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

Good morning, and welcome to the Alligator Biosciences KOL webcast. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Alligator Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host,Søren Bregenholt, CEO of Alligator Biosciences. Please go ahead, Soren.

Thank you, and good afternoon and good morning, and welcome to this key opinion leader webcast. My name is Søren Bregenholt, and I will be your host today. Next slide, please. So a listed company, a brief disclaimer. Next slide, please. Today, I am joined by our Chief Medical Officer, Sumeet Ambarkhane, and Weinberger Professor of Medicine at UCLA Health, Dr. Weinberger is Co-Director of the UCLA gastrointestinal oncology program and Dr. Weinberger has a special research interest for pancreatic cancer. Dr. Wainberg laboratory-based research involves novel therapeutics against gastrointestinal cancers. Dr. Wainberg use the receipt of several grants focusing on targeting cancer stem cells and in a molecular classifications of GI cancers. And needless to say, Dr. Wainberg has participated in a number of global clinical trials in pancreatic cancer and other GI cancers. Before I leave the word to Dr. Wainberg, let me just -- on the next slide, please introduce to you very briefly the program after my opening remarks. We will have an overview of the treatment landscape in metastatic pancreatic cancer and talk about mitazalimab as an emerging treatment opportunity, followed by Q&A, and analyst will have an opportunity to post their question lives, and there will also be an opportunity to put your questions on the chat. Next slide, please. Today, we are going to talk about mitazalimab Alligator's second-generation best-in-class CD40 agonist, which we're currently developing in first-line metastatic pancreatic cancer in combination with chemotherapy FOLFIRINOX, mitazalimab has orphan drug designation in the U.S. for the treatment of pancreatic cancer. And the Phase II study that we are going to discuss data from today is fully recruited in Europe. The first futility data from the study was announced in January this year. And yesterday, we announced a further interim analysis from this study, which we are going to discuss today. So without further ado, Dr. Wainberg, looking forward to your presentation on the treatment landscape in pancreatic cancer.

