Okay.
I don't think it's on. Okay, now it's on.
Fantastic. Okay, so we're dealing with some shot clock issues here. That last session with Dr. Schlechter was supposed to be 25 minutes, 30 minutes. We cut that pretty short. But since Dr. Schlechter is very familiar with BOT/BAL, we're going to have him on here with the team from Agenus or Zack from Agenus, the team. I'm delighted to have Zack Armen of Agenus with us. As I mentioned, Dr. Schlechter's just walked us through the MSS colon cancer setting here. Agenus is one of the companies betting it can change that whole proposition of resistance to immunotherapy. It's been an eventful 2026, a strategic pivot into the neoadjuvant colon cancer setting and up to $340 million financing that roughly doubled the stock in a single session. Just last week, the first marketing authorization anywhere of BOT/BAL.
We have now 25 minutes or so let's get right into it. Zack, thanks for being here as well.
Thank you. Thank you, Andreas.
Dr. Schlechter, chime in wherever you see fit.
Yeah. Absolutely. I will stop you before.
Picking up from that last session, in July, you made a decisive call, stopped funding BATTMAN in late line metastatic MSS colon cancer and put the company behind ROBBIN, an 850-patient neoadjuvant phase III high-risk stage II and III MSS colon cancer. Why is the earlier setting a better bet scientifically, regulatorily, and commercially? I know that was one of the points that you may want to address too. Zack, go ahead and then—
Sure. Thanks, Andreas, and thank you, Dr. Schlechter, for being here as well. We made the decision during the July financing discussions to move to the phase III ROBBIN trial as our sole registration-enabling trial focus. As Dr. Schlechter pointed out, there is a significant need in the late line metastatic setting, and the company continues to believe wholeheartedly in that need. We have pursued multiple regulatory pathways and other pre-marketing authorization pathways to ensure that patients have access to the drug. We have a compassionate access program where patients have access to the drug in 30-odd different countries. We have our program in France, which is through the AAC program, where the therapy is being reimbursed by the French government for patients in late-line refractory MSS colon and rectal cancer, sarcoma, and ovarian cancers.
As Andreas just mentioned, we just got our first marketing authorization in Armenia for the advanced metastatic MSS colorectal cancer setting. We are doing everything we can from a patient access perspective to ensure that patients who want access to the therapy have ways that they can access it in multiple different countries. We did enroll over 1,000 patients now across late-line metastatic settings. Dr. Schlechter and his team at Dana-Farber were a big part of many of those trials. We have a plethora of data that supports the value proposition of this therapy across major late-line tumor settings, and we hope that that will become part of future sponsored work. It may become part of the way that oncologists decide to prescribe the drug, even if we do not have yet a label there. That is a completely separate commercial topic, which I will not get into.
As far as the company's focus, and our strategic decisioning around moving to the ROBBIN trial in the neoadjuvant setting, there were many factors. One, it was a bandwidth and resource consideration. It is really hard to go stand up a global phase III trial for any small or mid-size biotech company. The idea of doing two of those at the same time was a concern around bandwidth and resources. Of course, capital resources being something that are an important consideration in our industry and needing to focus those capital resources on the Stage II/III colon cancer setting, was a decision that we came to. As Dr. Schlechter pointed out very clearly and elegantly, this is the area where we can make the most profound impact on patients.
You talk about the ability to deescalate the use of chemotherapy in the case of rectal cancer, to deescalate the use of radiation along with mutilating surgeries and preserving the organ, in the case of patients who have to receive an ostomy procedure, and then just the ability to drive higher event-free survival. These patients who have been treated with BOT/BAL in both NEST and UNICORN, those patients had a very short treatment course of BOT/BAL, and they all are remaining treatment-free now for multiple years in the case of NEST, and we plan to have updates to UNICORN as well in the coming weeks and months. This is an exciting setting for us and for many oncologists around the world, and we are really focusing all of our time and energy on getting the trial ready to begin enrollment.
Yeah. Maybe for Dr. Schlechter. So that question of, is earlier a better bet?
