Good morning, everyone, and thank you for joining the H.C. Wainwright global investment conference. My name is Emily Bodnar, and I'm an equity research analyst at H.C. Wainwright. This morning, I'm pleased to introduce Robin Taylor, Chief Commercial Officer, and Zack Armen, Head of Investor Relations of Agenus, and I'll pass it off to you to start with some slides.
Excellent.
Thanks a lot.
Thank you. Thank you, Emily. So I'd like to begin with an image, which hopefully you'll see here in a second. Sorry, having a little trouble advancing. There we go. So what you see on the left in this image is an eight- centimeter mass in the colon of a 40-year-old woman, and then, seven weeks later, on the right, you see what looks like a different colon. This is a clean, clinical, complete response, and on the left, the question is: why did the immune system not recognize this tumor? Well, part of the answer to that is that this is a Microsatellite Stable colon cancer, meaning that the tumor itself is not highly immunogenic. It doesn't have a lot of neoantigens.
With the addition of one dose of BOT, which is our CTLA-4, and three doses of BAL, our PD-1, seven weeks later, the immune system is capable of completely eradicating this tumor. That's what I find remarkable about this. First, this is what the immune system is capable of when it recognizes cancer in place. Second, the fact that there is a tumor there means that the immune system was not doing its job. It was not able to recognize and kill the tumor that you see on the left until it got a little help, and that help was specifically an Fc-enhanced CTLA-4 called botensilimab that is able to provide a stronger signal to the immune system to recognize these weak neoantigens, and then activate T cells to be able to kill the tumor.
This is an example of one pathologic complete response out of five in a study of nine patients, given this particular schedule of one dose of BOT and up to three to four doses of BAL, with a treatment interval of about eight weeks. And I'll come back to this study in a little bit, to show you a bit more. But it really demonstrates both the power of the immune system, and the necessity to be able to activate the immune system in these cold tumors. So when you look at BOT/BAL, we have a next-generation CTLA-4 that is going beyond what we can achieve with the first generation of CTLA-4 inhibitors, and a highly active PD-1 inhibitor with balstilimab. We have safety and efficacy in over eleven hundred patients treated with BOT and BAL, either monotherapy or combination.
And what's important is that this broadens the impact of immunotherapy to the 2/3 of solid tumors that have not been responsive to immunotherapy in the past. These cold tumors that are classically poorly recognized by the immune system and poorly treated with the current generation of immunotherapies. Microsatellite Stable colorectal cancer is a classic example of a cold tumor. Our broadest data set is in the relapsed refractory setting. You're seeing here a comparison between our phase I data, which is in patients who've had at least two prior lines of therapy, and many times, three or four lines of therapy, in Microsatellite Stable colorectal cancer in patients who do not have active liver metastases.
What you can see is that we have a response rate of 23% with the combination of BOT and BAL, and a 21-month median overall survival in this cohort of 77 patients from our phase I study, which is the most mature cohort of data we have with BOT and BAL in this population. The standard of care in this setting are multiple options: fruquintinib, which was a recently approved inhibitor; regorafenib, Lonsurf, and Lonsurf plus bevacizumab, and what you see in this patient population of patients with non-active liver metastases is that the response rate is anywhere from about 2%-7%, with median overall survival in the range of about 10-14 months.
So the comparison here you see, while not a direct comparison, is one that shows you the activity of BOT and BAL in a population that has a significant unmet need in terms of the available options, today. Coming back to the neoadjuvant data, this is all of the dataset that we have from the NEST study, which is an investigator-sponsored study. NEST-1 was a shorter course of treatment. It was one dose of botensilimab and two doses of balstilimab, with about a four-week interval to surgery. And you can see that we see clearly in the MSI-high population, which is very responsive to immunotherapy, that three of these patients had a major response and two with the pathologic complete response.
And you see this trend towards increasing activity in these patients, with about 2/3 of them actually having a response of 50% or greater tumor shrinkage. What we also notice is that with the longer treatment interval, with one dose of BOT and four doses of BAL, that the immune system is actually capable of going further, which is that we see five out of these nine patients with the pathologic complete response. For comparison, the current standard of care in colon cancer is typically not to provide any neoadjuvant treatment because the response rate is relatively poor with FOLFOX. Out of the FOxTROT study, the response rate was overall 8%, with a 4% pathologic complete response. So typically, chemotherapy is not used as a neoadjuvant treatment for colon cancer.