Good afternoon. Thank you, Soren, and a pleasure to be here to talk a little bit about pancreatic cancer and some of the hopeful new drugs that are being developed in this space. Next slide, please. So I think recognition that this is one of the more challenging cancers is an honest way to think about the disease. We know that about 3/4 of patients present with de novo metastatic disease. And even those who have had early detection ultimately recur. We see a patient population that is increasing in the United States, yet survival is not improving, unfortunately, along with the incidence increase. Next slide. We see about 35,000 new cases in the United States per year. This is going up though. This slide is probably already a little outdated even though it's from a couple of years ago. And so far as we see rising incidents in both men and women, 35 in men and about 30 in women annually for a total of about 65,000 to 70,000 new cases annually. Next slide. Unfortunately, as it relates to cause of cancer death, the incidents nearly equals the annual mortality from this disease. And so far as about 80% patients diagnosed and within that year will die within a year. Next slide. This is leading pancreatic cancer to very soon overtake colorectal cancer probably by the end of this decade. Because improvements in colorectal cancer outcome have improved slightly and that -- and yet pancreas cancer long-term survival is not. So we expect pancreatic cancer to become the second leading cause of cancer deaths in the Western world by the end of this decade. Next slide, please. So when we talk about pancreatic cancer, I think we almost exclusively speak about adenocarcinoma, ductal adenocarcinoma, which represents 85% of the disease. There are some rare entities such as neuroendocrine tumors, which are much less common 95% of the cell of origin here is the ductal epithelial cell. And those are the subtype of pancreatic cancer, which is the most lethal. Next slide. With respect to some basic risk factors and for those not familiar with this, this is a disease by and large, which is unpreventable. And by that, I mean there is no good screening detection with the exception of very rare genetic syndromes such as BRCA 2 and rarely BRCA1 and others. There's no real genetic predisposition to this cancer and therefore, no early detection methodology. There are a host of chronic risk factors, but many, many, many patients, I would say the majority have no clear identifiable risk factor such as smoking or history of pancreatitis. By and large. And certainly, this is the case in the United States and Western Europe, patients really present with no obvious symptomatology and the absence of risk factors and then quickly are diagnosed. And often, at that point are already found in Stage IV disease. Next slide. So in cancer, generally speaking, we find ourselves trying to develop drugs and targeted therapies or immunotherapies. This has been a challenge in pancreatic cancer with the exception of the very rare subtype of MSI high pancreatic cancer, which represents probably about 1%. There are no approved immunotherapeutic treatments for this disease. Targeted therapy has PARP inhibitor approved in the maintenance setting only for BRCA1 and 2 patients and really used very, very sparingly. There are a number of KRAS drugs in development, blocking different isoforms within the KRAS pathway but those drugs are still in Phase I early drug development. So by and large, where we find ourselves in this disease next slide is in the chemotherapy bucket, which is that chemotherapy is the mainstay of pancreatic cancer, and that's true whether it's Stage 2 in the adjuvant setting or more commonly Stage 4 in the metastatic setting. And it's based on these 2 large clinical trials, both were done about a decade ago. The first was FOLFIRINOX done by the French, which compared it to gemcitabine-based therapy and established it as a standard of care with 11.1 months median overall survival. On the right, you could see the [indiscernible], otherwise known as Abraxane, improved survival to about 8.5 months. So these two for the last decade have been the de facto standards of care for this cancer. Next slide. Now they were never -- those two regimens were never compared head to head. However, we did a clinical trial, which I -- was one of the principal investigators on comparing a derivative of FOLFIRINOX known as Nalirifox, which is a version of FOLFIRINOX with liposomal or in a [ Tecan ] in place of [Tecan] and compared it head-to-head to [indiscernible] in a large Phase III trial. And we did show at ASCO, we had an oral presentation and manuscript is in press shortly, in which improvement was shown of the Novira Fox regimen from 9.2 months to 11.1 months in head-to-head fashion. So the main outcome of the study may ultimately be that it establishes clearly and convincingly that a FOLFIRINOX based chemotherapy regimen is now the de facto standard of care in frontline metastatic pancreatic cancer. And we've already seen shifts away from [Gem-nab-Pac] to FOLFIRINOX in that frontline based on this study. Next slide. So there are many, many efforts to target pancreatic cancer with new drug development. We've participated -- I've participated in many of these myself over the last decade with respect to checkpoint inhibitors, which have struggled, as I mentioned, outside of the MSI high subgroups. And with a host of various immune therapy manipulations to try to engage the immune system to fight this cancer. There are different ways to think about it, including targeting T cells directly, activating T cells. But another way to think about it is also targeting the tumor microenvironment and trying to engage not just a T cell presence that will be active, but one that will be able to fight through the desmoplastic stroma and engage not just T cells in the fight, but also tumor-associated fibroblast and other immunogenic proteins that are heavy in the tumor stroma [indiscernible] that is pancreatic cancer. And I think when we think about this disease, and we think about those approaches that leads to opportunities for drug developments. Next slide. So CD40 has always been thought of as one of those possible approaches. And the reason for that is both that it can sustain some activation of T cells because CD40 is present in many, many T cells, of course. And you can engage it through agonistic antibodies to both activate the innate immune system such as the dendritic cell activation and also increase the natural immunity with T cell activation. It also activates macrophages. So preclinically, if you look at all the preclinical science in this disease, a lot of it is hopeful about CD40 agonistic antibodies having an important value in pancreatic cancer. Next slide. And this was hinted at to some extent. This was a trial that we participated in a number of sites in the what's called the PIC. The drug here was apixigens CD40 agonist so [indiscernible]. And this was a study that was done with chemotherapy in metastatic pancreatic cancer. It was done in academic sites and enrolled patients to either chemotherapy plus a checkpoint inhibitor alone, and that was nivolumab plus Gem-nab-Pac on the A1 group or the CD40 antibody plus Gem-nab-Pac and the RMB and the C was the nivolumab plus Gem-nab-Pac plus CD40. And this was, keep in mind, an older chemotherapy backbone, Gem-nab-Pac , which now, as I