Yeah, this is a challenge for the oncologist, right? I have different priorities. The best benefit you will ever see from BOT is going to be in the neoadjuvant setting, and I want to have it all. I want to give it in the neoadjuvant setting and the refractory disease setting. I think that it is a large population. It is a population with need. It's not that operative patients don't have need. It's a population with need. The idea that we can move away from chemotherapy that's nearly 50 years old would be nice. I think that biologically, the best place for BOT is in the neoadjuvant setting, but it addresses only one of the very important needs.
And maybe for both, and maybe Dr. Schlechter, you can start, but what about NEST and UNICORN gives you conviction that—
Yeah, look, you're talking about people who have their diagnostic colonoscopy, they get the uh-oh, you have cancer conversation. They have a CAT scan that says, oh, look, there's a big thing in your abdomen. We can see it on CAT scan. They receive six weeks of therapy, and then nearly half of them have no cancer. That is a remarkable response, and you can't ignore that response. We don't know if that means they're cured. That's an important caveat, and it takes a lot to convince oncologists that you cured people. We have very high standards for that word. But I would say that was really impressive data that we could have a major response, and it makes perfect biological sense.
Yep. Perfectly said.
Perfectly said. Let me ask you the opportunity question here. There are about 38,000 newly diagnosed U.S. patients a year, translate to roughly $7 billion in annual U.S. sales. What has to happen to get there?
The trial that we're about to embark on needs to read out positively, which we have a strong degree of confidence that it will. If it reads out positively, it means that we have reduced the recurrence rate by a significant margin. We have a hazard ratio of 0.65, so that would mean at least a 35% improvement in the recurrence rate. We believe we'll exceed that hazard ratio, but that's up to the outcomes of the trial. We very likely will also see a considerable de-escalation of chemotherapy as part of the study's secondary and exploratory endpoints, and a maintenance of ctDNA negativity, which, as Dr. Schlechter alluded to, is the best predictor we have of long-term survival and EFS outcomes that exist today.
If all of those things happen, we believe there's a very strong risk-benefit equation for any patient and oncologist to say, why would I not give this short course of an immunotherapy that has no delays to surgery, that has less than 5% Grade 3 AEs, all of which are manageable and have been managed very strongly in the clinic. I still get to go and have the standard of care surgery and if I need it, chemotherapy. This IO regimen over a four to six-week time course could cure me and avoid me having to deal with any more treatments for my cancer that no longer exists.
Agree. Let's think about the upcoming catalysts. There's quite a few. Walk us through the ROBBIN timeline. First patient Q1 2027, an interim pathologic response look in the second half of 2027. Interim event-free survival in the second half of 2029 and a final analysis in the second half of 2030. What role does the 2027 path response interim play? Is it a potential accelerated approval readout or an internal go, no go?
Well, I won't comment on accelerated approval because that's been a subject of this company for a long time. We've made it clear in many different instances that we believe the therapy should be made available to patients in the United States immediately. I won't go to any regulatory strategy beyond that. When it comes to this trial, the timelines actually, I think, are very well-designed to give the public investor out there a very clear understanding of where there are value inflection points along the pathway from today to a potential approval in this setting. We designed the financing to actually align very closely with those milestones. The first you mentioned, Andreas, we expect to have first patient enrolled in Q1 of next year. We do believe that this study will enroll quite rapidly.
There's a ton of enthusiasm among oncologists around the world, Dr. Schlechter being at the front of that line. If we see the enrollment that we expect, then the first catalyst that relates to the transaction is the 60th patient enrolled, which we anticipate to be a Q2 2027 event. That would trigger the first tranche of warrants that were part of the financing, which would generate $85 million of additional proceeds if all warrants are exercised. The second major catalyst is the pathologic response rate interim readout that you mentioned. This is anticipated to occur in Q4 of next year, and that's on the first 100 patients treated in the study, 50 on the BOT/BAL arm and 50 on the control arm.
That will simply be the pathologic response rate, which is 50% or greater tumor shrinkage, the percent of patients who had a PR, the percent of patients who had a major path response rate, which is 90%-99% tumor shrinkage, and then the percent of patients that had a pathologic complete response rate. This is not a gating or go, no go milestone related to the trial. It is not a primary endpoint. It is simply meant to deliver a read-through on a near-term endpoint for the company and for the market to see what that response rate data looks like. It's a confidence generator from the perspective of the investors and the financing that we did. They see that as a very strong correlation in terms of pCR to EFS hazard ratio.
