It's my pleasure to introduce John Celebi with Sensei Biotherapeutics.
Thank you, Henry, and thanks to the Jefferies team. It's a pleasure to be presenting at the conference here today. Sensei Biotherapeutics, as you can tell from the cover slide here, is an immuno-oncology company, and we develop conditionally active antibodies for immuno-oncology. So I'll talk a little bit more about what we mean by conditionally active antibodies. But before we get there, just a disclaimer: we are a publicly traded company. We may be making forward-looking statements. So just to give you an overview of Sensei, we have a proprietary platform that we have developed, really in response to our lead program's requirements, that is now extendable. And the idea is to widen the therapeutic window and enable druggability across a range of promising oncology targets.
The way we do that is by creating antibodies that only bind and activate their targets within the confines of the tumor microenvironment. That's really important for a range of targets in immuno-oncology that are expressed more broadly and therefore are subject to toxicity issues. SNS-101 is our lead asset, and it's currently in a phase I-B study, and it targets the immune checkpoint VISTA, which is an important regulator of T cell function and has been known for over a decade to be an important immune checkpoint target. But VISTA has some really specific challenges associated with it. Specifically, prior antibodies that were developed targeting VISTA had some toxicity issues, immune-mediated toxicity, CRS, as well as poor PK profiles. We'll talk a little bit about why that is. SNS-101 so far, and data just released last...
Over the weekend at ASCO, has demonstrated the ability to overcome those hurdles. And we showed data that demonstrated clear signs of a good PK profile, well-tolerated, as well as early promising signals of activity. We also have phase I data for our expansion cohort that will be available by the end of the year. We also have a pipeline that we've developed that targets other checkpoints with similar challenges, and we think this platform is particularly important to address those needs, and unlock those targets for further development. We have a good cash position, cash runway into the fourth quarter of 2025, and that would get us roughly through halfway through our planned phase II study.
So there's a couple of things I wanna talk about, just in terms of VISTA, that are really important and fundamental to the Sensei story. Aside from being an important member of the B7 family, which is the same family as PD-L1, VISTA is expressed primarily on myeloid cells of myeloid lineage. Myeloid cells, such as neutrophils and monocytes, are expressed very broadly, not only in tumors, but also outside the tumor in the periphery. That is what presents the particular toxicity and PK-related challenges that I talked about. I'm gonna give you an example of that in a minute. The other important thing to note about VISTA is its immune checkpoint function is activated in a pH-sensitive manner. So under normal physiological conditions, VISTA does not bind to its T cell receptor, which is called PSGL-1.
But under low pH conditions, it does, and that's what creates the immunosuppressive function of VISTA. When you block that interaction with a pH-sensitive antibody, you can unlock the... release the brake, if you will, on the tumor, on the immune system, in a pH-sensitive manner as well, and that's exactly what we've been able to do with SNS-101. So that expression pattern that I talked about is both the opportunity and the challenge. Because VISTA is expressed so broadly on cells of myeloid lineage, it's found across a range of tumors, including colorectal cancer, non-small cell lung cancer, melanoma, and head and neck cancer.
What's interesting about these particular indications is you've got, indications that are both, quote, unquote, "hot tumors," where they typically respond to immune checkpoint drugs, but also cold tumors, like colorectal cancer, where the response rate to PD-1, PD-L1 drugs is 0%. That's really important to note. But the challenge and the flip side of that is the, toxicity in PK that can come with broad expression. That was demonstrated very clearly in 2016 by Johnson & Johnson and more recently by Pierre Fabre, that just released data in April of this year. What they showed was that after treating about a dozen patients, they had to terminate the study due to Grade 3 CRS-associated encephalopathy. CRS seems to be a class effect of VISTA antibodies because Pierre Fabre showed very similar issues.
The other challenge that J&J ran into is the PK of the drug, and you'll notice the X-axis here. This is human PK, and these are very low doses of drug, 0.1, 0.3, and 0.6 milligrams per kilogram. And you can see that the antibody is essentially undetectable after about 26 hours, which is really not an acceptable PK profile for a biologic. So how to solve these challenges and unlock the real power of VISTA while not creating toxicity and PK challenges? Well, we developed SNS-101. SNS-101 is a pH-sensitive antibody. So what do I mean by that? As you can see from the table in the left panel, SNS-101 binds to its target. It binds to VISTA very potently at pH 6, which is a sub-physiological pH. It's a sub-nanomolar binder. It's a picomolar binder.