mentioned, people have moved away on. And the challenge of the study is that there was no control arm. And we struggled with interpretation of these results because it did not have a chemotherapy-only arm, which was a conscious decision made at the time but response rates here were encouraging in all 3 arms, I would say, with 1-year overall survival rates be encouraging as well. Interestingly, the Gem-nab-pac-Nivo arm did better than expected. That's been a struggle. But the median PFS in many respects, which I think is a better landmark sometimes for this disease and median OS was improved in the CD40 containing arms. Next slide. So when I heard that Alligator had, in fact, a more tolerable CD40 agonist because I will say that I've had that experience at sotigalimab. We did have some tolerability concerns as it relates to liver toxicity and cytokine release syndrome and keep it in mind that was a number of years ago, and we were less comfortable with this field. I was excited by the prospect of a different agonistic antibody that had less toxicity. And based on what I've seen, certainly with mitazalimab, that seems to be the case here. Some background for this study, which was done in Europe, and I didn't participate in, but I've had an opportunity to see the data and spoken to the investigators in a number of meetings is that mitazalimab is combined with modified FOLFIRINOX, which I think is the appropriate backbone now for these combinations. Patients were treated with mitazalimab preceding chemotherapy, which is a scientific approach in which to cycle the chemotherapy and engage CD40 in advance of cytotoxic chemotherapy. The doses studied were included 4 and 50 micrograms per kilogram in a small segment of safety evaluable patients. And then a larger group, which we'll talk about at 900 micrograms per kilogram which has ultimately become the recommended Phase II dose. Next slide. So we had the opportunity to look at this in a few different snapshots. The first was after 23 patients, which included the 5 patients with the lower dose. And this was really done to make sure that indeed we were going to see adequate response rates with which to move forward to the next segment. And indeed, it was an encouraging response rate with a response rate of 52%, 12 PRs out of 23 patients total, a disease control rate, which was very high at 91%. And so that was -- that's always for us encouraging in the field to see above 40% to 50% response rate in a well-controlled cohort and thinking about how to develop that further. So the first interim analysis certainly passed the futility and moved on to the next phase. Next slide. This was a second interim analysis, which was just the Alligator just had a snapshot of this very recently. First, safety. I think the big thing that strikes me here is that how safe the combination is, which points to two things, in my opinion. Number one, you are going to get, obviously, treatment-related adverse events, but not unexpected ones for the most part in this study. Only 12% of patients at SAE attributed mitazalimab which is actually far lower than the existing literature and CD40 agonist antibodies. A small group of patients had an infutigion-related reaction, which was grade 2, but quickly dissipated, and no patients had cytokine release syndrome. And perhaps most importantly, because this really limited Sotigalimab drug development was a very low rate of LFT abnormalities, only 5 patients have that, and they were all reversible. So when I put this in context, of course, the other CD40 programs, I'm certainly pleasantly pleased by both the safety of this drug as a single agent with respect to the toxicity profile and more importantly, its ability to be combined with FOLFIRINOX, and in essence, not increasing FOLFIRINOX toxicity beyond what we might expect with FOLFIRINOX well. Next slide. The efficacy evaluable, and this is a very early data cut. So we -- I think the -- this is sometimes hard to interpret when you just have on the bottom of this spot, you can see there's a number of patients who have only had been on study for about 8 to 10 weeks. And so interpretation of this can sometimes be a little early and premature. And nonetheless, what we have so far is a 44% response rate with 25 patients having a PR out of 57 who are efficacy evaluable. The disease control rate remains quite high here at 77%. The duration of response, which is an early marker of durability, of course, on these regimens is quite impressive with 8.7 months. That's longer than certainly than we would expect with chemotherapy alone and even longer than the majority of these other combination immunotherapy studies that have been reported I caution sometimes at interpreting too many of these patients because as you can see, the bottom 8 to 10 patients have had only one scan on study and a lot of these could potentially be converted to responders and also theoretically don't give us a snapshot at all, a snapshot of progression-free survival, which is a very important landmark here. Next slide. So if you look at the -- go back to the first data set, which obviously is longer follow-up, there you follow-up of up to 17 months and a response rate of 57%. Again, that first 23 patients, some of these patients did convert from stable disease to PR. So we've seen that with other similar agents. And that's encouraging in that many -- some patients are ongoing now for -- some are ongoing, 7 of the 13 responders are ongoing as of the data cut more than 10 months and the longest of 17 months. So we're starting to see some durability with this regimen, and that's especially important with a regimen like for FOLFIRINOX that gradually over time, people drop off the intensity of the chemo and rely on the combination with immunotherapy to keep the response going. And certainly, that's what we're seeing here. The next slide. So when we look at this in context, of course, with what's been demonstrated in the literature I am encouraged by the early signal of response rate of 44% here in the 57 patient cohort relative to what we would expect with chemotherapy alone. I do think that we have some work to do and certainly follow-up will be critical to determine both the sustainability of these responders. But what I see here on the right is the duration of response, which is also more encouraging than we might expect with chemotherapy alone. And as I mentioned, as the chemotherapy manipulations continue in this disease, which means that patients after 4 to 6 months drop-off certain parts of the chemo, they rely on these drugs to help us with the duration of response. Next slide. So in summary, there is an overall response rate of 44% with the disease control rate of 77% durational response and a tolerable safety profile was seen in the OPTIMIZE 1 study. Next slide. In summary, pancreatic cancer, as many of us know, is highly aggressive and does have challenges in drug development. There is, though, encouraging preclinical data and real good hope for further immune manipulations beyond checkpoint inhibitors, in my opinion, in this disease. Mitazalimab represents one of those options, in my opinion, as a potent CD40 agonistic antibody which is well tolerated and combinable with what is now the de facto standard of care, which is modified FOLFIRINOX. And in my view, further frontline therapy of this combination should be developed. Thank you for your attention.

