All right, we're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us in the next presentation, Cue Biopharma. Representing the company, we have Dan Passeri, who is the CEO, and we have Matteo Levisetti, who is the Chief Medical Officer. I think Dan's going to start us off with a few intro slides. We're going to jump into Q&A. This is informal. If anyone has a question, feel free to raise your hand. Dan, thanks for coming, and I'll turn it over to you.
Okay, thank you, Steve. And welcome, everybody. And I want to thank Stifel for giving us an opportunity to be here. So Cue Biopharma is a NASDAQ-listed company, the symbol C-U-E. So let's start off with this first slide. This is an overview of kind of the continuum of our platform's development. And what I want to emphasize here is we have a growing platform of molecules that are interrelated and have been specifically engineered to accomplish a particular function in terms of targeting a particular repertoire of T cells, whether that's for treating cancer or autoimmune disease. So I'm going to start off from the left to the right and show you how this platform has evolved. I'll then turn it over to Matteo to review some of the clinical data that we've generated. First, starting off with 101, 102, which are exemplary of the CUE-100 series.
These two programs, as we stated in August, we did not divest them or put them on hold because we weren't developing them. We actually put them in a stage where we were going to let the data continue to mature. That data is maturing. Matteo will show you some of this emerging data, which we believe continues to differentiate our approach and give us a competitive positioning because of what we can achieve. Starting with 101, that was our first molecule from the 100 series that went into the clinic. It's specifically designed to target T cells that recognize, have a T cell receptor recognizing the HPV epitope for targeting, in this case, head and neck cancer. It's designed for simultaneous engagement of the T cell receptor, or the TCR, concurrent with IL-2. I'll elaborate on how that's designed in a moment.
And that gives you selective activation and expansion of targeted tumor-specific CD8 T cells. Now, from that, we derivatized this or we modified just by changing the epitope there you see circled in that red hash mark. It's a nine amino acid sequence sitting in the HLA pocket. So the framework, the molecule itself, is 99% the same for 102 and 101. And this gives us a modular expansion just by exchanging the peptide. And there are real advantages for this particular regulatory process. And that enables versatile targeting of any T cell population. So Matteo is going to review the updated data from the maturing clinical study that we have, and that'll basically show you how this data is starting to differentiate us. So from the 100 series, we looked at how we could modify and induce Tregs, which require both IL-2 and TGF-beta concurrently.
This has been in the literature, multiple publications over the years showing that if you want to induce Tregs, you need to stimulate both our signal, both IL-2 and TGF- beta. And what we did is we basically took the IL-2 variant that we have in the 100 series and deployed it on an Fc scaffold, TGF- beta on the other end that's masked. And we're emphasizing avidity. The molecule will only bind and signal when both are engaged. This incorporates, again, the IL-2 variant, which is an ablated alpha and an attenuated beta. And we're seeing FOXP3 induction, Treg induction from CD4s, and we're seeing that expansion, both induction and expansion, require both IL-2 and TGF- beta when we're achieving that. This partner has partnered with Ono. I'll elaborate upon it further on in the presentation.
From the scaffold from the 100 series with the HLA and the Fc backbone, we deployed it with the 500 series. The first molecule coming out of that is 501. This molecule is specifically designed to engage, in this case, CD19, but it could be BCMA or CD20 on B cells. This allows us to specifically deplete B cells by incorporating the HLA framework of the 100 series and presenting a viral epitope. What we're doing basically is painting a B cell with a virus-specific epitope, which then redirects endogenous antiviral T cell repertoire that's meant to eradicate cells that are infected with virus. They're circulating, they're in a killer state, and this basically will eradicate pathogenic B cells. From that, we have the 500 series. For both, by the way, this can be deployed for targeting cancer cells as well as autoimmune.
So the 500 series broadly incorporates through that scFv fragment, depleting target cells. It paints any target cell with a viral epitope, and it basically marshals viral-specific T cells to attack and destroy that target cell. So what you're seeing here is a modular platform that gives us depth and versatility where we're able to target a variety of specific T cells for a particular therapeutic function. We've been very successful at this. And again, we've created a balanced business model. Ono has partnered with 401, 501. We're in late-stage discussions. And 101, 102, we continue to look at that data's maturing, and Matteo will touch upon it momentarily. I just want to emphasize this 100 series that 102 and 101 represent.