But at pH 7.4, there's essentially zero binding. And as you can see, in the panel on the right, it inhibits the key interaction with PSGL-1, which we believe is really what drives VISTA's immune-related function. So we developed SNS-101. And we believe that that is what drives its selective activity. So as you can see from this cartoon, what it's illustrating on the left here is that at neutral pH, VISTA does not bind its target, but more acidic pH, VISTA binds its target very potently, and we have data that supports that.
So in the panel on the upper right, you can see in the periphery at neutral pH, SNS-101 in the pink, the curve does not shift to the right as it does with other antibodies that are not pH sensitive, such as Johnson & Johnson and Pierre Fabre's antibody. So there is no binding in the periphery, which is at neutral pH. However, in the tumor, which is a more acidic pH and well known to be, SNS-101 does bind, and it accumulates very rapidly, even as early as six hours post-dosing. So we feel that this was very critical to the feature of the antibody, but obviously, the first real test is in the clinic, and that's the data I'm gonna talk to you about today. We designed our first in-human study to answer those key questions initially.
Our corporate objective was to rapidly de-risk, the PK and the safety profile that I've already outlined. You can't do that. You can't get to a pharmacologically relevant dose, dose level. You can't really test the efficacy. And what I'm gonna show you here today is that we've been able to do just that and really position SNS-101 now to be the first VISTA antibody to really test, and confirm the initial signs of activity that we're now seeing. So this was the study design. As I mentioned, this study was designed to rapidly confirm the mechanism of action, which is conditionally active, and confirm the lack of severe CRS, an acceptable PK profile, and to dose, patients at acceptable levels. So we designed this phase I dose-escalation study. It's a boring design.
It's fairly standard, and we wanted to include all comers. Why? Because, again, we wanted to design this study to rapidly answer the first few questions about safety and PK. And so we were able to enroll about 33 patients in less than 1 year. You can't rapidly dose escalate if you're running into dose-limiting toxicities. We didn't see any, so we escalated from 0.3-15 milligrams per kilogram in the monotherapy cohort, and in parallel with that, or almost in parallel with that, we also dose escalated from 3-15 milligrams in combination with cemiplimab. Cemiplimab is Regeneron's FDA-approved PD-1 inhibitor. So what did we see? So in terms of the patient disposition, I don't think there's anything too unusual here.
Again, we enrolled about 33, sorry, excuse me, 34 patients. You know, several patients discontinued due to progressive disease, totally normal for this type of patient population. There was one patient that withdrew consent. I should mention there was one death on study that was not considered related to study drug. This was a patient with an endobronchial lesion that unfortunately bled and died on study, but that was not determined by the investigators to be related to study therapy. One patient advanced due to clinical progression. That was a very interesting patient with... that had an immune-mediated toxicity, also experienced some tumor shrinkage, so we'll talk a little bit about that patient when we get to that part of the presentation. Excuse me.
In terms of the profile of the patients on the study, nothing too unusual here, on the left panel. On the right, what I would point out is that, when you put together an all comers, phase I dose-escalation study, you typically get patients that are cold tumors. What I mean by that is patients that don't typically respond to single-agent PD-1, PD-L1 therapy, and indeed, that's what we saw, maybe even higher than what we anticipated. But about 85% of the patients enrolled had tumors that were typically unresponsive to PD-1, PD-L1 therapy. I mention that because it's really important context as we move through the presentation, and despite that, we were able to see some initial signs of a very promising clinical activity. Safety profile, I already mentioned there were no dose-limiting toxicities observed.
This appears to be a well-tolerated drug in general. The majority of the adverse events were grade 1 or grade 2. There were 2 patients that experienced a mild form of CRS, grade 1, and confirms that this is a class effect of VISTA-targeting antibodies. But we're encouraged to see that. That means that the drug is very likely doing what it's designed to do by blocking VISTA, but we don't see the severe CRS that was experienced by Johnson & Johnson or Pierre Fabre. So a little bit more about the CRS, I think just for transparency. There were 2 patients that experienced CRS, but as you can see from this table, we also include patients that had infusion-related reactions. The investigators did not determine that this was CRS, but there are some similar symptoms.
With CRS, you see you typically see symptoms occurring well after treatment. With infusion-related reactions, it's usually during or just after treatment. So there were two patients at 15 mg per kg, which is the highest dose, that experienced CRS, both grade 1 and 2 patients, with infusion-related reactions that were grade 2, one at 3 mg per kg in the combo and one at 15 mg per kg, in the combo. What about the PK? That's the other parameter I've really been talking about here. So as you can see here, this is a drug that is readily amenable to once every 3-week dosing, which is the same dosing schedule as the PD-1 antibodies. Excuse me. This was dose proportional exposure. It's consistent with a lack of what we call target-mediated drug disposition.