It is used to some extent, radiotherapy plus chemotherapy in patients with rectal cancer in order to reduce the size of the lesion. But again, it's not typical to see responses such as this, and that's the impact that this drug potentially can have in the neoadjuvant setting, which is not only can it provide a potentially higher rate of pathologic complete response, which we hope will correlate with event-free survival and improvement in long-term survival. But secondly, has the potential to reduce the morbidity of surgery, particularly in rectal cancer patients, where organ preservation is a key goal, and we have the opportunity potentially to spare that debilitating surgery for rectal cancer patients. So I'll leave you with this image because I think this speaks to the power of the particular agent we have in development, which is botensilimab, an Fc-enhanced CTLA-4.
And happy to speak to what makes this special and how we can bring it forward in further development.
Great. So maybe to start, for those who are a bit less familiar with BOT/BAL, what exactly makes botensilimab differentiated from the first generation CTLA-4 inhibitors?
Yeah. Thank you, Emily. So there are two specific point mutations in the Fc region of the antibody that enhance the binding to Fc gamma RIIIa. What this does is it creates a tighter synapse to antigen-presenting cells and myeloid cells. And so BOT actually does a better job of educating the immune system to recognize neoantigens, which is particularly important in these cold tumors. Secondly, BOT also increases the depletion of T-regulatory cells, and T-regulatory cells are immunosuppressive cells. And therefore, what we're seeing is an enhanced sort of two different things. One is you're activating the immune system, you're priming it, and secondly, you're removing one of the mechanisms of suppression to the immune system.
A third mutation on the antibody also inhibits the binding of complement, and complement-mediated toxicities can be some of the more troublesome immune-mediated AEs that are seen with the first generation of CTLA-4. So we see a lower rate of hypophysitis and some of these complement-mediated toxicities.
Great. You recently presented initial results from your phase II mCRC study in the relapse/refractory setting. So maybe walk us through the efficacy data that you've observed there and how that related to the phase Ib data that you had.
Right. So the phase II study was five arms. This was a study that compared BOT at two different doses, with either monotherapy or the combination of BOT with balstilimab, and also had a fifth arm, which is a standard of care arm. In this study, we saw the activity in the 75 mg, BOT mono-BOT combination arm at about 19.4% overall response rate. OS is too early to assess, but what we did see at the six-month mark was that 90% of patients were still alive, which is consistent with what we see at the six-month mark in the phase I study. We also have data, of course, from the other arms and have publicly disclosed the response rate in those patients.
We did see actually a dose response in terms of the monotherapy activity. At the lower dose of BOT mono, we saw no responses, and at the higher dose of BOT mono, we do see about an 8% response rate. And then in the higher dose of BOT combo, the response rate was about 9% at this data cut. One thing that I would say about the phase II is that this is still a relatively immature data cut that we disclosed publicly. But these were data that we presented to the FDA to be able to show that there is a consistent signal between our phase I and our phase II.
So coming out of the end of phase II meeting with the FDA, what was the FDA's advice to you, in terms of next steps, and what's kind of your current thinking about…
Yeah
... potential phase III and design?
Thank you. We had several objectives in going into our FDA end of phase II meeting in July. The first objectives were really to define the parameters of our phase III study, which we came out of the meeting with agreement on the dose to take forward in phase III, which is the lower dose, 75 mg botensilimab plus 240 mg balstilimab. Secondly, we sought to demonstrate contribution of components, which was the way that the phase II study was designed. At the time of the data cutoff, the FDA didn't think that we had quite demonstrated that yet. We will have a later data cut in November that we will take back to the FDA to have a discussion around contribution of components.
That said, if at that point we have not demonstrated contribution of components, we also have the option to add a monotherapy arm to our phase III study to be able to demonstrate that in the future. You know, we wanted to make sure that we had the statistical design, the patient population characterized, and we received feedback from the FDA on, you know, some minor feedback about the things we need to adjust or make sure that we take care of in the phase III, and we've incorporated those into our phase III design. The other aspect of what we were looking for from the FDA was a signal on bringing the data package we have, the phase I and the phase II, at a later point in terms of data maturity for a potential BLA submission for accelerated approval.
At this point, the FDA did not support bringing that package forward, but we plan to come back to the FDA with a longer interval in terms of both the response rate assessment as well as the overall survival assessment, to have an additional discussion with the FDA in the future. I would say in the fall, we are also seeking advice from EMA in terms of scientific advice. So we will be asking similar questions of the EMA, making sure that the phase III design that we have is sufficient to take forward. Secondly, also asking the question around a potential conditional approval submission for Europe.