It's basically meant to achieve simultaneous engagement of the epitope, which is that yellow circle which binds to a particular T cell population through the TCR and delivers IL-2 only to those T cells because the IL-2 has been engineered to be affinity attenuated. It needs avidity to bind and signal. This molecule has been in over 120 patients treated to date. We've seen over a two-times median overall survival enhancement over standard of care, which is based on historic data, a greater than doubling of the ORR and survival in combination with anti-PD-1. Importantly, we're seeing a very favorable tolerability profile. I think that's the real advantage of this approach. We're delivering IL-2 only to the T cells that we want to engage. And because this is an antibody-like structure, it's similar manufacturing. It has antibody-based modular design, expression, CMC, and cost of goods.
Astonishingly, the molecules are very stable over 36 months of stability. I'm now going to turn this over to Matteo just to run through some updated data.
Very good. Thanks, Dan. So here on this slide is the Kaplan-Meier survival curve of 20 patients that we treated with CUE-101 monotherapy. So these are patients that have progressed on prior chemotherapy and checkpoint inhibitor therapy with now advanced refractory recurrent head and neck cancer. We initially went into the clinic with CUE-101. We treated 80 patients, and we started treating patients in the later line. We treated 49 patients in total. And this is now really the mature Kaplan-Meier plot of those 20 patients in the 4-mg/kg expansion cohort. And what we observe now is a median overall survival of 20.8 months. And so on the right is a graph that has that value graphed with the survival that was observed in the two pivotal trials that led to the approval of nivolumab and pembrolizumab of 7.5 and 8.4 months respectively.
So here what we're observing is quite extraordinary. So in a later line, really in the third line setting, we're observing more than a doubling of survival when you compare it to the pivotal trials in the second line. And I have the.
Yeah, you have it.
And so here now is a Kaplan-Meier plot looking at two populations of patients, the same patients in the second line and beyond, really third line patients that were treated with higher doses or lower doses of CUE-101. So in the absence of a control arm, okay, this is a single arm trial, 1b expansion. It's very informative to look at these two populations and compare them because the lower dose population basically serves as a control for the higher dose. And what we observed is a separation in the survival curves at about a year. And so if you look in the upper right, we observe a median overall survival in patients treated in the higher doses of 20.8 months. And if we look at then the patients treated at the lower doses, we see a survival of 12.2 months.
These patients went on to receive the same subsequent therapies. It's really very informative to see this separation in the same population. Now we're going to move into the frontline setting. The first part of the trial, we treated patients with recurrent metastatic head and neck cancer that had failed two prior lines of therapy at least. Then in the second part, we combined CUE-101 with pembrolizumab, the anti-PD-1 inhibitor. We did a very brief dose escalation in combination with the labeled dose of Keytruda without observing any DLTs or any concerning toxicity. On the left here is the waterfall plot of the 24 available patients treated at the RP2D combo dose of CUE-101 at 4 mg/kg plus pembrolizumab. What we observe is an objective response rate of 46%.
So if you look on the right in the red bar, we have a complete response and then 10 partial responses. We have three patients that actually remain on treatment, all three of them on treatment now into their second year of treatment. We have several patients that have completed 35 cycles of CUE-101 and pembrolizumab, so two years of therapy. This, we look on the right now, is a survival curve for these 25 patients. And very importantly, what we observe at the 12-month OS now is an overall survival, 12-month survival of 91.3%. The Kaplan-Meier estimated the median survival is currently 21.8 months. So to put this in context of the results of the pivotal KEYNOTE-048 trial, in the same treatment naive population, those patients treated with pembrolizumab monotherapy had a response rate of only 19%.
We're observing a response rate of more than double that at 46%. Also, what's very notable is that we see responses in patients that have low PD-L1 expression, patients with tumors that have low PD-L1 expression or a CPS score of one to 19, where with pembro monotherapy, that response rate is only 15%. In combination with CUE-101, it's 50%. Now back to the survival curve, we look now at 12 months, 91% of patients are alive. In the KEYNOTE-048 trial, the 12-month survival in all patients with CPS greater than equal to one is 51%. So really now with the penultimate marker and measure of clinical benefit, we're seeing almost a doubling of survival. The CPS low population, treated in combination, 100% of those patients are alive at one year. So that's CUE-101. Now I'm going to go on to CUE-102.
