Alligator Bioscience AB (publ) (ATORX) Earnings Call Transcript & Summary

Good morning to those of you in the United States. My name is Søren Bregenholt. I'm the CEO of Alligator Bioscience, and welcome to this key opinion leader webcast following the release of top line Phase II data from OPTIMIZE-1, our study with mitazalimab in first-line metastatic pancreatic cancer in combination with FOLFIRINOX . If I could have the next slide, please, a forward-looking statement. And the next slide, please. So with me today, I have our Chief Medical Officer, Sumeet Ambarkhane; and Zev Wainberg, who is Professor of Medicine at UCLA and Co-Director of the UCLA gastrointestinal oncology program, and Zev has served as primary investigator and co-investigator on a number of Phase I, II and III trials in gastrointestinal oncology, including pancreatic cancer studies. If I can have the next slide, please. So today's agenda is an introduction and overview of the treatment landscape in pancreatic cancer and how mitazalimab is positioned as an emerging treatment in this disease as Professor Wainberg will introduce us to and then next steps in the development of mitazalimab will be taken care of by our CMO, Sumeet. And finally, we will open up for a Q&A to the audience. We get the streaming here. So if I could have the next slide. As you may be aware, mitazalimab is a best-in-class CD40 agonist. CD40 is highly expressed on the so-called dendritic cells, macrophages and B cells in the immune system. And CD40 acts as a switch to activate dendritic cells for robust priming of tumor-specific T cells and also induces macrophage activation leading to tumor stromal degradation and improved chemotherapy and immune cell penetration into the tumor and mechanism that we will touch upon during today's talk. We have developed mitazalimab in a way to give the optimal efficacy within the tumor while balancing the systemic immune activation to develop a drug with a significantly improved efficacy and tolerability balance. We have obtained orphan drug designation, both at the FDA and for EMA for mitazalimab in pancreatic cancer and the molecule also have an IND accepted for advanced bladder cancer. OPTIMIZE-1, the study that we are going to discuss today is a Phase II study in first-line metastatic pancreatic cancer. The study is conducted in Europe and mitazalimab is tested in combination with the standard of care chemotherapy modified FOLFIRINOX. Earlier, we have released data from the study in January last year. We presented futility data. Further interim data were analyzed in June last year. And then finally, today, we have released the primary analysis from the OPTIMIZE-1 study that Dr. Wainberg will now discuss. So Professor Wainberg, over to you.