We actually showcase that in our webcast and our latest corporate materials that we did a review of all of these prior neoadjuvant studies and saw that there is a very strong correlation between pathologic complete response rate and EFS hazard ratio. It's simply meant to be something that's a catalyst for people to see how the trial is going. Then ultimately, as you mentioned, the EFS endpoints are an interim read at 75% information fraction anticipated in the second half of 2029, and then a final read anticipated in the second half of 2030.
Yeah. That's fantastic. Thanks. Dr. Schlechter, you can comment on the importance of the interim 2027.
Yeah, that's hard. It's not biologically important. It will be important to know that in multi-center studies that the path CR rate holds, and that I think will rapidly amplify interest in the study. Patients will know about it because I'm sure there will be an abstract and presentation somewhere. There'll probably be a paper on path CR and some biological correlates. Hope so. Be my advice, happy to be author. That will rapidly expand interest in enrollment. One of the biggest barriers to enrollment on this study, and I hope that the initial timeline isn't too ambitious.
I actually think there's going to be a little slow start, and then it's going to massively ramp up when the data comes out, is that if I said to anyone in this room, you have cancer right now, you could do a trial, and maybe it comes out later, or you could get it out right now. I think that the sales proposition of this will be hard in the beginning, and if you can get a 40%, 50% path CR rate, I think this trial will just rapidly enroll once that first bit of data comes out. That's my prediction of what would happen. Patients want it, doctors want it. I think.
Fantastic. Near term, there are three investigator-sponsored posters at ESMO in Madrid next week, including NEOASIS in [inaudible] neoadjuvant colon cancer and long-term survival data and agenT-797 combination work at SITC early November, plus NEST and UNICORN manuscripts in the second half. A great question for both. Dr. Schlechter, you can go too. What should investors take away from this flow of data?
I can't speak for investors. I would say the data from NEST that has now been published is very compelling. There's the wink, nod. The GONO group says the UNICORN's going to look pretty similar. If we have two publications with similar path CR rates at an effective dose and schedule, I think that's going to be very compelling, and that might be enough to generate massive early enrollment in the trial. So two trials coming out with similar results, one in Italy, one in New York, that'd be great. In terms of MMRd, whatever, I feel like MMRd is already a settled issue, and there was something else you talked about.
What else did we have? Long-term survival data and the agenT-797 combination.
Which is 797. Oh, cool. Yeah, I don't know if [inaudible] is a very cool concept, but I don't know the data well.
Yeah. Just to go back to the NEST and UNICORN data, I think I'll say it in lay terms because that's how I think about this stuff. I'm not a scientist or a doctor. In NEST, which we did publish the updated data with maturity out beyond two and three years, we have had no disease recurrences. Typically, patients who get standard of care surgery and chemo in this setting, around 25% of those patients will have recurred. So among those 40-odd patients between NEST and UNICORN, you have very likely 10 of those patients would have had a disease recurrence, and I believe it's typical that those are metastatic patients when they recur.
Those are 10 lives that would have likely been negatively impacted that are not because of a very short course of therapy that is administered through an IV and has a less than 5% chance of having any material adverse event. From a patient perspective, we hope that this data generates confidence, and obviously from an oncologist perspective, we believe that it will, and we have seen that already. When UNICORN is updated, then we will see whether that data is consistent, and we feel strongly that it will be. The MSI-High or dMMR is, of course, a setting where IO has proven to be beneficial.
We will see the NEOASIS data in full that the abstract came out yesterday, and long story short, it was clear that there was a benefit as expected, but these were in highly advanced diseases where the tumor was protruding other parts of the biology and organs. That seems to be an area where oncologists are looking for a novel IO regimen to potentially benefit beyond what first gen does. Overall, Andreas, it is about this data continuing to support the rationale in this setting and continuing to generate a very strong risk-benefit proposition, which hopefully drives excitement and enrollment in the ROBBIN trial.
We have got about five minutes. One more technical question for you.
Sure.
You just talked about dMMR being neoadjuvant, where there is already a strong setting. Why does CTLA-4 combination add value there? Why should that be?