[Operator Instructions] Our first question comes from [ Sebastian Bendershut ] from Kempen. Please go ahead and unmute yourself Sebastian question out loud. Okay. Our next question comes from Patrik -- Our next question comes from Patrik Ling at DNB.

Just a couple of questions, first on the data. I mean if we look at original analysis that you did, and we can see that response rate has increased over time as some patient has converted from stable disease to partial responses. What are the views of Dr. Wainberg regarding the timing of this? And what should we expect from this new readout that we have, where we see that overall response rate comes down a little bit. Should we expect that to, over time, increase again as we've seen with the initial data?

Yes, that's a good question. I mean, I think that we've seen this pattern in pancreatic cancer, where as we expand the patients, the response rate sometimes trend -- tends to drift down. I would say two things. Number one, I do think based on the preceding 23 patients, a number of these patients have converted PRs, then there is good reason to expect that in the next batch as well. Certainly, as you saw, a lot of those patients are just early on, have only had one CAT scan. And so often on the first CAT scan, we don't see a response what we do on the second one. That is not uncommon, certainly up until the third CAT scan it's not uncommon to see patients convert to PR and sometimes after that. We've seen that with a few different drugs, not just CD40. We've seen that in the early checkpoint inhibitor experiences, and we've seen that with other immunotherapy combinations. So I would expect that to continue. Number two, and I do personally think that response rate is a tough snapshot in this disease. I don't think we're -- it gives us a signal and it gives us some security here that we are certainly not jeopardizing efficacy and having increased over what would expect chemotherapy to do by itself, which I do think this is a signal of that. Obviously, the median PFS numbers and landmark PFS and OS numbers will be very, very critical in a much more meaningful way, in my opinion, over a response rate snapshot in this disease.

Great. My second question is actually if you have seen any differences when it comes to -- I know it's a small sample, but since you had 5 patients with lower doses, do you see any differences in response rates or in durability of the responses with the lower dose versus the higher dose?

Yes. I think that was a small sample size. So there were some responders there, too, but obviously, with an NFV, it's hard to prove too many conclusions based on that number. But certainly, that's reassuring that increasing the dose I think based on the Phase I data has good biologic rationale didn't jeopardize any toxicity. And so they did the right thing by moving quickly to a more active dose that corresponds better preclinically with an expectation of CD40 activity.

Great. And then last question from my side before I'm jumping back into the queue. I mean, you as a treating physician, I mean what type of data, would you say is good enough for you as a treating physician to actually bring a drug like this to your patients? I mean, given the strong safety data that we have for mitazalimab.

Yes. I mean it's a good question. And I think based on what we've seen so far here in my view, at least, this warrants further investigation in some form of randomized fashion. I do think that we are in this position in a field where we need to provide the field with randomized data. And I do think that an N of 57 with an encouraging safety signal, encouraging early efficacy, which I expect will get better over time. And certainly, when the corresponding PFS values can be applied to this data set, would lend itself really well to a randomized study. And I certainly think that a mistake, as I mentioned in the past, with some of these combinations is we didn't do a proper randomized controlled trial earlier on and jumped straight to a larger randomized trial. And I think we have a data set here personally that really deserves further exploration from this disease in some form of randomized trial at this juncture.