There is no draining of the antibody due to the binding in the periphery. There's no effect of the combination of SNS-101 and cemiplimab on the PK. That's very promising. There's really no notable accumulation, and there was no immunogenicity detected in terms of anti-drug antibody. So we're really thrilled with this profile, and it really is a good rationale to continue with the 3, once every 3-week dosing schedule. So we didn't see any severe CRS, but what about any changes in inflammatory cytokines that can be lurking, maybe at sub-CRS levels? We didn't see any significant changes in key inflammatory cytokines either. Another really promising sign that the conditionally active approach that we've taken with SNS-101 is working. There's a very large battery of biomarker testing that we're doing.
One early, very interesting signal that we're seeing is dose-dependent changes in specific T cell populations, and what you're looking at here in the upper two in the upper panel is what we call TEMs. Those are CD8 T cells that are designed to home to tumors and to have increased killing. And you're seeing another population called TEMRA, which are terminally differentiated and are modified from TEMs. So you're seeing a decrease in the TEMs and an increase in the TEMRAs. So this is proportional. And that's really important because TEMRAs have an even higher ability to home to tumors and to kill tumor cells. So we're excited about this.
Of course, this is small patient numbers, but we're expanding on this data set every day. Here are the waterfall plots that you're seeing here. I think there's a couple of important patients to point out. Six of them, three on monotherapy and three on the combination that I'll just spend a minute on. So first of all, on the monotherapy, there were 16 total patients enrolled, and 15 of those received both baseline and at least one follow-up scan. Seven patients achieved stable disease as the best overall response, which is very promising in this population. There was one patient that was known to be resistant to pembrolizumab coming onto the study.
This was a patient with HPV-positive head and neck cancer, that had a tumor regression of 17% on SNS-101 alone at a dose level of 15 mg/kg. That's the patient I talked about earlier that had the immune-related toxicity, and that patient came off at week 12 due to progressive disease. There's also a patient on at a relatively low dose level of 1 mg/kg of SNS-101 that has been on study for more than 42 weeks, and this is a patient with an adenoid cystic carcinoma, and that patient continues on study. And one patient with a leiomyosarcoma that's been on study for quite some time at a dose of 15 mg/kg. Turning to the combination dose escalation, we enrolled a total of 18 patients.
17 of those received at least one follow-up scan. Several patients of interest here, and two patients with microsatellite stable disease. Microsatellite stable endometrial and colon cancers typically don't respond to PD-1 therapy, so we think this is very promising and potentially indicative of the activity of SNS-101. The endometrial patient, I'll talk a little bit more in a minute, but this was a patient that had a confirmed partial response and remains on study. The colon patient came on at 3 mg per kilogram as well, had a tumor regression of 27%, but unfortunately, discontinued at week 18. There was also a patient with renal cell carcinoma that had tumor regression of 18%. That's the patient that discontinued due to immune-mediated toxicity.
So I wanna spend just a minute more on the 2 microsatellite stable disease patients because this seems to be an emerging story, potentially, early in this study. You know, looking at the literature for microsatellite stable endometrial cancer, the numbers are very relatively small, but looking at the literature, the response rates to single-agent PD-1 are anywhere from 0%-10%, so we'll just say less than 10%. This is a patient that came onto the study with prior lines of therapy. Interestingly, this patient did have a grade 3 diabetic ketoacidosis 4 days after their cycle 3 infusion. This is a toxicity that is on the label for cemiplimab and other PD-1-related drugs, but it's relatively rare. We can't rule it out, that it may be related to SNS-101.
But nonetheless, despite this toxicity, this patient went on to now have a 59% tumor shrinkage, and you can see, the scans here. So this patient started out with a fairly large lesion, and it's now, you know, shrinking, dramatically. So that's very interesting. Perhaps even more promising, is the patient with microsatellite stable colon cancer. From the literature, we know that the response rates, the single-agent PD-1 in microsatellite stable colon cancer are 0%.... So we think that this, this activity is being driven by SNS-101. This is a patient that had a 27% decrease in their target lesion. That was their best response. And unfortunately, then they, progressed, as is not unusual in this stage of, disease. So where are we now? Where does this position SNS-101 and Sensei Biotherapeutics?
