Good morning, everyone. Thank you for joining us at the HC Wainwright 27th Annual Global Investment Conference. My name is Emily Bodnar. I'm an Equity Research Analyst at HC Wainwright. Pleased to be doing a fireside chat with Agenus. We have Richard Goldberg, Chief Development Officer, and Robin Taylor, Chief Commercial Officer of the company here. Maybe to start, for those a bit newer to the story, your lead asset, Botensilimab, is a next-generation Fc-enhanced CTLA-4 inhibitor. Can you walk us through kind of what that means in terms of construct and how Botensilimab differs from first-generation CTLA-4 inhibitor ipilimumab, which is FDA approved?
Certainly. Thank you, Emily. Pleased to be here. The key differentiation for BOT lies in the Fc region. There are two-point mutations that enhance the binding of BOT to both antigen-presenting cells and myeloid cells. This tighter binding to antigen-presenting cells creates a stronger immune synapse. That actually allows CTLA-4 to then create a stronger priming and activation of the immune system. This is really important because this is one of the key ways that CTLA-4 works. The other aspect in terms of the binding to NK cells activates NK cells to basically deplete T-regs. You're both upping the immune response and you're also dialing down the immunosuppressive aspect of T-regs. That's a sort of key element of how BOT works and is able to actually be more active than the first-generation CTLA-4s.
Right. One issue that we've seen a lot with checkpoint inhibitors is that they often don't really have efficacy in cold tumors, whereas with Botensilimab, we've seen a number of cold tumors that you do have efficacy. What kind of do you think is driving that benefit there in indications like MSS CRC and pancreatic cancer, for example?
Yeah, that's exactly right. I think what's remarkable about Botensilimab is that it's notable that we see the activity in a classically cold tumor, like microsatellite stable metastatic colorectal cancer. This is a tumor where there are a couple of different immune phenotypes that result in a cold tumor. One is a classic immune desert where you're just not getting an immune response that's sufficient to generate a lot of immune infiltration. The other is immune suppression. We've seen actually both examples in the clinic. In our neoadjuvant study, we've actually seen examples of being able to up the amount of immune infiltration into tumors while also depleting T-regs, which is then suppressing that immunosuppressive environment. That's not only in colorectal cancer, but many other cold and immunorefractory tumors. This is the phenotype that you see. It's the mechanism of BOT that's able to overcome that.
Does the Fc-enhanced design also potentially improve tolerability, particularly immune-mediated adverse events?
We engineered into BOT a third-point mutation. This one is actually designed to abrogate complement binding. There was an observation that some of the immune-mediated AEs you see in the first-generation CTLA-4 are related to complement fixation. A classic example of that is hypophysitis. If you look at the ipilimumab studies, you see a rate of hypophysitis of about 5% to 9%. In the BOT studies across the program, we see less than 1% hypophysitis. It is evidence that that mutation that abrogates complement binding is actually having an effect on these sort of more difficult-to-manage long-term AEs, which is an improvement over the first generation of CTLA-4.
For those that are a bit less familiar, can you kind of walk us through your ongoing studies with BOT-BELL currently and where you are in clinical development?
Yes, I can do that. We actually have 35 investigator-initiated studies that are currently active. It really covers the body from head to toe. We have CNS tumors down to melanoma. We also have had studies in head and neck cancer, in esophageal cancer, in pancreatic cancer, in MSS and MSI high colon cancer, in appendix, rectal cancer, really across the board. Perhaps one of the most interesting and exciting areas is activity we're seeing in both triple negative and positive breast cancer. We also cover the landscape from early disease, meaning stage two and three cancers in the neoadjuvant setting, as well as late line, which we'll talk more about, our Batman study, which is a fourth line refractory metastatic colon cancer MSS study, which is our principal registration strategy in the immediate future.
Yeah. Maybe narrowing down onto MSS CRC, or microsatellite stable colorectal cancer, which is your lead indication, as you mentioned. You've had quite a number of data updates from phase 1, also phase 2. Can you walk us through some of the latest efficacy data from those studies and how that kind of fits into the context of existing standard of care?