Our next question comes from [ Sebastian Bendershut ] at Kempen.

Thank you very much for the insightful presentations and my apologies for not connecting properly before. I was wondering whether you could comment on the use of ofarnoxen-based regimen versus not [indiscernible] regimens in the U.S. and Europe, what makes a physician decide to use one regimen over the other? And how do you foresee that the use of FOLFIRINOX will grow into the future? And do you think that maybe other FOLFIRINOX based regimens should be used in future clinical trials.

Yes, I think it's a good question. And right, until this NAPOLI-3 trial, we had no head-to-head data, and now we have head-to-head data. And the purpose of an NAPOLI-3 trial was to answer fundamentally questions for the field about optimal frontline therapies. And leaving aside the question of liposome or Gem-nab-Pac. The most important thing people field to come out of that study was that it established that the FOLFIRINOX based regimen is a superior regimen to Gem-nab-Pac and Gem-nab-Pac should now be reserved in second line. And you are going -- you've already seen that in what I've seen data in the United States, people converting from Gem-nab-Pac to a modified FOLFIRINOX in frontline therapy for ECOG performance data 0 to 1 fit patients. That has been the preferred regimen for some time in academia in the United States and in Europe as well and now is moving over in the community as well. There is no question about it. I see it in all my referrals from the community. And since the data started to penetrate, I think we'll only continue. I also think that companies, like Alligator and others will now look to do combination trials with FOLFIRINOX as their base moving forward and not use Gem-nab-Pac as a partner anymore. Because, quite frankly, in my view, at least, it's not the best control arm in frontline therapy anymore. I'm not going to say that's right for everybody because this is a disease where some patients just don't have the performance status to handle it. But in terms of a benchmark, yes, I think that should be our control arm moving forward.

Great. Very insightful. And then maybe I missed it before, but I was just wondering whether a deepening of response, is that something that you see with chemotherapy alone in [ PEETA ]?

Yes. So that's uncommon with chemotherapy alone, especially because what tends to happen with chemotherapy alone is that at the 4- to 6-month range we have to decrease dosage, and we have to drop the drug sometimes for peripheral neuropathy. So keeping in mind that if you see deepening responses without with those circumstances, which is very common in the 4- to 6-month range, you expect you expect that your investigational agent is contributing to those responses, in my opinion.

Got it. And then I was wondering, I believe there was also a tumor biopsy data taken or tumor biopsy is taken. Is there any evidence of local activation of the tumor micro environment with maybe influx of innate immune cells? Or is there something that you can comment on?

Yes. I think if I recall, and Sumeet can also talk here, but there are more a series of patients in which biopsies were done. Sumeet, maybe you can...

Yes. So basically, we do have biomarker data coming from the peripheral blood as well as from tumor biopsies. And the results from the biomarkers in the peripheral blood indicate as expected, an activation of CD40 sort of driven cytokines and suggesting that this is confirming the biology of mitazalimab, the tumor biopsies will take a bit longer to be evaluated. And I think we'll be also reading out in the near future. So we will just need to hold on a bit until we can comment on the biopsy readout. So yes.

Got it. And then my final question is regarding the durability. Can you comment on how many patients are still on treatment and in response of the total patient population? And then final question is whether we can already say anything about the medium progression-free survival, whether it's still maturing or headed in the right direction.

Should I answer that? Yes? Yes. So approximately half of the patients are still ongoing in the treatment. And that gives an indication in terms of the effect that this combination is having. And if we try to correlate with the previously published analysis, I mean, we can sort of try to interpret the proportion of patients who will sort of remain on treatment for a reasonable amount of time and also will contribute to the response and the survival results of the trial. And your second question, can you say that again?

Yes, whether you can say something regarding the medium progression-free survival or at what timeline we can know more about that.

I think in terms of progression-free and overall survival, the analysis is as of now pretty immature. There hasn't been long enough of a median like follow-up for the whole cohort of the trial. It will be much more meaningful to look at that when we have the primary analysis of the trial reading out probably in the beginning of next year.

Our next question comes from Richard Ramanius from Redeye.

I wanted to know what is the difference between -- exactly between modified FOLFIRINOX and FOLFIRINOX. And how does that impact the comparison with the 33% objective response rate in registrational study, which I think is FOLFIRINOX?

