I'm by the company's CEO, Danny Lanfear, and the Chief Scientific Officer.
Scientific and Development Officer.
Scientific and Development Officer, Theresa Lavallee. Dennis, I do not know if you know this, but I think we now have known each other for a decade, which makes me feel kind of old. The company has certainly evolved and changed dramatically from when we first got to know each other as a biosimilars company. You are now sort of an innovative IO company. Why do we not start with, you recently presented data for your CCR8 antibody in recurrent metastatic head and neck squamous cell carcinoma. You had one partial response in a patient with very advanced refractory disease. What was so encouraging about this? I think some investors are like, it is just one patient, and maybe missing some of the context around the severity of the disease and what the patient was facing.
Yeah, so I think there's a couple of things for those unfamiliar with the CCR8 target. It's just that our compound, CHS-114, is a targeted therapy. People have tried for decades to target and kill T regulatory cells because they're known to dampen anti-cancer therapies broadly, but also well-characterized to be important cells to drive PD-1 resistance. Having a target that's selectively overexpressed in the tumor and not broadly on T reg cells so that these are cells that are very important for immune homeostasis. If you broadly knock out T regulatory cells, you end up with autoimmunity, which doesn't help. We've been able to show safety that this does preferentially target T reg cells in the tumors. That also was on the poster, showing marked depletion, greater than 50% depletion of T reg cells in the tumor in response to CHS-114 monotherapy.
For targeted therapies, the important thing is where's the target present? And when it's present, is it driving the disease? The highest prevalence of the target, CCR8, is present in gastric cancer, cervical cancer, and head and neck cancer. When we combined CHS-114 with toripalimab in the safety cohort, we did three patients at one dose, four patients at the higher dose, and saw a response. In a fourth line head and neck squamous cell carcinoma patient, this patient had had every available therapy, including PD-1 treatment, and progressed. This fourth line patient having a dramatic response with CHS-114 and toripalimab was highly encouraging that this targeted therapy really is doing what it's set out to do.
Now we have the second line study, which is, you know, still a very sick patient population, but going in the fourth and fifth line for any cancer therapy, but particularly an immune-based mechanism, is a pretty high bar. The second line patients looking immediately progression on PD-1 to see if the T regs are the true target for the PD-1 resistance. That study will enroll this year and read out early next year. I think it is encouraging for the class and just really looking at the development path to go quickly with this program.
I would also add that we believe this is the first U.S. data on a CCR8 on a T reg. Many view this as an emerging superclass of therapeutics. Certainly, there is a strong relationship between overall survival and the presence of T regs in all these tumors. You could see very broad applicability across a number of tumor types. This is very exciting to see this manifest now. Theresa may want to comment a little further, but I think what is very interesting for me is the translational read-through here from CCR8 to the getting rid of the T regs and then, you know, that we have seen some of our biomarker data. Maybe you want to go through that for just a moment, Theresa.
Yeah, so the aspect that we looked at that I said that we saw, so it's a binding kill mechanism. It's an afucosylated antibody. So the killing is done by the immune system, ADCC or ADCP mechanism. There are several antibodies approved with that approach across different targets. The thing that we did not expect to see is that just the depletion of the T regulatory cells would lead to this large infiltration of CD8 T cells. And that really has us excited about the potential, not just to combine with PD-1, because obviously you need T cells there to reinvigorate antigen experience exhausted T cells, the mechanism for PD-1, but also T cell engagers. I mean, the biggest issue with getting T cell engagers successful in solid tumor treatments is the lack of T cells for the CD3 to bind onto.
We also think it could go across many different classes of agents to combine with. This translational data, as I said, the data shows safety, which was really important for the class, the anti-tumor activity in a patient population where the target is broadly expressed, and then to see the biomarker data where it's doing exactly what it said it would do, but more than we expected has us very excited.
Just as well, when you say doing more than what you expected, what are you specifically referring to there?
The immune infiltrate, the CD8 T cell infiltration into the tumor just in response to T reg depletion.
T his has been an area of some interest broadly by the industry. What makes your molecule unique?
Yeah, so I think that there's a couple of things to know about the class. CCR8 is a protein called a G protein-coupled receptor. About a third of FDA approved drugs are against GPCRs, so it's a well-known target. But there's hardly any antibody drugs against GPCRs. I think there's about five last I counted of the total drugs on the market against GPCRs. And that's because they're very challenging targets because of the way that they weave in and out of the membrane. There's not a lot of protein on the outside of the cell to have the antibody latch onto for selectivity and specificity. So in all of the screens, in our screens and screens of other molecules, there is one and only one antibody we found that exclusively binds CCR8.
This is important because if you have off-target binding, you have characteristics that you may not understand for your drug. Like one of the proteins that we, one of the CCR8 antibodies we characterize binds J chain as an off-target binding, which is broadly, that protein is broadly expressed in the gut. You could worry about GI toxicity. That selectivity is really important to understand on target biology, both for efficacy and tolerability.
