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CMD 2021
May 20, 2021
Welcome everyone to KantarGA's R and D Day. I'm Joren Forsberg. I'm CEO of KantarGA. I'm very glad to have this event, which I think is caused by So several very interesting events. So we have new data in pancreatic cancer, which was disclosed during the night.
And we also have new data around preclinical activities in our second project, Can10. So before Starting the activities, I would just quickly like to present what Kantargia is to put everything into context. So and by doing that, I'd like to show our pipeline. So Contargia is an antibody company. We are based in Sweden.
We are focusing all our development on 1 molecular target called IL-1RAP. And this Target is found in another large array of different cancers as well as have a relevance in autoimmune inflammatory diseases. And the lead asset is called the Kano4 and is being developed for pancreatic cancer, non small cell lung cancer. Most of the activities right now are focusing on combination with chemotherapy where we are in Phase 2a in both these indications. But we also done some monotherapy to primarily get data on biomarkers, mechanism of action and safety.
In a number of solid tumors. We are doing activities where we combine KANO4 with pembrolizumab in patients that have relapsed on pembrolizumab therapy, which is a Phase 1 trial ongoing in the U. S. And we're about to start several new trials in other cancer forms, again looking into chemotherapy combinations. The second product, Canten, is another antibody directed against different epitope in IL-one rep and it's been designed for treatment of autoimmune inflammatory diseases and the lead indications are systemic sclerosis and myocarditis.
And then behind that, we have several 100 different antibodies in a platform project called CanX6, where the idea is really to fish out new antibodies which are complementing CAN 04 and CAN10. And to put this in a little bit more context, we or very much driven by that we have positive interim data in cancer. We have very much focused on, let's say, combination therapies, which I think is very much a way to go here. And IL-1 rep is interesting because it's a target for several different cytokines, starts the interleukin-1, interleukin-forty three and interleukin-forty six pathways. And this opens up lots of opportunities in lots of different diseases.
And we are definitely working on indications where the medical need is very high. Besides, Let's say, with drug development strategy, we also have a very unique and robust patent portfolio. So Besides having compositional matter patents on the KANO4 antibody valid until 2,035 and recently filed patent on KAN10, We also have a granted patent on the IL-one rep as an antibody target in oncology, which is valid until 2,032. And we listed on the stock exchange and we have a market cap of around US400 $1,000,000 and a cash position of which is pretty good with slightly more than US100 million dollars on the bank end of last year. So going into today's programme, I'm very excited to say that I think it's a broad and nice program where David Lieberg, who is Vice President of Research at Kantargia, will start to explain more about Canofor and or Nadunolimab in its mechanism of action.
Professor Achmat Awada, who has been the lead investigator for our ongoing Phase 12a trial of this antibody We'll present the latest clinical data in pancreatic cancer. These data will then be put into context of the pancreatic Cancer Environment and Pancreatic Cancer Disease by Doctor. Manuel Hidalgo from New York. After that, Ignacio Garcia Ribas, who is our Chief Medical Officer, will explain more about what we how we are moving our Portfolio Forward in Cancer. And after that, David Lieber will come back and present the latest on the Canton project.
And after that, we have time for questions and answers. Each presentation We'll be running without questions, but there will be time for 1 or 2 questions afterwards if there is an interest before we join into next subject. But otherwise, I suggest we leave questions for a question and answer session. So by that, I'm very happy to Let David enter the stage and present a little bit more on Canoforonadunelimab and its mechanism of action.
So thank you very much. It's a pleasure to introduce I1RAP As a target in disease, which we believe is a very unique and intriguing target, and we start with oncology then and the mode of action of KANO4. And I'll focus on the subjects of today, which is chemotherapy combinations and pancreatic cancer. So I1rep is a protein that's found in tumours, both on cancer cells, but also on other cells in the tumour vicinity that Helps the tumour to grow. I1 wrap is a protein expressed on the cell surface and it acts there as a receptor or a sensor, So it picks up signals from the environment.
These signals are signals of danger, of stress, of inflammation, And it relays the signal inside the cell then, and the cell has a response to this. So in this way, I1 wrap Scans the environment and is involved in cell survival and also, which we believe is really interesting, in resistance to therapeutic interventions. So it works like this. You have and I don't have the ability to point here now, but I'll try to guide you through these pictures. You have IL-one RAP in red here to the left.