So the key differences are that it's a lower dose of irinotecan, and there's no 5FU bolus therapy. And those were modified for toxicity reasons because in the original FOLFIRINOX trial, there was a high rate of GI toxicity and higher rates of neutropenia and cytopenia. So they made those modifications about 5 years ago, and actually the modified FOLFIRINOX is now -- that was utilized, for example, in the second [indiscernible] regimen, and that has been utilized on subsequent therapies as control arms. And so those are the main differences. And I don't know if we would expect an efficacy difference in so far as response rate. But it certainly is much less toxic. And cross-trial comparisons as very, very similar efficacy numbers but just a more tolerable regimen.

Okay. I think [indiscernible] have asked most of the questions. One thing I found interesting was the long responses from the first 23. So if I understood it correctly, they cut off chemotherapy up to for 6 months and then continue treatment with mitazalimab. So with that then, does that suggest that what keeps them responding is the continued treatment with mitazalimab?

This is having to do with some of the nuanced details, but the thing about modified FOLFIRINOX is that at a certain point, adjustments to the chemo are always made. Sometimes the adjustments are dropping the oxaliplatin because of peripheral neuropathy. Sometimes the adjustments are dropping or [ T CAN ]. Sometimes there's dose adjustments. And those usually happen in 4 to 6 months. And those were done in this study as well in a number of the patients. That was, if I recall, to me, it was left at the discretion of the investigators. But when we looked at that data, we saw it repeatedly being done, which is the standard of care in which I do in all my patients. And so when we do have the other drug in that backbone, in this case, I mean, is mitazalimab, we are seeing if we would not have mitazalimab, the context would see early progression much more commonly. So we don't always convert stable disease to PR by dropping drugs, of course, but we -- if we already have PRs, if we already have stable disease, it's helpful for the durability in my experience, and this is very consistent with the pancreatic cancer literature of adding agents to FOLFIRINOX.

Okay. But for example, this patient who has been [indiscernible] for 17 months, which is quite long, does he receive or she received chemotherapy for that whole period?

Yes, maybe I can comment on that. So yes, so the patient receives basically the trial protocol, allows patients to remain on the combination until progression. And there is no need to stop chemotherapy after a certain length of treatment. However, as Professor Wainberg said majority of the patients after like several months being on the FOLFIRINOX therapy required some sort of modification, either dropping off one of the components or reducing the dose because of toxicities. But the patients that we are -- I mean, we have on the study, they continue on a modified version of modified for FOLFIRINOX, basically, so some sort of chemotherapy together with mitazalimab. And that's also pretty much in line with the sort of mode of action of mitazalimab and the chemotherapy combination that the two sort of complement each other in terms of like the chemotherapy releases than your antigens and mitazalimab uses them to sort of activate the antigen-presenting cells and results into an influx of the T cells, right? So that's a sort of biologic, but essentially, the protocol is also in line with the biological basis. Such that it allows a patient to continue on the combination.

Yes. I totally agree. I think that's a key element here is that oftentimes after a year, let's say, patients are just on 5-FU alone. But having some chemotherapy combination and backbone in mitazalimab makes sense biologically. So I think from what I've seen, that's the best way to use these combinations in this trial as well.

I would now like to turn the call over to Soren to read any questions that have come in from the audience. Please go ahead, Soren.

Thank you. And first of all, thank you to Dr. Wainberg and Sumeet for taking us this far in the program and also thank you, Sebastian, Patrik and Richard, for your questions. We have a number of questions coming in on the chat here, and I'm going to try to group them a little bit. The first question here is from [indiscernible], Danish analyst, and it pertains to PFS data, and you already mentioned this, Sumeet. First of all, is median PFS attained? And if not, when do we get that PFS data? And could you please educate us on the median participation for the patients in the trial at the interim cut off.

Yes. So I mean, in line with what we discussed previously, the PFS follow-up as well as the overall survival follow-up is immature, and it's not really interpretable at this stage because several patients only started the treatment recently, and they didn't have sufficient length of treatment neither enough of disease evaluation, they are just ongoing in treatment and they will need longer follow-up before the PFS is interpretable and mature, which will be the case in our upcoming analysis around the end of the year or start of the year. And the second question, I didn't really understand that. This is a second part of the question, the categorization that you said.

How long has the patient been on -- what is the follow-up on the cohort we have in the full interim analysis?