When we think about your broader portfolio, sort of your first approved asset is LOQTORZI, which is a PD-1 inhibitor. What does the potential LOE for Keytruda, right, which is still a couple of years away, but, you know, sort of looming over the horizon, what impact does that potentially have on the market and, you know, sort of how you advance LOQTORZI, both in NPC, but more broadly in other indications?
You know, certainly we are very cognizant of the LOE date in 2024 for Keytruda when we set upon our development path with LOQTORZI a couple of years ago. It's important to keep in mind that these indications are labeled specifically with PD-1s in the combination agent. You can't really therapeutically exchange one PD-1 for another when you develop a therapy such as a CCR8 or a casdozokitug, you know, for example, with toripalimab. Theresa can comment a little further, but it's also important to keep in mind that these PD-1s are differentiated, you know, on the basis of their epitopes and their activity and so forth and give very different results. Overarching, you know, the thing I think is that while you'll see the biosimilarsation of Keytruda probably in 2028-2029, it really won't have any substantial impact commercially or therapeutically as we're proceeding, Theresa.
Yeah, and I think, I mean, it's important to note that our strategy with our pipeline is to look at both the novel agent, CHS-114 or casdozokitug, in combination with toripalimab. We get two drugs approved for the development price of one, but then Keytruda won't have the IL-27 PD-1 combination data. Whatever biosimilar comes up, it won't have the label to replace Tori there. We feel that the strategy is further strengthened by improving patient care and standard of care by adding combinations that are outside of the other PD-1s' labels.
You've been obviously prosecuting an aggressive sort of development strategy with Tori in combination with your internal assets, CCR8 or casdozokitug. You've also talked about in the past about sort of wanting PD-1 or LOQTORZI to be sort of the PD-1 of choice in partnering. You've signed a couple of partnerships, but I think there was some hope that Tori would sort of proliferate across the IO landscape, and that hasn't necessarily happened.
Yet.
I guess, you know, is it a question of yet or has it been sort of a change in your prioritization and maybe some perspectives there?
No, we have many conversations ongoing. What we changed is when we announce them. Because, you know, by the time you get together, what's really important with these partnerships is seeing clinical data with the novel combinations. You know, we're looking to news flow and when we can anticipate readouts. We have changed our strategy for the collaborations to wait till closer to first patient in. A few of the collaborations that we've been in discussions with companies will be forthcoming, but have not been announced to date because we're waiting for that. The important thing is not that we have a collaboration. The important thing is that we'll have interesting clinical data next year with novel mechanisms.
One of the things we have, a couple of pillars that we look for in the collaborations, is a novel mechanism of action, safety, because we're very cognizant of not having that impede any other programs, but spillover effect, but also some activity in tumor types that we're really prioritizing for our development. I think you can look forward to collaborations where we're looking at clinical data sets in liver cancer, head and neck, lung cancer, tumor types we're developing Tori in with our assets as well, just to really broaden the data set. Stay tuned, Doug.
Maybe it's just a follow-up, Theresa, when you think about the structures that you're perhaps pursuing and as you wait to sort of go until a first patient dose, does that imply that's maybe sort of different structuring of partnerships than what you initially contemplated?
No.
Maybe how versus are your partnerships structured differently than how the industry broadly interprets or thinks about partnerships?
Yeah, so the way that we've looked at the toripalimab drug supply collaborations is just that, is drug supply an opportunity to look at Tori plus a novel mechanism in a very capital efficient manner. By providing drug and expertise to biotech companies with their compounds, we can move quickly and get data sets, but not invest large amounts in the development of the discovery. We're very excited about our assets and have really prioritized our spend on the development of CHS-114 and casdozokitug. We do see there's huge opportunity for continuing to improve on PD-1s through combinations and through these partnered drug supply collaborations. The nice part is we're small and because it's drug supply, I mean, we've been able to get these collaborations in place in as short as six weeks. We can work fast.
You know, you've spoken, and I think you alluded to it, I think, Danny, in your comments earlier about LOQTORZI having a differentiated mechanism, sort of binding epitope than other PD-1s. We've certainly seen that in MPC in terms of the efficacy, especially in PD-L1 low patients. Broadly speaking, right, you know, sort of different binding epitopes or that hypothesis has not necessarily played out in IO. I guess I'm just curious, do you, and I think that's a conventional wisdom, perhaps do you disagree with that? Do you think it hasn't necessarily been tested properly?
I do disagree with that. I think that, I mean, the field knows that epitope matters, right? I mean, look at HER2 with pertuzumab versus trastuzumab, very different activity with two different epitopes. The question is, toripalimab has two features, the FG loop, which we think is the important epitope, others have published that it is the preferred epitope for designing inhibitors, so a small molecule against the PD-1 domain. It also has the potency difference, it is 10-fold higher binding affinity. The two characteristics and the differences in the pharmacology have translated clinically to seeing activity not just in MPC, but in esophageal squamous cell carcinoma and non-small cell lung cancer. The esophageal squamous cell carcinoma showing activity irrespective of PD-L1 status is noteworthy because no other PD-1 that is approved has that profile.