And the signals it detects are called IL-one alpha and IL-one beta, which are 2 extremely Patent inflammatory molecules, so called cytokines. These actually interact with another receptor called I1 receptor 1. But to do that, this first step to interact with I1 wrap and signal transduction into the cell is allowed. And I1 wrap is required for this interaction or this signaling. So what Canofor does, as you see to the right there, it's that it binds I1 wrap.
It's and by doing that, it blocks the interaction with the I1 receptor and thereby you have no signaling. At the same time, Kano4 is an antibody, so it has 2 parts, 1 which is the binding part, which is the 1 binding type 1 wrap here, And the other part is a part which immune cells can recognize in order to kill the cells that express side 1 RAP. And actually, Cano 4 is engineered, so that it has a much more potent effector function like this than the normal antibody. So both of these mechanisms, we believe, is very important for Canophore function. So as I mentioned, Canophore is And this is, of course, how we found I1 RAF in the 1st place.
When we look into different tumors, these are solid tumors for different variants, We see that we haven't actually found a tumour yet that does not express CY1RAP, but if we look at the cancer cells, which are the blue bars here, you see that you have a varying expression. So for example, in non small cell lung cancer to the left, you have about 80% of the tumors where the cancer cells express I1RAP And it's varying degree in other cancer forms. What is true though is as well that if you look to a large extent throughout the tumour, All of them will express IL-1BAP in the tumor stroma and the stroma is then the surrounding tissue or the intervening tissue into the tumor, where you find, for example, blood vessels infiltrating immune cells and so on. To the left, you see a biopsy from the CHEM-four study. This is non small cell lung cancer And you see at the top and the bottom, you see tumor cells, which express IL1 rep, which is in brown here.
And you see the intervening sheet here, which is the stroma then, you find as well there brown cells that express IFRS. So what are these then? Well, a tumor is, of course, not just cancer cells. It can be described almost as a badly organised organ, which grows and contains a lot of the supported cells you find in normal organs. So for example, it requires a blood supply.
So you have blood vessels growing into the tumor, which is, of course, what we You have other cells like fibroblast, the cuff cell, the red cells. You have, which are very important, for example, in pancreatic cancer, where they form a very solid environment, which is even hard to penetrate for drugs. You have infiltrating immune cells like so called myeloid cells, macrophages, monocytes, neutrophils, That are inflammatory and help to create an inflammation. Here, we should say though that this is not a productive inflammation, this is more like it's In lichen to a never healing wound, it's more repair mechanism trying to soothe the tissue. It helps in creating, In getting blood vessels into the tumour, it keeps the active part of the immune system out of the tumour.
So this is a suppressive kind of chronic tumor inflammation that is required for the tumor to grow. Now all of these cells express i1 wrap, The tumor cells, the fibroblasts, the myeloid cells and the endothelial cells, and they all respond to I1alpha and I1beta. So they communicate through this system, Which is important in many aspects. But one aspect where it is really important is in resistance to therapy. This is not something that we made up ourselves, of course, but this has been described in many ways, not just for chemotherapy as well, but for example, EGFR inhibitors for And of kappa B inhibitors and other therapies.
And this is something that we're exploiting. So what happens is here that chemotherapy hits the tumor cells and they start to die. So they send out these stress signals I talked about in the form of IL-one alpha. So IL-one alpha is released from the tumour cells after chemotherapy, And they will then activate these fibroblasts, the cuffs and the infiltrating immune cells, who will start producing I1beta. So now, you have both I1alpha and I1beta in the tumor communicating to I1 wrap, and this is involved in tumor system.
It's not absolutely clear how this works, But clear is that both of these cytokines are connected to kidney resistance. So we can see this as well in our preclinical systems. So this is an experiment in where we have Human tumor non small cell lung cancer that's implanted under the skin into mice, and we treat with, in this case, gemcitabine and cisplatin. And what you see then in A to the left is that we kill the cells, we have increased necrosis and cleaved caspase 3. These are markers But we also get an outprogression of I1alpha, which is there in the middle.
Now, at the same time, if you look to the right, you see I1alpha and C in the left part of the C figure. But in the right, you have the green flashes turning up in the stroma, so that's the non cancer cell part. And this is active interleukin 1 beta converted enzyme or IS caspase 1. This protein is involved in an I1 Beta activations, it's a sign of I1 beta being activated. So here we have this communication.
We have Chemotherapy activating I1alpha killing cells in the tumour part, then activating the stroma that produce I1beta. Now, if we're adding Kano 4 to this, we see that we get a better effect. So chemotherapy alone is not as good as Chemotherapy plus KANO4. This goes for, in this case here, this is the same model lung cancer, cisgem or CARBOGEN. We've done this though in several different models, even in mice models, we've done Zebra fish with good results.