Yes, yes, yes. So in the full interim analysis, as I said, there have been some patients who started in the treatment very recently, like just a couple of months. Whereas the longest who have been on treatment and follow-up like has been 1.5 years. So that is the kind of a range that we have in front of us. And that's why it's so important for the follow-up to be mature. And only then we can draw meaningful conclusions for time to even 10 points.

Thank you. Following up on primary and secondary end points. Here is a question from one of our shareholders. Do you expect to publish state related to overall survival in January, or is more follow-up needed to get a mature readout here?

Well, I -- what I would comment and I would also appreciate input from Professor Wainberg is we would be intending to have a meaningful overall survival readout in our upcoming analysis. Obviously, we will have to look at the length of the follow-up and then interpret that. The longer the median follow-up is, the better interpretable the survival data could be. And that has also been the case for the trials that have been like published so far. Maybe Professor Wainberg can comment on what is -- what can be thought about as a good length of follow-up across the whole trial for this data.

I think we do need a little more time. Obviously, as we mentioned, a number of those patients on the 57 on the latter group of the cohorts, just only had one scan. So we need to follow these patients out for longer. And that certainly could be in line with what you mentioned earlier at the beginning of 2024, which is about another 6 months. I think you'll have really sufficient data at that point to calculate a coherent and median number. And that would be something that I think that will give us, obviously, a lot more comfort. We obviously don't want to wait for that to plan the next step. But I certainly think that those timelines could be intersecting.

I would agree. Thank you.

And then in line with this, and this may be a little bit more speculative, but Professor Wainberg, can you comment on any potential correlation between the duration response, PFS and overall survival?

I mean the better duration response usually corresponds with better PFS. So response rate as an absolute number doesn't always correlate with PFS, unfortunately. But duration of response, and that's what gives me early encouraged from here is the durability corresponds with a median of PFS. And so I think based on what I've seen so far, I really like that number here quite a bit, actually. That gives me hope for that it will correspond with a high median PFS, upwards of what we would expect with chemotherapy alone.

Thank you. And now a question here from William Jennings, and I'm not going to read it out loud. It's quite long. But we talked about FOLFIRINOX replacing gemcitabine in the first-line setting in the ECOG 0 and 1 patients. The question is basically: Would you expect more patients with ECOG 2 and potentially higher to be treated with FOLFIRINOX based on the NAPOLI 3 data?

I mean not immediately. I think that ECOG 2 patients they are challenged and they don't -- can't always handle a multi-agent chemo and -- but some modifications are usually done in practice. And so -- what we might see gradually over time is even in that group of patients movement to a modified version of modified FOLFIRINOX. So you can manipulate the doses anyway you want, in essence, but not certainly for clinical trial purposes just yet.

And then I guess the second part of that question is with how in such a modified FOLFIRINOX machine would meet [indiscernible] potentially fit in?

I mean we never want to study these drugs and give them a fair chance in an ECOG 2 patients. So the principle is to get the drug regimen approved in the proper context. And then modifications are done all the time in practice, and we do that every single day not applying the exact same patient that was done in the study, but doing our best judgment once the regulators have ruled that it's permitted to do so. So those are practice things that in the real world, we do every single day. And I would expect here too, that would be the case if we get that far, hopefully.

Then following that, I guess, spurt two questions from Sebastian from [indiscernible]. So could you please, Dr. Wainberg, expand on the results of NAPOLI-3 study? What were the durability data and that was found in that study?

Yes. I mean the durability there was nice, too. I was happy with the durability of response rate there, upwards of 5 to 6 months in the responders. Certainly, I think there, there's no real innovative chemo -- innovative drugs. So patients were kept on chemo. But I do think we had some comfort there, that the -- again, the FOLFIRINOX space regimens have the durability that we want to see. And so that provides comfort for this program as well.

And this may be a bridge too far, but Sebastian also asked whether the expectation is that the new regimen NALIRIFOX or FOLFIRINOX will become standard of care in [indiscernible].