Sure. We updated our data at ESMO GI on our refractory colorectal cancer patients. This included third-line patients as well as fourth-line patients. One of the observations that we made was it didn't matter in terms of efficacy whether patients received BOT-BELL in the third line or the fourth line. They hadn't been previously exposed to IO agents. Our activity levels were consistent across those two subsets of patients. That's what led to our strategy to look in the fourth line for our Batman trial. Just to reiterate, we're seeing median overall survivals that are consistent in around the 20-month range. We're seeing response rate around 20%. Most exciting is that we're seeing 24-month survival of over 40%, 42%. This is consistent across our phase 1 and phase 2 studies. I will mention that our phase 2 study is not fully mature.
The last patient in will have two years of follow-up in November. Our intention is at that time to rapidly submit a paper for publication as well as a data update to scientific meetings to illustrate the consistency of our data.
In your Batman trial, the comparator arm is supposed to be best supportive care. Maybe just discuss a bit on what the expectations would be for best supportive care in terms of overall survival and how that compares to the 20 months that you've shown in trials.
As everybody in the room knows, the best supportive care was the control arm for the four important studies in third line, that being the REGO CORRECT study, the Lonsurf, and Lonsurf plus Bev studies, as well as the FREQUITNIB studies. We have very good data from four large randomized trials with best supportive care as the control arm to show that these late line patients have a pretty dismal survival expectation of about five months. We also have looked at the data from the Canadian CO26 trial, which was a DERVA-TREMI study, which included both liver metastasis and non-liver metastasis patients. We have benchmarks for that population as well. We're again seeing 20-month median overall survivals as compared to single-digit overall survivals in the other studies. We're also different in terms of the response rate.
The best response rate was in the SUNSHINE trial, which is Bev plus Lonsurf, and that was a 7% response rate. The other three drugs, Lonsurf, REGO, and FREQUITNIB, have all had response rates in the low single digits. Our 20% consistent response rates look very promising to us and I hope to you.
Yeah, I guess on that front, obviously, you've had median overall survival in phase 1. In phase 2, you, as you mentioned, had consistent overall response rate about 20%. Does that kind of give you increased confidence that you'll likely see a consistent median overall survival in phase 2 as well?
It certainly does. You know, if you look at the data that we do have, we have 12-month survival of around 60%, 18 months of about 50%. In the studies that are mature, we have a 42% consistent 24-month survival. The flattening of the curve is what we all hope for when treating these patients. I'm a GI Medical Oncologist, so I'm confronting this disease with patients in the clinic. What matters to them is more time, better time. I would remind you that the treatment with BOT-BELL is a short course of treatment in general. Patients often are treatment-free, not sitting in clinics, but still getting the benefit of their primed immune systems, fighting their cancers. Of course, what we hope for is what we observed in the pembrolizumab studies in MSI high patients. Just last year at ASCO, we reported a 52% 10-year survival for those patients.
That's what we aspire to deliver to our MSS patients.
Yeah. Can you discuss the results of the end of phase 2 meeting you had with the FDA? What was their feedback regarding phase 3 design and how to incorporate that into the Batman phase 3 trial?
We met with the FDA in early July, and we felt like we had some big wins there. A year ago, when Agenus met, that was before my time with the company, they were not convinced of the contribution of components. This time, they basically said, we aren't questioning the contribution of components. You don't have to do a third arm in your phase 3 study of BOT alone. They also agreed on our dose of 75 milligrams of BOT with BELL, and they agreed on the design of the Batman study, which is an 834-patient study, so a big study, one-to-one randomization, overall survival as an endpoint, best supportive care as the control arm. They agreed that we could do this with the Canadian Clinical Trials Group, who had approached us to do this study. The study will be done in Canada, France, and Australia.
The groups have collaborated before, and they're used to putting patients on late line colon cancer studies and have a good record of accrual. One of the most important things is that when we ran studies with best supportive care control arms in the U.S., we found that U.S. patients were not satisfied with being on a control arm, which was best supportive care. If they were randomized to that, they'd drop out of the trial and find either BOT-BELL as compassionate use access or find another trial to go on to. Because of the relatively rigid controls in these national health insurance programs in Canada, France, and Australia, that option doesn't present itself to patients in those countries. We were pleased that the FDA accepted all of those parameters and were prepared to move quickly forward with the Batman study.
Yeah. Can you discuss your decision to include both patients with and without liver metastasis, given in your earlier stage trials, the majority of patients were without liver metastasis? How do you kind of think about potential for positive data in both of these patient types?