So this is a phenomenon that we feel Very confident about that we have a potentiation of effect of chemotherapy in experimental systems. What is also interesting what you see in B and D here, chemotherapy will induce weight loss in also in mice And especially, platinum compounds. In fact, cisplatin is used as a model for cachexia in mice. And what we see is that when we have this kind of weight loss, actually, Canoford counteracts this. So we have a better anti tumour effect, but we also have reduced CCT seems this is this makes sense.
It this can go through inflammatory signals, and it's, of course, something that we're really interested To have an ion in the clinical studies as well. So, Kano4 and chemotherapy is a good combination. Some words about pancreatic cancer then. This is extremely difficult cancer form with very poor survival And it's a difficult to treat tumour. But still, when we started some years ago to outline A strategy for development kind of 4, we had pancreatic cancer as one of the main indications.
And this is because there is a connection between I1 Pancreatic cancer, I1 alpha and beta, that is very interesting. So if you see in the middle graph, for example, The blue curve there is patients where tumours have low amounts of IL-one RAP and the other curve, the Purple curve is where you have a high amount of IL-1RAP. And as you see, if you have a lot of IL-1RAP, your survival is very poor, but you have a better survival If you have a low amount of 5,000,000,000 RAP. And there may be a mechanistic explanation for this because pancreatic cancer is driven by A number of driver mutations, and perhaps the most important of this is KRAS. So over 90% of tumors, Pancreatic tumors have mutated the KRAS and activating mutations.
And KRAS have been shown to induce i1alpha directly. So now you have a situation where KRAS drives the cancer, drives production of IL-1 alpha, which then communicates with Fibroblast macrophage in these cells would start producing IL-1 beta. And this inflammation has been shown to be important in pancreatic cancer. So to the left there, you see as well that the similar bars for KRAS compared to I1PAP. And again, it's The same is true.
If you have high amounts of KRAS, you have a reduced survival. But if you have lower amounts, you have better survival. They look very similar. So this connection between I1alpha produced by tumor cells, fibroblasts, which are so important in pancreatic cancer, It's actually something that we can model in vitro that is in the test tube. Now, bear with me, I'm aware that this is a complicated picture, But I think it's really interesting.
So if we grow pancreatic cancer cells here, PDAC cells, Together with the cancer associated fibroblast, the cuffs, they form structures that almost look like a tumour in the cell culture dish. So you have the cancer cell areas, and you have intervening sheets of these cancer associated fibroblasts. And if you look in the middle picture, it's shown again what I said in the last slide, that it's actually the cancer cells that produce I1 alpha, this is the white bar, By the fibroblast, the orange bar, they do not produce that. If you grow the cancer cells and the fibroblast together, you have About the same amount as you have just cancer cells, showing that this is produced by the cancer cells themselves. Now, if you look at IL-1 beta here, the right Then, you see that pancreatic cancer cells on their own or fibroblast on their own do not produce any I1beta at all.
But if you put them together, now something happens and you get up regulation of IL-1 beta. Not just phi1 alpha and beta, we looked at many different genes. We've done RNA seq, it's called, so it's basically looking at 1,000 and 1,000 genes at the same time. What is quite obvious is that when you do these kind of cultures and mix the fibroblast and the cancer cells, you have Large changes in gene expression, so you have cells change, and the cells that change the most are the cancers associated with fibroblasts. Tumour cells reprogram them into something else.
When we add KANO4 into this, we see to the right there That genes go up and down. This is red and blue. And when we add kind of 4, we have a few genes that change in these cancer cells. It's just 4 here, But we have a lot of genes that change in the fibroblasts. It's 230 genes that are influenced by CANO4 here.
So, the The conclusion there is then that this crosstalk between cancer cells and the stromal fibroblast involved by 1 alpha and beta and if you add Canofor into this, You have a large impact on the cancer associated fibroblasts that are so important for this tumor to grow. We can do this in vivo as well. So, Again, if we do this in mice, we take these cultures and we put it under the skin in the mouse and you will start growing a tumour That's on the left here. And again, you see the same kind of pattern. You have areas of cancer cells, PDAC here.