It's a common question, and I certainly don't think that it will replace modified FOLFIRINOX. And having been the PI of the study, I can speak to -- they have submitted for regulatory approval for the regimen. The challenge with it is, quite frankly, that it's too similar to the FOLFIRINOX. So I don't know if we're going to see dramatic people -- dramatic changes moving from FOLFIRINOX. Certainly, not ex U.S. We might see some people using NALIRIFOX if it finds its way to an FDA approval, which we won't know for another 6 months. But I don't think it will change the standard. And I certainly -- in all of the new trials we're doing now, we're filing for modified FOLFIRINOX as the base.

Thank you. Then we have a question here that also comes to new treatment regimes and let me rephrase here. So you talked about the PD-1s in MSI high patients. How do you see the prospects for a PD-1 combination in general pancreatic cancer with or without chemotherapy?

I see them as very limited, quite frankly. I think that we've done -- and a lot of this is not published data, but it's been presented. We've done many, many PD-1 combination trials in pancreatic cancer over the years. Whether it's nivolumab, pembrolizumab or others, we've done them. Whether it's with CTLA-4, whether it's with OX40, CD40, chemotherapy combinations, radiotherapy, we've done them. We have not been able to clearly identify a group of patients outside of MSI high, where there's benefit of these checkpoint inhibitors. So I really feel like the only way forward for checkpoint inhibitors with pancreatic cancer is in a context of a different new as to yet, I don't know, immunotherapy manipulation where it really makes sense. And in my opinion, that does not include mitazalimab. But it may include others down the road that are not yet developed.

Thank you. We have a question here from one of our peers in the field. Could you please comment on the study population in OPTIMIZE 1 in correlation to the original FOLFIRINOX study? And before Sumeet answers, of course, we've not published all the demographic data yet. Sumeet, maybe you could comment on that in general terms.

I think overall, the patient population was very similar, so newly diagnosed patients without prior systemic therapy and OPTIMIZE 1. However, what we have seen from the previously conducted studies, and that probably included FOLFIRINOX as well, I think some of them included or had received prior therapies. I think that has been the sort of reported data, whereas in OPTIMIZE-1, we didn't have patients with any systemic therapies that had joined the trial. But other than that, we can say that the populations in terms of their baseline characteristics can be sort of considered as pretty comparable. So yes. And the feedback that we've been getting is from our investigators is that this cohort actually, I mean, represents newly diagnosed and untreated metastatic pancreatic cancer patients. So yes.

Thank you. And then in the interest of time, and we have two questions or two general questions remaining, and I'll group a number of questions here. So is there a biomarker that sort of already now can predict responders in pancreatic cancer or in based on the early data in mitazalimab? I think Dr. Wainberg, if you start generally and then maybe Sumeet can add to that.

Yes. Biomarkers are very hard to combine this disease. We have not had any. And I think they're very hard to develop because of challenges with tissue acquisition and readability of those biomarkers and reproducibility. The only one so far is MSI high, as I mentioned. And even BRCA is not -- doesn't show that much efficacy for PARP inhibitors.

And I wish I would have had something to add to what Dr. Wainberg said. Unfortunately, not much at this stage, apart from the fact that we are -- so biomarker evaluation is a very like important component of OPTIMIZE-1 program, and we will continue our efforts to look at all the data that we are generating and make correlations with response and survival and so on and so forth, with the hope that this gives us an important hint towards clinically relevant biomarker that can be implemented.

Thank you. And then the last question, and Dr. Wainberg, that's to you, and I think it's given in the context of you being a professor in GI cancers. So looking at the data that we discussed today, do you see other indications that would be -- if not straightforward, then at least sort of propose themselves as a next step for mitazalimab and FOLFIRINOX or part of that regime?

So I think that a lot of the really good data for CD40 does exist in pancreatic cancer. So I really think this is the good approach. This is the right disease to study here. I think it's challenging, and we all know that in this disease and -- but yet, I think the preclinical data all points to pancreatic cancer as being the best cancer of which to study. So as I mentioned earlier, I think this program is ripe for some sort of randomized trial design. And I look forward to being involved in the future.

So with those words, thank you, Dr. Wainberg. Thank you, Sumeet. Thank you to all of you, Richard, Sebastian and Patrik for asking engaged questions. Thank you for watching this webcast. Remember, mitazalimab in OPTIMIZE-1 Phase II clinical development in pancreatic cancer study fully recruited. We expect to read out the top line analysis from the study in January. And the drug has often brought designation in the U.S., and we look forward to keeping you updated on our progress. Thank you and have a lovely afternoon and morning.