—with Compass Therapeutics. I am pleased to welcome Tom Schuetz, CEO. Tom, welcome. Thanks for joining us.
Thanks so much, Michael. Thanks for inviting us. Thanks for having us here.
Great. I am Michael Schmidt, Senior Biotech Analyst with Guggenheim, in case you do not know me. Tom, this has been a, I would say, arguably a difficult year for Compass. How would you describe the company's strategy and priorities today?
Sure. Of course, I am not going to argue with you. It has been somewhat of a difficult year. Luckily, we are extremely well-funded. We just announced our earnings this morning. We are funded into 2028 for all of our development programs. I think, like all difficult times, right, really focus on the mission. We are really focused on developing a set of new drugs. We have got four drugs in the clinic. We can talk about each of those individual drugs, and we are really focused on advancing these programs to so-called inflection points, which will be driven by the clinical data. So, we are just really, really focused on not the difficulty, but the real opportunity with developing these drugs in these indications.
Yeah. I do want to spend some time to discuss the COMPANION-002 data. You obviously just came off the ESMO presentation, the first sort of full presentation at a medical conference. Maybe just stepping back, what have we learned about tovecimig today and its opportunity to treat biliary tract cancers?
Sure. In addition, of course, to the ESMO presentation, we simultaneously published all of the data in the Journal of Clinical Oncology, on October 24, online. I think, what have we learned about tovecimig? I think, let's start sort of very, very simply, if you don't mind. The drug clearly works, right? There's just no question about it. We more than tripled the overall response rate. Progression-free survival had a hazard ratio of 0.44, a hazard ratio on PFS that you don't see every day. There's clearly activity with this drug. And I was very encouraged. We had a whole series of meetings with KOLs at ESMO, and every meeting we had, the KOLs started the meeting by saying, "Well, this drug clearly works." So, we have an unequivocal efficacy signal, and I think that's a very, very good place to start the conversation.
Obviously, the overall survival endpoint did not succeed for various reasons. We can get into this. But I just wanted to step back and maybe then bridge over to what this means for your regulatory submission and what the feedback has been to date from the FDA around that.
Sure. Let's talk about the endpoint first. On the overall survival endpoint, the study allowed crossover, of course. More than half the patients who were randomized to the control arm crossed over to receive combination therapy with tovecimig. And even though they crossed over, of course, in an intent-to-treat analysis, they are, quote-unquote, "counted" with the chemotherapy control arm. That's just the way the statistics work. So 85% of the patients in the study received combination therapy. The study was effectively a randomized trial of tovecimig versus paclitaxel versus tovecimig plus paclitaxel. The overall survival in the intent-to-treat analysis was not different. Fascinatingly, during the review of the draft of the JCO manuscript, one of the reviewers of that manuscript specifically asked for the Two-Stage Estimation method, and we did that, and that showed a hazard ratio of 0.85 when you correct for crossover.
So, this question about the hazard ratio being above one, hopefully we have put that question at least to rest. The second half of your question, of course, is very complicated, right? How does this all connect on the regulatory front? We submitted a meeting package in the summer. As I have said publicly, we were not afforded a meeting, and all of the responses were written responses only. We never really had a discussion about the survival data. As I sit here today, I don't really know what the answer to your question is. What we have said publicly, and I'll say again today, we're working to re-engage with the FDA. We're right in the middle of that right now.
We expect to have a meeting with the FDA, and hopefully, like many other companies, which you know these companies full well, over the past six to nine months, have had rather dramatic reversals of their FDA trajectory based on a different approach. So, we're trying that different approach. We're right in the middle of that. We'll see. Hopefully, that will put us in a position where we can say something more definitive about the regulatory path.
Right. And remind us, what was the initial feedback that you've received?
We received written feedback, which was very short feedback. We attempted to go back and get that clarified, and the clarification was not super helpful to us. So we were in this very difficult position where we felt like we needed to make a disclosure. FDA, quote-unquote, "recommended" that we do a study to demonstrate a survival advantage. So that's what we disclosed.
So obviously, going into this, you obviously knew that crossover is going to be an issue, right, in the study to show survival. That is why you had actually implemented some statistics to account for that. I guess, how persuasive is this alternative method that was included in the JCO paper compared to the RPSFT analysis?
The RPSFT analysis could not be done, because the statistical assumptions for that method were not met. So, how persuasive will it be? I do not know the answer to that. I will say, we only very recently disclosed that, and that entire analysis was not included in our original submission to the FDA in the summer.
Okay. And outside the OS question, did the FDA have any other feedback on the magnitude of benefit, for example, on PFS or any of the other activity measures that were assessed in the study?
So, I think the short answer to that is, if you force me to say yes or no, I suppose the answer is yes. They had some additional comments on the data in the study, but again, we did not have any discussion whatsoever about those comments.
Okay.