Thank you, Søren, and it's a pleasure to be here really to go over some exciting data. So we'll be going over some of the background, of course, of pancreatic cancer, and in particular, the role of mitazalimab, which we think has a role in the future treatment of this disease. And next slide. So just as context, I think we all know that we're dealing with one of the most difficult cancers. There's no screening strategies that have been proven. The symptoms are often nonspecific. The majority of the patients are diagnosed in advanced disease. There's very few patients who are found when they're surgical and the majority are found when they've already had metastatic disease within systemic therapy as the main option. Simultaneously with that, we are seeing a change in the incidence of the disease, which is rising every year. The 5-year survival of pancreatic cancer remains 10%, and it's even lower than those patients who present with advanced disease. Next slide. We can see here that in these estimates are the United States, but we're talking about a cancer, which occurs in up to 35,000 cases annually and cause nearly the same amount of deaths annually in both women and men. Next slide. And this is the mortality, which has been increasing instead of the year after year, such that by the end of this decade, by 2030, the expectation based on these projections is a pancreatic cancer will replace colorectal cancer, when you look at combined men and women as the second leading cause of cancer death. Next slide. And as we know, we've seen dramatic improvements in lung cancer with respect to therapy and with respect to options as it relates to targeted, I mean to therapies, but as the improvements in that disease have been clear and consistent based on current Phase III trials, we haven't seen the same extent in metastatic pancreatic cancer, where in any large Phase III trial, the median survival is still under 1 year. Next slide. So when we talk about pancreatic cancer, we're talking about a very sinister disease, which is most of which is called pancreatic ductal adenocarcinoma. These cells arise from the exocrine component, not from the endocrine component of the pancreas and are very aggressive, progress very locally, very quickly, often cause pain and sometimes back pain and very often spread and metastasizes to the liver. Next slide. The risk factors are not well understood for this disease, but certainly some of them include smoking history, a high history of chronic pancreatitis and a bunch of other random things, which are importantly understood. There's thought to be a genetic component of this disease and up to about 10% of patients. And there's also thought to be a dietary linked to this disease, which is poorly understood. Next slide. So what it boils down to for pancreatic cancer is unfortunately, we do not yet have any approved targeted therapies outside of the very niche indication for Olaparib in the maintenance setting. But when we look generally speaking, in pancreatic cancer, we're talking about systemic therapy and in particular, cytotoxic chemotherapy, which has been the only mainstay of proven therapy, which includes gemcitabine-based regimens, FOLFIRINOX based regimens, NALIRIFOX emerged recently. And then the other targeted therapies and immunotherapies have been -- have affect very, very few individuals and really for immunotherapy only the MSI-high patients and for target therapy only in the maintenance setting in which Olaparib is utilized in people with BRCA term line. Next slide. And we've known for about a little more than a decade that the standard of care is in frontline therapies either one of two regimens, either FOLFIRINOX, which showed an improvement over gemcitabine or Gem-nab-pac, otherwise known as Abraxane, Gemzar Abraxane, which also showed an improvement of gemcitabine. These two became the mainstay Phase III regimens about a decade ago in which they showed improvements in survival over gemcitabine. Next slide. Last year, we published a study, one of the largest studies done in pancreatic cancer, which compared Gem-nab to NALIRIFOX, which is a derivative of FOLFIRINOX using Liposomal Irinotecan in which the study did meet its primary endpoint with a statistically significant p-value improving overall survival by about 2 months from about 9 months to about 11 months with the NALIRIFOX regimen. Next slide. So as we try to move on beyond chemotherapy because I think we've all realized that chemotherapy, we have hit the wall in this disease with respect to what we can add drugs wise to these chemotherapy cocktails. We have -- continue to remain interested in immunotherapy, generally speaking, as a field, but we're a lot less interested in checkpoint inhibitors right now. Because checkpoint inhibitors such as PD-1 inhibitors, the CTLA-4 inhibitors have been extensively studied in pancreatic cancer and they've never shown any improvements beyond small Phase I trials. What I think what people are excited about is now moving beyond checkpoint inhibitors. And obviously, CD40 has always represented a key rationale in pancreatic cancer. The reason for that is that it activates not just checkpoints such as T cells, which may have trouble penetrating into the dense stroma but also activates tumor-associated macrophages can enhance chemotherapy sensitivity by releasing dendritic cells, also somehow affects enhanced T cell infiltration which is a critical element to pancreatic cancer through a dense trauma. And I think what we'll show you today is very provocative and exciting with respect to the role of the best-in-class CD40 agonistic antibody mitazalimab. Next slide. So OPTIMIZE-1, launched a couple of years ago, as you just heard, it is a Phase II trial in which patients were enrolled in combination with metafied FOLFIRINOX and mitazalimab. Modified FOLFIRINOX is the most classical chemotherapy regimen we use in frontline patients now with metastatic pancreatic cancer. And the study design enrolled patients with newly diagnosed disease who were metastatic. The primary endpoint was overall response rates with secondary endpoints, including duration of response, PFS, overall survival and safety and PK and PD. What's unique about this study is that it had a few features which are unique. You don't see often in clinical trials in pancreatic cancer. One of them is at a priming dose of mitazalimab prior to chemotherapy. The purpose of that is to engage CD40 before the onset of cytotoxic chemotherapy. And this is based on preclinical data that have been done by several groups that suggest that that's the optimal time to prime CD40 is not after T cell suppression may occur from chemotherapy, but rather before. The second thing is that it combined with modified FOLFIRINOX, which for many people, we feel it's a superior regimen to Gem-nab-pac. And while not exclusive, the idea of combining it with a more active chemotherapy regimen, which has a higher response rate and overall survival was felt to be a superior