I'm not actually sure. We think about where to focus our scientific and financial resources on patients. If CTLA-4 is a few years ago, I would have said you absolutely need a CTLA-4. Now I'm less certain, but there's enough data from Myriam Chalabi's NICHE that I think neoadjuvant ipi/nivo, which was a three-year 100% disease-free survival and a 90-something % path CR, that there's great data already, and I'm sure BOT and BAL would do just as well. Maybe marginally better, but the numbers are so good that I'm not personally convinced that that's where resources need to be committed when there's. I think dMMR, I feel like is close to settled in the neoadjuvant setting. In the refractory setting, for those patients who don't respond, which is about a third, then there might be a place for the next generation CTLA-4s or other approaches.
That's personally where I would see the landscape for dMMR. dMMR is rare. dMMR is really biologically important, and it's interesting. It's not as important as MSS.
Very fantastic. Zack, for you, let's address the regulatory history directly. You alluded to that earlier. Today, you have marketing authorization in Armenia and revenue from authorized access programs. How should U.S. investors weigh ex-U.S. approval and access revenue?
It's an important part of the full story. It's not the main driver of what we believe to be the upside value in our story, which we believe is going to be driven by the ROBBIN trial and hopefully further sponsored work in the neoadjuvant setting, where there is a game-changing opportunity with, in our minds, multiple billions of dollars worth of revenue on the other side of that. These current paid access and compassionate programs will never get anywhere near that as far as a revenue driver, but they are important validators of a few things. Number one, there's a demand for this therapy today from patients. There's a willingness from oncologists to prescribe the therapy to patients.
In the case of France, there's a willingness and a recognition from the marketing agencies, or the regulatory agencies rather, in that country that this therapy should be afforded to their patients, and they should reimburse for it. That, in our minds, is a powerful message that we think investors should really pay attention to and acknowledge the fact that this therapy, while it's still experimental, has a strong degree of demand from patients across multiple different late-stage tumors, and in multiple different jurisdictions around the world.
Then we got the BATTMAN trial. BATTMAN had only just started enrolling people for the program or the funding. How did investigators react? Does that affect ROBBIN going forward?
I can speak for myself. Honestly, we were pissed, okay? It was like an unexpected breakup with your high school girlfriend or boyfriend. It was very disappointing. It's not that it's not understandable. We all deal with constraints, but it was very disappointing because, again, the people in the exam room who it's just gut-wrenching, is refractory disease. I understand that the drug is best suited in the neoadjuvant, and I understand that there are financial and market forces, just like I have to make decisions as the colon cancer and rectal cancer director for Dana-Farber about how we allocate our resources for exam rooms and procedures like that. But it was pretty rough. At the same time, we all believe in immune therapy. I mean, who doesn't, right? I don't think that will hamper ROBBIN, but I think people were pissed.
That's a very reasonable reaction, and we knew that this was going to be a tough outcome. It was a tough decision for us to make internally, and a big part of that was because of the impact we knew it would have on patients, and especially on those sites that were already enrolling patients. Our team has done a really great job of managing that as best as we can in a tough situation. As far as ROBBIN enrollment goes, we're managing those interactions with potential sites very rigorously and in a very detailed fashion. We're ensuring primarily that these oncologists and the collective team, including surgeons and including the gastroenterologists, are on board with the idea of giving something that is very novel in this setting.
Understand that there's ultimately a huge benefit that we're going to be able to unlock to patients, with their support and their recognition and rigor in executing the trial. We've not experienced what I would say significant resistance because of the BATTMAN outcome. We're being really thoughtful and rigorous in how we're selecting the sites for ROBBIN to make sure that the trial is conducted in an efficient and scientifically rigorous fashion.
We want to give people the drug, right? Same thing like compassionate use programs make scientists mad because we just want to do the damn trial. But at the end of the day, we just want to give people this drug.
Yeah, we want to get the drug to patients, and we've really tried, and we have a very strong medical affairs effort around education so that everyone has at least a chance of knowing the information and being able to make an informed decision about BOT/BAL.
Hopefully capital constraints.
One day we hope it won't be an issue.
Standing day. Yeah, exactly.
That's part of this group's job.
Yeah. All right. Well, look great. Zack, Dr. Schlechter, thank you guys for a great discussion here. Following us right now is [inaudible].
Great. Thank you.