FDA had an ODAC for Merck, BMS, and Beijing saying, "Not so much." We shouldn't give you the label for PD-L1 low in esophageal squamous cell carcinoma or gastric cancer because you've shown no patient benefit and in one case, actually detriment. Europe approved toripalimab irrespective of PD-L1. The other PD-1s didn't get that. It is not just the literature, it is actually health authorities seeing this difference. Why this is important for us and our partners for the drug supply collaborations is any future standard of care is going to go against an approved PD-1. The dominant one is Keytruda.
We've heard lots of chatter with some of the phase two, particularly the TIGET studies, "Oh, well, did it not work because their PD-1 is inferior." If you think about when you go head to head with PD-1, if your PD-1 is not as good, you start here. Your combination to get a hazard ratio and a P value to get approved has a bigger climb. Whereas if you start equal footing or perhaps higher, you have a higher probability of success. I think we've just seen the ImmunoTEP data in head and neck cancer showing activity in PD-L1 low with Keytruda, which makes a complete different regulatory scenario for contribution of component as well, right? I think Tori is well set up for a higher probability of success with this combination strategy.
Is it through the combination strategy, do you go through those instances where perhaps as you reference, regulators have acknowledged difference, right, between efficacy or not granted approval in PD-L1 patients? Does that make it a natural sort of area that you target?
Absolutely.
Turning to LOQTORZI from a commercial standpoint, right, because we're now into the launch, you know, there was in the first quarter some disruption just given your divestiture, your Denyeau from a Salesforce standpoint. I guess, Danny, is that now in the rearview mirror and, you know, how do we think about the launch and commercialization through the rest of the year?
That's a fair question. Q4 saw the announcement of the divestiture as well as the initiation and resolution of the supply interruption, which carried on through Q1 when we actually then bifurcated the Salesforce and, you know, separated folks into which, whether they're going to go with Accord, whether they're going to stay with Coherus. So while the NCCN guidelines came out, I think, in late November of last year with the repositioning of LOQTORZI as the only preferred therapies across these lines, you know, I think it wasn't really until we've gotten here now into Q2, we're able to make a practice out of that. I can say that the team is hitting their stride here in Q2 and things are moving a little bit, I think, more consistently upward.
It is true that if you separate your organization and you go ahead and get over your supply interruption, there was a little bump in the road, some turbulence, but I think that's been in the rearview mirror at this point.
Maybe sort of saving the best for last or close to last, but we are running out of time. I wanted to touch on casdozokitug, your IL-27. M aybe before we start sort of getting into the data that you've generated so far, just talk about the importance of that mechanism and, you know, what really stands out.
Yeah, so I think this is an antibody against a cytokine, so IL-27. Antagonistic antibodies against cytokines are well understood in inflammatory diseases, right? IL-12 family, IL-23, which is part of the IL-27 family, well validated for rebalancing the immune system in autoimmune diseases and inflammatory diseases, hasn't been seen in oncology till casdozokitug. The safety profile has been really well tolerated. We've shown by complete inhibition of the cytokine, we have activation of T cells and NK cells and monotherapy responses in tumor types that the preclinical models said should work. I think the important things with this program is cytokines are immune regulatory. Depending upon the context, they have different biology. Everything from the mouse to where the expression is to the human studies has said liver and lung are particularly sensitive to IL-27 being immunosuppressive in tumors.
To see those monotherapy responses in lung cancer and activity in liver cancer is very exciting and I think different. That's been one of the problems with immuno-oncology is which trial do you do for that efficacy, right? We have strong what we call line of sight, knowing the patients to do, the trials to do and get the answer about go, no go for registration. Seeing in the phase two study in first line liver cancer in combination with PD-L1 and VEGF, a 17% CR rate. I don't think many people appreciate that IO has well below 10% CR rate. In lung cancer, PD-1s give a 4%. In liver cancer, the highest reported across all of the approved phase three studies is 8%. We saw 17% CR rate. That depth of response is highly unusual and differentiated. That has us excited.
We're doing the randomized study with Tori Bev now. That should fully enroll this year and read out next year, and seeing that type of efficacy would set us up well for a pivotal study.
We have maybe a minute left. Dennis, you touched on it earlier. You did divest Udenyca, which was the first full product, and one of it was enjoying a lot of success in the marketplace and certainly proved your sort of commercial capabilities. What was the strategic importance of that transaction?
You know, we're very proud of our accomplishments in the biosimilar space and we did as well as or better than anybody there. I think it's important to keep in mind that for the maximization of value of a biosimilar, you require a large product portfolio, you have to deal with the payers, and you really have to leverage your overhead across a number of products. That we did not have. On the other hand, innovative oncology is a place with a small targeted team. There's a long history of people creating disproportionate value and making disproportionate impact with patients. That's really where our heart lies.
With that, I think we're out of time, so we'll have to wrap up. Thank you so much.
Thank you.