Maybe discuss how confident you are in your phase II survival data, kind of mimicking the phase Ib data based on what you've seen so far with the initial data set.
Yeah, I think, you know, we've only disclosed the results of the low-dose combination arm. That was right on track with what we had seen in our phase I study. This was a fairly early data cut in terms of overall survival, with only about an eight to nine-month median follow-up. So we will need to see more, but what I will say is that, at that data cut, we were already seeing that the data was tracking with what we would expect based on the phase I.
Right. I think, also importantly, you had a standard of care arm in the phase II study, so maybe just discuss how those results compare to what we would expect to see from standard care.
Yeah, we had a small standard of care arm. It was regorafenib or Lonsurf in the phase II. And in that study, we had a 0% response rate out of that group of patients.
Right. Maybe on the neoadjuvant setting, how are you kind of thinking about next steps there, and what is the status of the NEST study that you have ongoing?
The NEST study. Sorry, I was trying to go back to that slide, but it seems stuck again. The NEST study, I think, is a really strong signal for us that there is significant power in the neoadjuvant setting. We have a lot of enthusiasm from GI investigators to actually continue to advance. We also have two additional investigator-sponsored studies that are ongoing, one in Italy, called the UNICORN study, and the second in the Netherlands, run by Mariam Chalabi, called the NEOASIS study. And with the addition of both NEST, as well as the data coming from those studies, we would, in the future, plan to go to the regulatory agencies for a discussion around the path forward in both neoadjuvant rectal and neoadjuvant colon cancer.
How do you think about the timelines for those kind of studies relative to the relapsed/refractory setting?
So the traditional endpoints in the neoadjuvant setting are event-free survival, and of course, overall survival, which takes longer. The studies would be planned such that these endpoints would be incorporated. But we would also seek the potential for earlier endpoints that could result in approvals. There is a precedent in breast cancer for pathologic complete response to be an approvable endpoint. And there is emerging data now in multiple different solid tumors of the correlation between pCR rate and event-free survival.
In fact, a recent example is from the plenary session at ASCO, looking at Christian Blank's presentation, in stage III resectable melanoma, a comparison of neoadjuvant ipi/nivo to adjuvant nivolumab, which showed a significant increase in the, you know, a high pCR rate with the neoadjuvant treatment, correlating to a clear separation at 12 months in terms of event-free survival that was quite dramatic. So we expect that if we see that same correlation across pCR in colorectal cancer with EFS, that there may be the opportunity for an earlier approval. Secondly, in rectal cancer, organ preservation is a key objective of physicians who are treating patients with rectal cancer.
If you imagine younger patients, who basically have the removal of their rectum will have an ostomy bag for the rest of their lives, so the ability to be able to spare patients that surgery would be a really significant impact on their lives.
Great. Maybe with our last few minutes, if you could touch on some of the other indications that you've explored with BOT/BAL-
Sure
... and where you are with those programs.
Yeah, we have a broad program, as we noted on the second slide, so over eleven hundred patients treated across multiple solid tumors. We've seen responses across nine IO-refractory or cold tumors, including in IO-refractory melanoma. We have data being presented at the upcoming ESMO meeting in sarcoma that are showing a response rate that is also a very durable response in angiosarcomas and leiomyosarcomas. And we've seen activity in non-small cell lung cancer in both PD-1 refractory and in TKI-refractory patients, and so, you know, a breadth of activity across both hot and cold tumors. And particularly notable that we're seeing the activity in patients who've progressed on immunotherapy.
Great. Maybe to sum everything up, if you could kind of walk us through upcoming catalysts, maybe for the next 12 months.
Certainly. Well, as I mentioned, we'll have data at ESMO, and then we're expecting that the data from our phase II and from other studies will be presented at upcoming major medical meetings. Secondly, another catalyst will, of course, be the outcome of our discussions with the EMA, which will happen in the Q4. And so those are sort of the near-term catalysts that we can anticipate. Finally, we are actively involved in partnering discussions and also looking to fill out the remainder of the royalty financing that we had concluded with Ligand earlier this year.
We have additional ability to fill out that syndicate and fund, not only through the royalty financing, but then, of course, you know, our key goal is to find a partner for BOT/BAL to broaden its development.
Great. Thank you so much, Robin. Thank you, Zack, and thanks, everyone, for listening.
Thank you, Emily.
Thank you.