approach in this particular disease. Patients were treated until disease progression or because of toxicity were taking off. And this study, as you heard, enrolled pretty quickly in Europe. Next slide. So the baseline characteristics of the patient population are listed here. This had a split, of course, of 65 or older and a split of female and male patients. The ECOG performance status was also balanced in this cohort. Keep in mind that this was a fairly large cohort for a Phase II study. Usually, our Phase I combination studies include about 30 patients. And here, what we've seen is a total of 57 patients, which included the first batch of patients and now the second batch of patients. And so that really is much more robust than a typical Phase I study expansion cohort. What's of interest here, I think, is that very, very few patients had prior surgery, and that's unusual in academic sites where the study was done in Europe. In so far as the majority of patients who are enrolled in academic sites as opposed to the community, in fact, have had no surgery but about 20% often do. And here, we only saw about 3.5% of patients had prior surgery, which is -- may reflect that it's a poor prognostic group of patients than your typical patient population. Also about a full half of the patients have an elevated CA19-9 over 1,000, which is also a poor prognostic group. Next slide. So here are the top line results. The response rate confirmed by central review was -- excuse me, confirmed response rate was 40%, which met the primary endpoint of what was set out to be achieved. There were 38.6% partial responders with a disease control rate of 79%. The duration of response is what I think is one of the most exciting things here, 12.5 months. That's not been shown before in metastatic pancreatic cancer with a durable response like that as we'll describe in a minute. The median PFS of 7.7 months with an overall survival of 14.3 months with a mature follow-up time of 12.7 months. So really a very nice package of efficacy that's presented here with a well manageable safety profile as we'll discuss with the toxicities largely consistent with modified FOLFIRINOX toxicities. Next slide, please. And here you can see on the swimmer pot that really shows just how long many of these patients remained on study. So a response duration of 12.5 months is, as I mentioned, highly unusual for pancreatic cancer. Usually, the response rates in some of these trials are in the range of 35% to 40%, but the duration of response is quite a bit shorter, sometimes half this. So the fact that there are still 51% of the patients still ongoing in the study at data cut with 32% of patients ongoing on treatment at the time of data cut would suggest that, in fact, we're going to end up seeing quite a bit longer duration of response in PFS as the data matures. The longest treatment duration of the patient was 23 months, which is ongoing at this time, obviously, now down on reduced doses of chemotherapy, but remains on mitazalimab. And so when you see this, you start to really start to inquire as to the role of the experimental agents beyond chemotherapy. When you see durations of response like this and many patients on the study for over a year. Next slide. So some preliminary PD biomarker work was done in collaboration with Alligator to look particularly at what the mitazalimab PD biomarker could look like. And based on some pre and post whole blood analysis, one can see that there is an increase in CD4 effector cells being generated by CD40, which is in line with the mechanism of action of the agonistic antibody. And that did correlate with some degree of clinical benefit and such that responders seem to have a higher rate of CD4 production consistent with the impact of CD40 agonistic antibody. Next slide. So when we compare how this OPTIMIZE-1 cohort did relative to some of the other published literature, which include primarily Phase III trials, you can see that response rate in fact, compared -- about the same, I would say, some of the larger trials, a little better than some, obviously, that use Gem-nab-pac. But with respect to FOLFIRINOX, there has been a higher response rate with that regimen. However, when one looks at the duration of response, one certainly sees that OPTIMIZE-1 is an outlier here with a far greater duration of response than any other chemotherapy regimen ever reported in the literature. And the overall survival, of course, albeit this is a 57 patient cohort also compares very favorably. Keep in mind, these numbers may improve as the data continues to mature, particularly insofar as overall survival as many of these patients are on study for quite a while now. So the fact that the 57 patient cohort can demonstrate these promising signs of efficacy to me as an encouraging sign. Next slide. When we benchmarked this in a table, which is a busy table, but you can sort of see on the right, the OPTIMIZE-1 data. We are struck by a couple of things. Number one, there is no prior chemotherapy regimen and only 3.5% of patients who had surgery. And as you can see, in some of the other Phase I studies that have been done, Phase I/II studies in which I participated in many of these. The imbalance is there. Here, we have a group of patients in OPTIMIZE-1 who did not have chemotherapy before as opposed to the PRINCE trial, which was another CD40 agonistic antibody with Apexigen at a 22% of patients had prior chemotherapy and if one looks at some of the other literature with respect to the Seagen trial, also with their CD40 agonistic antibody 26%. So what we're starting to see here is that this OPTIMIZE-1 regimen, perhaps because it was done in Europe, where there were less of these clinical trials ongoing at the time. Just simply had a different group of patients, which was poor prognostic No chemotherapy in the past, no adjuvant chemo, no new adjuvant chemo and almost no patients had prior surgery. Those represent two definite positive prognostic markers. And so the lack of those patients in OPTIMIZE-1 suggests a poor prognostic group of patients enrolled in OPTIMIZE-1. And of course, landmarking the duration of response relative to these other studies as well as median overall survival and 12-month overall survival rate of 59.3%. All of these compare favorably, in my opinion. Next slide. So the summary of this primary analysis reveals that OPTIMIZE-1 represents a previously untreated patient population that would combine with FOLFIRINOX met its primary endpoint for response rate and was safe and well tolerated. Highly durable responses were observed, providing an overall survival of about 14 months. This will continue to mature. This combination, in my opinion, deserves to be evaluated now in a frontline Phase III trial and these encouraging data also were an evaluation of mitazalimab across the board to see if we can understand where the impact in other cancers may be as well. Next slide. So hopefully, the next steps, we'll pass it off to Sumeet to discuss these.