That's really what we're trying to accomplish here this quarter.
What about safety? Any safety concerns?
I don't think so. Nothing specific was brought up. I think we disclosed the entire safety data set in the JCO paper and the ESMO presentation. I think for the most part, it looks fairly similar to what you see with VEGF-targeted agents.
Right.
Maybe a little bit more hypertension, but a little less proteinuria, maybe a little less clotting and bleeding. But for the most part, it's similar to other drugs in the class.
Okay. The other thing that had been discussed also came up in the ESMO discussion, actually, was the control arm choice.
Sure.
Is that something the FDA okayed, the paclitaxel as opposed to using FOLFOX, which is recommended?
The answer to that is definitely yes. The FDA specifically requested to have paclitaxel as the control arm. I think interestingly, the three-drug combination FOLFOX is more commonly used in the second-line setting in the EU than in the United States. In the United States, there is an incredible variety of second-line regimens that are used, FOLFOX, FOLFIRI, even some, the SWOG S1815 that looked at ABRAXANE. Some people use that. So, there is a whole series, liposomal irinotecan. None of these drugs or regimens, by the way, are labeled for this indication in the United States. So, it is amazing today that we have a disease like biliary tract cancer in the U.S. that, outside of actionable mutations, has no labeled second-line therapy. I think it is one of the almost only diseases out there that does not have a labeled second-line therapy.
Right. Can you walk us It seems like it all comes down to this OS, the way OS is being analyzed in the study at the end of the day.
I don't know. Honestly, that sounds crazy that I can't answer that question, but I honestly don't know—
Okay.
—what it comes down to because we haven't had a conversation with them.
Then walk us through the next steps. The meeting, when is it coming up, and then what would you do subsequently to that?
Right. We have not disclosed anything about the details of the upcoming meeting. Ideally, we'd like to get alignment on the regulatory path forward with FDA, and I alluded to the fact that there were so many other companies that have gone through this, the recent disclosure by Biohaven, for example, right? They recently disclosed that they have a PDUFA date now in the coming year, in which that was something completely new, obviously. You and I have talked before about Replimune, right, and how that completely turned around from a negative CRL. Yeah, just hopefully we'll be able to make some disclosure like those companies did, where we reach agreement on next steps—
Okay.
—with FDA. That is the goal for this meeting.
If the answer, I guess, maybe walk us through what are possible outcome scenarios and how likely. No, let us not go there. Just walk us through the options—
Sure.
—post-meeting, in your opinion.
Sure. I think one option would be, okay, your ORR and PFS data support accelerated approval. Let us talk about the design of a confirmatory study, and let us get that study up and running. Okay, that would be one potential outcome. I think there would be, we are talking about a couple of different potential confirmatory studies. Probably the absolute simplest design would be another second-line study with tovecimig plus paclitaxel versus FOLFOX as a straight-up randomized overall survival study. That is a study that we are talking to some cooperative groups about, which could be very financially efficient for us if we were able to do that. Of course, we could have a conversation about full approval.
At the end of 2025, there was a 10,000-patient meta-analysis published in the Journal of Hepatology in biliary tract cancer, which showed that a PFS hazard ratio less than 0.61 is predictive of an overall survival benefit. This is a little bit of a technicality, but once a surrogate endpoint is validated with a meta-analysis like that, it is no longer a surrogate endpoint. It's a full endpoint, right? I think the best example of this is serum cholesterol, right? There's a long time when serum cholesterol was considered a surrogate. Not anymore, right? That is also a possibility. I suppose, just to complete the thought and be fair to your question, I suppose FDA could say, "None of this supports approval." Okay. Then we would probably again continue the conversations with the cooperative groups.
We also have a number of investigator-sponsored studies ongoing, including in a frontline biliary tract cancer study, adding tovecimig to GemCis and durvalumab. We're starting to see some interesting data coming out of that right now, which could inform a frontline study, maybe with a partner. We could do that study, for example. So that would be a study that will get data from that. We also have a gastric cancer and colorectal cancer, as well as a glioblastoma study that are ongoing, and we're continuing to sort of see interesting data tumbling out of these studies.
Okay. There's been some new data reported on ivonescimab—
Sure.
—in BTC. How does that factor in, or does that factor into your thinking at all for next steps?
Sure. The ivonescimab data were also presented at ESMO two weeks ago. I listened. I was at that presentation. I was super happy to see that result, because I think what the ivonescimab data showed is that VEGF blockade in this disease is a valid therapeutic target. We already knew that checkpoint inhibition was meaningful in this disease, with both IMFINZI and KEYTRUDA labeled in the frontline setting. So ivonescimab provides PD1 blockade via one end of the molecule and VEGF blockade via the other end, and that was superior to IMFINZI. I think what the HARMONi-GI study showed was that blocking VEGF and the angiogenesis pathway is a valid therapeutic modality in this disease. So I was super happy about that. In terms of what that means for us in a frontline study, I do not know. I am not sure.
