efficacious dose range. And that's what we're testing.
Did J&J ever mention how high they wanted to go?
I don't recall that they mentioned they want to be at XYZ.
Okay. And then you quickly mentioned, John, the only other one that had tried this pH approach was BMS. Any color there on how or what happened or where they stand, or is it just hard to find that information?
There's a very, very nice paper that's been published on that work. I don't have any crystal ball that gives me insights into the inner workings at BMS, but I do know that following the Celgene acquisition, this is all public information, many of the people that were listed on that publication I just referenced are now elsewhere. And so who knows? I mean, I think that that's an asset they still own, but usually, you need a champion internally to push it forward.
Interesting. I think we're close to coming up on time. I just wanted to open it up. It's a big year for you guys. You went through the milestones. The rationale for the approach seems to make a lot of sense. Seems like no one's. It's not that it's failed. No one's really tested it at doses that could probably work. The preclinical data has been great. The clinical data so far has been very consistent. Anything you'd like to close out with in our last minute here?
I think I would just point here again to the milestone chart and highlight that we've hit every one of our milestones and actually exceeded them in some cases. The enrollment on our clinical study has been excellent. It's exceeded our expectations. There's a lot of reasons for that, but you can't do that without investigator enthusiasm. And we've certainly been very gratified by the involvement of the investigators we have. As we look ahead, I think this is, as you said, Frank, a very exciting year for the company. This data that's coming out mid-year-ish, I think, will be an important validation point for Sensei for our investors and for the patients that are on this study, both in terms of Vista blockade, but also in terms of the pH-sensitive approach. So that's what I would highlight as we look to the future.
Excellent. All right. Well, thank you so much for joining. Hopefully, this was helpful to you guys and to the listeners here. I appreciate it.
Thank you, Frank.
Thanks, everyone.