Well, we are releasing a data set at the end of this year, which is potentially transformative for the company. I think what this data set that was presented today does shows that SNS-101 is indeed well-tolerated. It's now being dosed at a level 50-fold higher than where Johnson & Johnson had to terminate their study due to CRS. We've shown potentially best-in-class PK among VISTA antibodies, and as I've just shown you, we believe there are initial signs of encouraging clinical activity here. The plan forward is to test this in a larger number of patients, confirm the signal, and we do plan to share some of that data before the end of this year, positioning 101 to be the first VISTA-targeted antibody to really test VISTA as a therapeutic axis in immuno-oncology.
As I mentioned earlier, this is a potentially very large commercial opportunity and, of course, fulfills an unmet need for patients that may be resistant to checkpoint inhibitors in general. Looking ahead, we're now in our dose expansion phase. We started enrolling at the beginning of the year. This is about. We're estimating about 50-70 patients. In the monotherapy setting, we continue to test in colorectal cancer patients. And in the combination setting, we're doing a basket study in colorectal, non-small cell lung cancer, head and neck, and melanoma. Why did we select these indications? Well, it's, you know, one of the blessings and the challenges of going after VISTA because it's so broadly expressed. What's the rationale you use to test these patients?
In the absence of a clear scientific rationale, we chose indications that are both typically responsive or considered hot responsive to PD-1 therapy, such as lung cancer, head and neck, and melanoma, as well as one indication, which is cold, which is the colorectal tumor setting. Patient enrollment is advancing in dose, in both cohorts. We're exploring two dose levels. As you can see in the combination setting, both 3 and 15 mg per kilogram, plus cemiplimab. We think that's really important. We know the drug is well-tolerated, and if we can achieve equivalent levels of activity at a lower dose, I think that's the right thing to do for patients. But it's also what FDA wants, as we know from Project Optimist, so that's what we're doing. It's also an opportunity for us to rebalance.
I mentioned earlier that 85% of the patients on study had cold tumors. We're gonna be adding some hot tumors here as well to see what that looks like. So that's underway. Our cash runway guidance remains unchanged, despite the fact that we recently announced that we're adding some patients to this study, so that's Q4 of 2025. And we should have initial data from this dose expansion a year ahead of that in Q4 of 2024. Again, we view this as an important catalyst for Sensei. I'm gonna stop there. I'm gonna thank everybody for their time, and if there are any questions, I think we have a couple of minutes to answer them. Please.
Why should this work in a cold tumor? I mean, especially since VISTA is in the same family as PD-1. PD-1 don't, why should this? And then maybe the other question, why never -
Great question. So the first question was, why test this in cold tumors? And the second question was, why combine it with PD-1? Why not other things such as chemo?
Why should it work?
Why should it work in cold tumors?
It's a new checkpoint. New checkpoints don't. By definition, they don't. So why should they?
So one important feature of VISTA, that makes it very different from PD-1 is its expression profile. So it's expressed on cells of myeloid lineage. Cells of myeloid lineage, and sometimes we call them, MDSCs or myeloid-derived suppressor cells, represent a different population, and they're commonly found in tumors. They're even found in tumors where T cells aren't present. What we're interested in is settings where T cells are present, but you still don't get response to PD-1 agents. So colorectal cancer is a good example of that, and we think those MDSCs expressing VISTA, represent perhaps an important play an important role in primary resistance to PD-1 agents. So that's why we're exploring, settings such as colorectal cancer. We think there is a mechanistic rationale for PD, for VISTA to, to...
anti-VISTA antibodies to play a role and drive anti-tumor responses, even in settings where PD-1 won't work. With regard to the second question, why PD-1? Well, there's two types of resistance. There's primary resistance, and there's acquired resistance. So we also think that VISTA plays an important role in patients. We saw one of them, which is the RCC patient, where a patient may have an initial response, but eventually does not respond to PD-1. So there, we think, VISTA also plays an important role. The third part of your question or maybe the second part of your second question was, why not other agents like chemo?
Well, one of the benefits of having a really well-tolerated safety profile is that you can combine very broadly, with other agents, and certainly it's in our plans to do that. We, we have an important collaboration with the National Cancer Institute, a CRADA, where we are combining experimentally, pre-clinically with many other different agents. And, indeed, we don't, we don't see any, issues with the safety of doing that. We just haven't done it yet. Any other questions? If not, again, I just want to thank the Jefferies team for inviting us to the conference, the opportunity to present, and thank you very much.