We have heard rumors about a cooperative group study in the U.S. I do not know anything about that.
Okay.
Just heard rumors, so I do not know. I think ivonescimab has a PDUFA date coming up, so obviously we will follow that very, very closely.
Sounds good. When will you, just to summarize this, when will you be able to update markets on these regulatory discussions and next steps?
Sure. I think we'd love to I would love for that to be able to happen this calendar year. I don't know if we're going to be able to do that or not. That is forward-looking, as our lawyer friends say. I think sometime in the next several months, at minimum, we should be able to provide an update on the regulatory path forward in the U.S.
Okay, great. Looking forward to that. Maybe then a few minutes on the pipeline, the rest of the pipeline. Which of the programs are you most excited about right now?
We have four drugs in development, so I'm excited about all our drugs, of course. I think on Friday, only three days ago, we announced, and Saturday we presented, novel scientific data for our own PD-1 VEGF bispecific antibody, which is called CTX-10726. So, interestingly, we showed a couple of years ago that our PD-1/ PD-L1 bispecific antibody, which I'll come to in a minute, was able to mediate PD-1 stripping off the surface of effector T cells. So our drug CTX-8371 converts PD-1 positive T cells into PD-1 negative T cells. It's a very unique and novel mechanism of action. Because we took the component, the PD-1 blocking component, out of that drug and put it into the PD-1 VEGF bispecific, we wondered whether or not we could also mediate PD-1 stripping with that drug. And fascinatingly, we do mediate PD-1 stripping, but only in the presence of VEGF-A.
VEGF-A is able to mediate the formation of multimers, probably, that then mediate PD-1 stripping. So that drug also converts PD-1 positive T cells into PD-1 negative T cells. And we believe we have a very well-differentiated mechanism of action within what is now unequivocally a new class of drugs. So that's very exciting. We're in a dose escalation, a phase I study right now. We'll be in a position to provide just a status update and perhaps a data update from that study prior to the JP Morgan meeting in January. So very much looking forward to that. The dose escalation's going very well there, and we're moving through the dose escalation cohorts in patients with renal cell, gastric, hepatocellular, and endometrial cancers.
Our PD-1/PD-L1 bispecific antibody, we presented data at ASCO in June, and in a dose escalation phase I study, we saw, I think, very important responses in the post-PD-1 patient population in patients with triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. Based on that, we initiated cohort expansions in the phase I study in those three indications. The enrollment into the cohort expansions is going very well, and we will be in a position to report a status update and some new data by the end of the year as well. Ideally, some report on some additional efficacy signals that we are seeing. Then finally, our CTX-471 drug, our CD137 agonist antibody. I think we made a very important biomarker discovery there, which is NCAM expression on tumors.
Now we have initiated an NCAM-positive phase II study, which is going to enroll patients with mostly neuroendocrine tumors. It is interesting, some others have now made this observation that neuroendocrine tumors are sort of uniquely amenable to CD137 targeting. So we have initiated a phase II study in patients with neuroendocrine tumors, and that is a later 2027 data event. That is another study we are very excited about.
Just on that one, are these patients selected based on NCAM expression?
Yes.
Yes. Okay. Maybe just to follow up on, I am sorry, CTX-10726, the PD-1 VEGF antibody. The dose escalation study that you are conducting, will that give us some insights into potential differentiation from ivonescimab, or would you expect a similar profile to emerge there?
That is an interesting question. We believe, of course, that that drug is better, okay? It is better pre-clinically. It is better in vitro. Let's be serious here for a minute, right? Ivonescimab has done thousands of patients of randomized trials. The only way we will ever be able to say we are better is with clinical data. So, I expect us to be able to show differentiated activity. I think ideally, frankly, I would love to see monotherapy activity in the post-checkpoint patient population. That would be ideal. I think the ivonescimab data are all non-small cell lung, BTC, et cetera, are all combination with chemotherapy or checkpoints or ADCs. There are, among the indications we are studying, I think there are indications where a monotherapy signal would be very, very meaningful. So, renal cell, for example, right? Post-cabo-nivo, post-salvage VEGF TKI.
There is a population where we could potentially go straight into an approval study, conceivably.
Right.
I think hepatocellular also, frontline bev-atezo. I think post-frontline bev-atezo would be a place that would be sort of very straightforward for us to go.
Okay. Just a quick one in the last 22 seconds on CTX-8371. The status update by the end of this year, I guess, how many patients will be included in that?
I'm sorry. It's probably going to be in the 20s, I would say, something like that. I don't know the exact number today.
Up from 12, I think it was before?
Fifteen.
15. Okay, great. Looking forward to that.
Great.
Our time is up, right on the dot.
All right.
Appreciate it, Tom.
Great. Thanks, Michael.