Yes. Thank you, Professor Wainberg. This was very helpful to hear your expert opinion and very valuable perspective on the primary analysis data of the OPTIMIZE-1 trial. And of course, with such compelling and exciting data, comes a question, what are going to be the next steps. So just before the end of last year, we had a very valuable scientific guidance and interaction with FDA, wherein they also endorsed the value of these emerging data and mentioned that the next step from a development point of view from mitazalimab will be -- or would need to be a randomized Phase III trial to be performed head-to-head against modified FOLFIRINOX as a standard of care. So following that guidance from FDA as well as the results of the primary analysis that we just saw. The plan is to continue the dialogue and the discussions with FDA as well as European authorities, so that we get additional guidance on what the patient population should be the detailed inclusion, exclusion criteria, the statistical approach and importantly, the end points for the randomized Phase III trial from a confirmatory point of view. So we are fully committed to continue these interactions. And also from an operational point of view, do everything that is necessary to be ready as soon as possible to start the Phase III trial and with the hope that mitazalimab can be brought to the patients as soon as possible. So I think that's these are going to be the key next steps and maybe I pass it back to Søren for a concluding remark.

Yes. Thank you, Sumeet. Thank you, Dr. Wainberg. Very exciting data indeed and interesting to see the data put in context in todays and potentially the future treatment landscape in pancreatic cancer. We should now move to a number of questions that we have received on the chat. The chat is now open.

And I think the first one is to you, Professor Wainberg, and it goes like this, looking at NAPOLI 3 trial with NALIRIFOX, which you know well since you had a key role in the trial, what is your feeling when the data came out on. And how do you think the NAPOLI 3 data is going to change the treatment landscape in pancreatic cancer?

So as many know, we're hoping to hear from the FDA in the next 4 weeks about that particular regimen, the NAPOLI 3 regimen. The expectation is that hopefully it will be approved. But I don't think the impact will be that dramatic. And by that, I mean, I think there will be a segment of patients who utilize this regimen. But I don't think it will absolutely to place modified FOLFIRINOX or do I think it will absolutely replace Gem-nab-pac? I think it's going to be a choice for patients. There will be some people who will switch to that regimen. But many, certainly in the context of what the regimen represents we'll stick with the modified FOLFIRINOX. However, I do think that, that regimen needs to be exploited a little better and additions to it beyond just NALIRIFOX are going to be necessary if the regimen is going to have a larger presence.

Thank you. And this one is also to you, Professor Wainberg. And I think you touched on it -- upon it a little bit already. But looking at the patient baseline between NAPOLI 3 and OPTIMIZE-1, We note that patient OPTIMIZE-1 had on average an ECOG score better than the NAPOLI 3 trial. But how would you compare the patient population between the two trials beyond the ECOG score?

I actually think -- so the -- I think the characteristics of this group of OPTIMIZE-1 compared to the NAPOLI 3 group of patients quite well. ECOG performance status to me, is always a tricky thing to measure because most people try to get their patients on the study between zero to one. And so there is a lot of interchangeability there. But what I do think, which is quite unique here is that the characteristics of three things always strike us when we do small studies that we're careful, we're not dealing with a better prognostic group. And those include the lack of prior chemotherapy. The fact that they've had surgery in the past and an elevated CA19-9 and the Alligator cohorts in OPTIMIZE-1 really did represent the poor prognostic group, which I think is actually similar to the NAPOLI 3. And so far, as that was mostly community study that did not have these patients who had prior surgery or prior adjuvant chemo. And when I look internally at our studies that are being done now in academic centers, we see a lot of those patients. As I mentioned earlier, it could be up to 20%. And if you have a group of patients who are prognostically favorable in that smaller cohort, that higher percentage. It does make us puzzled sometimes as to whether we can read this truthfully. So that's why I think actually OPTIMIZE-1 cohort is more similar to a community oncology cohort, which represents a poor prognostic group of patients, which to me makes the efficacy a little more favorable.