We really modeled our statistical planning on the Canadian Clinical Trials Group CO26 study, which was DERVA-TREMI versus best supportive care. It's a smaller trial than our trial. There were 120 patients randomized to the DERVA-TREMI arm. They included both liver metastasis patients and non-liver metastasis patients. The response rate was exceedingly low, basically 1% response rate. Despite that, the hazard ratio in the overall study was 0.7 for overall survival. Even though patients weren't meeting the RECIST criteria for response, their immune systems were recognizing and combating those tumors such that there was a survival benefit. If you look at the 12% one-year survival in the DERVA-TREMI study, the CO26, our 30% one-year survival data in our liver metastasis patients compares favorably to that. That gives us confidence that we'll see that now.
We've designed the study to look at all comers as well as to look at non-liver metastasis patients and liver metastasis patients in the analyses.
How do you think about the market opportunity in the fourth line setting? Is your expectation to commercialize BOT-BELL alone, or are you planning to eventually seek a partner for commercial?
It's a great question. The fourth-line setting, the overall patient population in the U.S. is about 10,000 patients when you incorporate both liver MET and non-liver MET. That's comparable in size to the third-line non-liver MET population, which we had previously been looking at as well. It's a substantial population. We anticipate benefiting both the liver MET and non-liver MET populations, so a significant opportunity. With respect to commercialization, we're in the midst of discussions around looking for a global partner. That partnership could be regional, but it could also include co-development, co-commercialization in the U.S. If we are commercializing on our own, we're definitely capable of that. I've built and led teams across Genentech, Roche, AstraZeneca, Seagen, multiple launches. This would be a launch that I think any sales organization would be excited about, a differentiated product, first in class in a high-end MET need setting.
Do you have plans to potentially move BOT-BELL earlier into the treatment paradigm in CRC? Obviously, you have several investigator-sponsored trials in the first-line setting and also in the neoadjuvant setting. What might the regulatory pathway look like for those indications?
We're really excited about the early activity we're seeing in the neoadjuvant setting in MSI high as well as MSS colon cancer. We have studies that are ongoing at Cornell, in the Netherlands, in Amsterdam, in Italy, all of which are showing really satisfying activity. Complete response rates of about 30% in MSS colon cancer, some response in about 70% of patients. We think that there's going to be a strong application for BOT and BELL in the neoadjuvant setting, not just in colorectal cancer where we're concentrating our efforts, but in the study that Miriam Slaby is doing in the Netherlands, she's observed a number of responses in breast cancer and other diseases, including ovarian, with early initiation of BOT-BELL therapy. I'd remind you that these studies give one dose of BOT and two doses of BELL. They're relatively short-term treatments with dramatic responses.
We're thinking about trials, phase 3 trials in colon cancer and in rectal cancer. There's a rectal cancer study here in New York run by Andrea Sersik, who ran the studies in MSI high with Valsartan. The study has an accrual goal of 40. It's been open for two months and has already accrued 14 patients. There's tremendous interest in this among the patients who are having to confront MSS rectal cancer.
Maybe to close out, could you just comment a bit about your current cash position and also summarize for us some upcoming key catalysts that we should be looking out for in the next 12 months?
Yeah. One of the key transactions coming up is the close of the Zydus Lifesciences transaction. That will bring in $91 million in funding, which will allow us to both launch the Batman trial and also continue our operations for some time. We have a second strategic transaction that we're anticipating in the short term that will provide additional funding. In the long term, we're looking at a strategic partnership, as I mentioned, ideally a global partnership that may or may not include the U.S. You may have seen the press release today, we announced reimbursed access in France. That is important because ANSM actually reviews the data for any access program. You have to establish a positive benefit risk. That program is now reimbursed in France, and that will provide additional supplemental income moving forward.
In terms of catalysts, upcoming at ESMO, we have four abstracts that have been accepted for presentation. The highlight is an oral presentation of emerging plateaus in terms of survival that we're seeing in the phase 1 study across five different tumor types. It shows the consistency of Botensilimab and Balstilimab and the ability to be able to really activate the immune system and show this persistence of benefit over time. Finally, one of the key catalysts, obviously, is the start of the Batman trial. We anticipate that trial will be open shortly and then enrolling very quickly after that. Definitely anticipate this in the near term.
Perfect. Thank you very much, Robin, Richard. It's been great speaking to you. Thanks, everyone, for listening in. Please enjoy the rest of the conference.
Thanks, everyone.