This is the second Immuno-STAT in the CUE-100 series. If you look on the left here, as Dan alluded to earlier, again, we have a little diagram of the molecule. The only difference from 101 is the peptide in the HLA pocket here. It's a peptide derived from Wilms tumor 1, the 37-45 epitope specifically. We experienced many efficiencies in getting this into the clinic. First, the FDA did not require additional toxicology. We basically presented the safety data from the CUE-101 program and said, given the similarity of these two, that we don't anticipate any unexpected safety or tolerability issues, and we haven't encountered any. The FDA agreed.
And then furthermore, they allowed us to start the dose escalation at 1 mg per kg, where with 101, we spent about almost a year treating patients starting at a dose of 0.06 mgs per kg to get up to 1 mg per kg, so we saved time and money. We've taken this into late line patients with colorectal cancer, gastric, ovarian, and pancreatic cancers, so really a basket of four. We've characterized the prevalence of WT1 expression in these cancers. They're all above 65% and as high as 100% with ovarian cancer, so we've completed dose escalation. We had no DLTs. We expanded in all indications and have patients currently on treatment in three of the four indications, and as I mentioned, a very favorable tolerability profile in these patients with advanced cancers as listed.
Then on the right is a spider plot of three patients that were treated with CUE-101 monotherapy. As you can see, there's three different indications. So in the green line, this was a patient with gastric cancer, actually treated at the 2 mg per kg dose in the dose escalation, advanced on three prior lines of therapy. So this represented the fourth line of therapy in gastric cancer. This patient was on drug for over 36 weeks. As you can see, the target disease burden went below 30% at week 36. Unfortunately, at that time, a new lesion was identified. The investigator felt that the patient was really benefiting, so kept the patient on treatment for another two cycles. Then unfortunately, they started to have a bit of a growth in their target disease.
In the blue line is a patient here now with pancreatic cancer, treated at 4 mgs per kg. This patient had progressed on four prior lines, so fifth line pancreatic cancer. There aren't many of those folks around, and then very, very happily for this patient at her last scan, an unconfirmed partial response of -40% was observed. This patient remains on the study on treatment, and then in ovarian cancer, we have a patient that had basically an unconfirmed PR after four cycles, but unfortunately had a new lesion at that time. So, really very positive data showing single agent activity in the early 1b setting across three indications.
Okay, thank you. I want to just emphasize on that last slide. The important take home there is the drug is not affecting the cancer cells at all. It's stimulating the patient's T cells, so it's the patient's own immune system that's having that anti-tumor effect, and that's why we believe these patients are living longer, so we believe we're in the midst of a paradigm shift. This is the potential of immunotherapy. We're really pleased with the data that continues to emerge from this ongoing 101, 102, so now switching to the autoimmune assets, and I've stated in August, we are emphasizing autoimmune in the near term, and that's because we have limited resources. We're building the pipeline out while the data is maturing in oncology. This program is partnered with Ono, and it represents a sort of near midterm and long-term value proposition.
And that this molecule is designed to concurrently engage IL-2 and TGF-beta, which results in a very significant induction of FOXP3 promoter upregulation, which is the induction of regulatory T cells. So what we're doing is converting what we believe is a population of CD4s, both pathologic autoreactive CD4s and other sort of progenitor CD4s into regulatory T cells. And then we have expansion of existing T regs. We have studied several disease models under this partnership with Ono, which has been a very productive partnership. And the molecule seems to be doing what it's designed to do. We're seeing dramatic effects in animal models. So we're expecting to select that lead candidate and define the clinical IND path and strategy going forward in Q1. This is a really important program for us because we have 50% interest retained with Ono.
And then the next autoimmune program from the 500 series is CUE-501. This is for B cell targeting and B cell depletion. We're in late stage discussions on partnering. We believe a partnering strategy here will give us validation of this viral specific T cell approach rather than a pan T cell activator such as a bispecific, which binds to a B cell through CD19 and a CD3. CD3 is a pan activator. It's going to activate every T cell that comes in contact with it. There are obviously unwanted deleterious side effects with that, such as cytokine release, other side effects through this broad activation. What we're doing is actually not activating a subset of T cells. We're taking advantage of an already existing repertoire of T cells that have memory. And that protects us from viral infections, our cells that are infected with viruses.