Thank you. Then we have a couple of questions here about response rate and patients on study. And Sumeet, please feel free to chime in here. One question from Richard Ramanius at the Redeye is, should we compare the controlled ORR of 41% or the unconfirmed at 51% with the FOLFIRINOX benchmark at 32%. And maybe a comment about the ORR response rate in these trials in general.

Yes, I think that's an important question. I think the comparison should be made with the confirmed response rate because that is also how the original study performed with FOLFIRINOX reported their data. At the same time, the unconfirmed response rate gives an indication of how many patients actually benefited from the treatment such that there is substantial reduction in their tumor burden. So that is also helpful in understanding even if not lasting long enough, but the extent of patient that had a benefit from the experimental treatment.

Okay. Thank you. Zev, any additional comments to that?

No. I mean I think that's the fair way to compare it as Sumeet says. I mean it's a little tricky when you're dealing with a smaller Phase II study than with a large Phase III trial. But I think we're getting to the point where the response rate is not going to be that much more than it is in this disease. I mean, never been, particularly in pancreatic cancer -- never been particularly exclusively dependent on response rate. For me, response rate is tricky to measure sometime in this disease because the patients have large pancreas masses, which are poorly measured. But generally speaking, I don't think we're going to achieve more than a 40% to 50% response rate in this disease in most large studies. That's not where we're going to improve outcomes. We're going to improve outcomes in this disease, I believe, by improving duration of response, and that will translate into overall survival. And that's why I've been encouraged by this OPTIMIZE-1 data set when I've seen it now a few times.

Thank you. Then another question that might be hard to answer, and it goes like this, although it may be too early to answer, but did you notice a significant difference in the median overall survival between the responders and the non-responders and in particular, would you know what the median overall survival of the partial responders is versus that of stable disease? I think that's to you, Sumeet.

Yes, that is indeed an interesting but are not so easy to answer a question. what we can -- I mean, what I can say is that we are in the process of looking further into the data and identifying if there are like any important differences in the characteristics between the responders versus the non-responders as well as the pattern and durability of the response again between the responders versus non-responders, particularly the time to progression. I think what is worth noting, although from the swimmer's plot that professor Wainberg showed is the fact that many patients stayed long in the treatment and a lot of patients continue to experience only disease control, so only stable disease, but for a rather long duration of time, and that indicates that the immunotherapeutic contribution of mitazalimab. So yes, there may be differences in the pattern and time to progression between responders and non-responders. But the long stable disease is also a treatment effect and the benefit to patients that comes particularly from mitazalimab and this combination with FOLFIRINOX.

Thank you, Sumeet. And now that I'm trying to group the questions a little bit here. And now that we have you, there's another question here that says, you disclosed that 32% of the patients are still on [ EXIT ] treatment versus 51% still on the study. What were the reason for the discontinuation of treatment of those 19%?

Yes. So majority of the patients discontinued because of the progression of their pancreatic cancer that has been the case for almost more than 90% of the patients, and a very small minority of the patients discontinued for various other reasons and a couple also because they did not tolerate the treatment combination that well. So -- but again, majority discontinued because of the progression of the underlying malignancy.

And then one for you, Professor Wainberg, and I think you touched on it a little bit in your presentation as well. The role of PD-1 in pancreatic cancer, could we get an answer on that? Yes or no. Is the question here from the audience?

Yes. I mean I'm not convinced that all the PD-1 inhibitors have a role in this cancer. In fact, in the PRINCE trial that we did with CD40, if you recall, with their CD40 with chemotherapy with Gem-nab-pac, the patients that performed the best on that three-arm study where the group of patients who got the CD40 plus chemotherapy or CD40 with checkpoint inhibitor not the combination of these things. So I don't personally think that the checkpoint inhibitors play a role in this disease. I think there is rationale scientifically why they may -- but there's many studies that have been done in pancreatic cancer, some of which have been not published, but many Phase II, Phase III trials, which have shown no signal of efficacy with a checkpoint inhibitor. Now some of these may still be done because, scientifically, we all feel that engagement of T cells may help your partner work better, but we have not demonstrated that in the clinic. And so I am personally in favor of not mandating a PD-1 inhibitor in any large trials, and I don't see a role personally.