So we're in essence painting B cells with a viral epitope inducing that T cell population that's already in the patient to attack and destroy those cells. We have really solid preclinical data showing this both in vitro and in vivo. And we look forward to providing updates on our corporate development strategy and partnering strategy in the near term. Okay, I think from that, Steve, we can get into any questions you want to ask us.
Okay, so I know that you talked about in the opening there, right, that you're now trying to identify strategic partners for the CUE-100 assets. How are those discussions going? I guess is there a preferred deal structure that you're looking for specifically?
Yeah, it's a really important question. We're not looking to just partner for the sake of partnering. The one thing we don't want to be is a discovery company that's just partnering our assets. We're looking for strategic alignment with pharma companies that basically have complementary competencies that can enhance our insight on a particular drug's development, also enhance our capacity, most importantly, give us access to capital while we retain defined assets. So we're looking at our partnering strategy dynamically. We presently have a partnership with Ono for 401, where we have a retained 50% interest in the U.S. The 501 series, we're looking at a partnering strategy there with a large pharma that one gives us validation of the approach where we can use this viral specific T cell population to kill target cells, and we'll retain every other application outside of B cells.
And that would give us access to requisite capital and basically enhance our capacity. We just announced the hiring of a regulatory specialist who has a lot of experience in NDA submission, Dan Baker, with over 20 years at J&J and Janssen, has a wealth of experience over 15 drugs approved under his guidance. So we're looking at our overarching strategy with Matteo taking a greater and greater role defining what assets we ourselves want to develop in the clinic and hold on to and which assets we want to partner and what partnering strategies make the most sense for our continued sort of corporate development. We don't want to just be licensing programs out.
With respect to CUE-101, I mean, I know that there's a lot of development activity happening right now in the front line, head and neck space. Some of those are exclusively in HPV negative patients, so obviously kind of outside of your purview, but there certainly are some trials that are enrolling HPV positive patients. So how do you just think about the competitive density there and how that may or may not impact your ability to get the kind of deal that you want for CUE-101?
Sure. I'll answer from my perspective, and I have Matteo comment. So as you stated, that space has become very competitive. We had data emerge at last ASCO from a couple of these bispecifics, Merus in particular, which the data looks very positive from a standpoint of the ORR that they demonstrated. What one has to reflect on is these bispecifics are blocking pathways that the tumor might be using. In this case, it's an EGFR, the LGR5, which is a stem cell marker. EGFR has been around for 20, 30 years, and cancers are using, head and neck is using that mechanism. When you block it, it's a stress to the cancer. The question is, in combination with that reduction that you're seeing, so the ORR is impressive, are you also seeing the corresponding enhancement of survival? That remains to be seen.
We think, Steve, that's the real advantage of our approach. We're not stressing the cancer cell out with a blockade of a pathway. We're stimulating T cells that will recognize the cancer as foreign and marshal an attack. And the key is we believe because of the concurrent IL-2 TCR engagement, there's a qualitative feature here where these stem cells have, these T cells have a stem-like feature where we have a long, durable response. And we have evidence that's emerging that supports that general premise. And that we believe is going to be our real competitive advantage. So what you stated is one of the reasons we decided to enable this data to continue to mature over time because we think it will strengthen our competitive positioning because of the survival. And if you want to.
Yeah, just to add a couple of points. I think in this space, there's been some disappointing trials that really leave sort of a large space for development of a new standard of care, and I'm referring, for example, to LEAP-010. So the combination of lenvatinib and pembrolizumab, even though the response rate looked interesting and appealing in phase 2 and 1b, in the pivotal trial, the monotherapy had a longer survival, okay. So 19 months versus 15 months. I think that underscores the importance of looking at survival metrics, which we have now at a 12-month landmark, and then two other approaches, specifically in HPV positive head and neck cancer, that involve variations of vaccination or immunization, have recently shown data that really the activity that they observe is really only in the CPS high population.
They've shared that they may be only moving forward in CPS high. That excludes 50% of the addressable population with a CPI in the front line setting of head and neck cancer.
Yep, no, those are good points. On the CUE-500 side, right? Again, it sounds like you're interested in trying to strike a partnership here.
Yep.
Would a deal have to include kind of access to the whole CUE-500 series? So if I was a strategic and I was looking at the series itself as opposed to CUE-501, right? I think there's an opportunity to swap out the viral epitope. There's an opportunity for me to swap out CD19 with either CD38, BCMA, and maybe go after some of these more terminally differentiated B-cell diseases. So would you have to kind of offer up the whole platform to a strategic, do you think? Or do you think you could just carve out CUE-501?
Really important question. It goes to your earlier question about what we're looking for partnering. It's the space itself. It's B-cell targeting and depletion. That's what we're going to be partnering. The 500 series applications with other cell types will be preserved by Cue. That's going to basically be the spearhead validating. Our thought on this is that the whole B-cell targeting and depletion has become astonishingly competitive with large pharma, almost all of them utilizing bispecifics with CD3, which is a pan activator. This is a clearly differentiated approach, which we believe is going to have superior effects with the safety profile of the approach. Our thinking is a partner that is dedicated to B-cell targeting depletion, whatever modality that is, that will be the space that will partner. Outside of that, we'll control.
Okay. You showed some of the background biology around CUE-401. This is leveraging both IL-2 and TGF-beta. How do you think this approach is mechanistically superior to the IL-2 based approaches? And given you're toggling IL-2 and TGF-beta, do you see anything in your preclinical talks that would suggest you're either getting some of that fulminant IL-2 related tox or maybe some of the bleeding and cardiovascular AEs that's associated with TGF-beta?
Yeah, I'll touch upon it, and then I'm going to also turn it over to Matteo. So regarding the IL-2 muteins that are out there, we actually have compared our data with a well-known IL-2 mutein. And what you see with the IL-2 muteins is you see expansion of already existing T regs, which in essence is a very small population. What we're doing is not just expanding those T regs, but we're inducing new T regs from CD4s through FOXP3. And we've done direct comparisons in vitro. You don't see a FOXP3 increase with the IL-2 muteins. So what they're doing is expanding an already existing T reg population. It's the concurrent stimulation of IL-2 and TGF-beta that allows the FOXP3 promoter to be engaged and transcriptionally activated. And we're seeing a profound increase from that effect. And we believe that's going to be the real differentiating feature.
And as you know, there's been disappointing results so far with the IL-2 muteins. It still remains to be seen if there are applications where they'll show clinical effect. We believe that's the real advantage of what we're doing is the induction of new Tregs, which if you have a pathogenic CD4 and we're able to convert that to a regulatory T cell, that's going to have a demonstrable effect clinically. So that's what we've generated to date. In terms of the tox profile, we're in the midst of studying three species. What we are showing to date is we have the activity we desire, and we have a therapeutic window that we've been demonstrating.
Yeah, just to kind of add to this is to comment on the IL-2 moiety is identical to the IL-2 that's on 101 and 102 that's been in over 120 patients. So it's the same two amino acid changes, okay? So again, that's the risk here. It's just one molecule. It's a bispecific with the TGF-beta.
Okay.
The protein engineering of the TGF-beta is quite remarkable. It's a knob and hole. We're part of the endogenous receptor of TGF-beta sort of floats on and off of the TGF-beta moiety. It's masked in a way. Really for binding requires both the TGF-beta receptor and the IL-2 receptor in cis to really bind. The IL-2 we feel is dosed in over 120 patients. Of course, the TGF-beta, the assays we've done in vivo, I mean, in vitro show 100-1,000-fold less activity against some of the in vitro assays, which are complicated, as you, I'm sure, know with regards to the structure of the receptor.
Okay. Maybe last question. Can you talk a little bit about how the partnership on 401 with Ono works from a structural perspective? And I think there's a predefined trigger for Ono to opt in. I think you have your own opt-in trigger at your disposal. When do those decisions occur and kind of what should we expect in terms of what happens next?
Sure, so just to remind everyone, Ono in essence has been subsidizing all of the preclinical development, and I'd say they've been an outstanding partner to date, so we have a number of animal models that we have progressed with. We're now, as you asked about, finishing up the toxicology studies. Ono has the decision once those data sets are completed and we compile the reports. They have an opt-in for a lead candidate, then we have a period of time after that opt-in to decide to co-develop where we would share costs for U.S. development, and that's obviously something we're focusing on right now. There'll be a near-term value drive, and we think that'll be in the Q1, early Q2 timeframe.
All right. So if there's no other questions, Dan, Matteo, appreciate the time. Thank you very much.
Thanks.
Thanks.