You have sheets of fibroblasts growing around, Supporting the tumor to grow. This is now, of course, in 3 dimensions, but it's the same kind of picture. Now, what is interesting, if you just grow the cancer cells by themselves as a lump of cells without any microenvironment like fibroblasts, you don't really have any effect of treatment. But once you mix them, you have a good effect of Canofor reducing the tumour growth in these mice. So the conclusion here then is that the inhibition of tumor cell growth induced by Kano4 in this system is either mediated by cancer associated fibroblasts, Reprogramming them in some way or we're just destroying the cancer associated fibroblasts' ability to support the tumor.
So just to sum up this a bit here. So what I said was that Kano4, nadunolumab, blocks I1alpha and beta signaling induces antibody mediated cell killing of I1 wrap expressing cells. I1rep is broadly expressed in solid tumours, both on the tumour cells and the in the tumour stroma, the supporting cells. Canofort targets both of these cells, both the cancer cells and the tumor stroma. And remember, you can do this by blocking I1 alpha and beta, But also by actually killing the cells by antibody dependent cell killing.
If we add chemotherapy, We activate this system, so you get more A1 alpha and betas in the tumor microenvironment and this is involved in resistance to the therapy. So when we add KANO4 and chemotherapy, they act in synergy to inhibit tumour growth. So we believe that these effects on the tumour microenvironment Are crucial and that the effects with Chemerosystem makes Canophora intriguing and unique compound, Including then treatment of pancreatic cancer. I'll just show you how this looks in real life, so to say. These are now biopsies From the CANFOR study, so the two left slides are pancreatic biopsies from CALFOR.
And you see on the left there, The brown cells are tumor cells, and they're brown because they stain for I1 RAP. So, they express I1 RAP. The middle, you see the same kind of tumor cells that are standing brown, but you see it's Less tumor and more stromas. The intervening and surrounding tissue is very dense. It's fibrotic.
There's not much cells there, But you have these elongated cells that are cancer associated fibroblasts that stay in 51 wrap as well. So they are there. To the right, you have liver biopsy, also from CHAM4. So here, you have A tumour, which is weekly expressing I1 wrap. It's the top part of the picture there.
But you also have these cells that are brown, because they express I1 wrap. And these are tumor associated macrophages then that also sit in the stroma and mediate Tumor progression. So, all of these cells are important for tumor growth. We are getting a lot of this data now, so that's I think it's really interesting. We have biopsies that we're looking at different markets, We look at 0 markets and all of this will help us understand even better what kind of 4 does in the tissue.
This is Songoong, however. So, we'll present this at the conference at a later stage. Okay. I think that was my last slide.
There's no questions related To this segment, so I think we'll be able to move on. Okay.
Well, Then I would like to ask you to stop sharing, David.
And I'll ask you to
give Professor Achmed Awada to enter the Stage. And Professor Wade has been the lead investigator in this trial. And we're very pleased that you will do the presentation of this updated Phase 2 data.
I'm Ahmad Awada. I am the Head of Oncology Medicine Department here at Jutborday Institute. And my task to present today to you the preliminary data from the pancreatic cancer cohort. As disclosure, I am the study coordinator of this trial. I am involved in the development of It's a drug from the first in men's study 2 years ago.
So we heard really a nice introduction from David about This pathway, important pathway, important in many tumor type, but particularly true in small cell lung cancer, as well in pancreatic cancer. We are all aware of the importance to find the new solution for pancreatic cancer because this is Calnead. And so far in the clinical practice, we have only 1 or 2 regimen of chemotherapy. David explained really well to us the importance of this pathway, the IL-one pathway, I had one wrap interaction with the immune system and introduced really well the value of the scan04 in modulating this pathway. And of course, the best way to go In further development is not to give this drug alone as we saw early, But in combination with chemotherapy, and that's particularly true in tumor type like pancreatic cancer.
So in this slide you can see basically the clinical development plan of Cano Forsberg since the first in men trial, which included 48 patient and where I presented the data of this cohort, that's First IMEENT trial at ASCO as oral presentation. And of course, there are another study now, cohort Looking to the combination of platinum and gemcitabine and can offer in non small cell lung cancer and this trial is ongoing. And of course the focus of today is the combination of 1 standard regimen in pancreatic cancer, gemcitabine, Natpaclitaxel in combination with CAN-four. So we are Taking patient, stage 3, 4, pancreatic cancer in the first slide setting. Patient candidate for gemcitabine, Gemcitabine and Abraxane.
So we included so far 36 patient in 10 sites, where 8 patients receive KANO4 at the dose of 7.5 and we go down to 5 milligram for the following 28 patient In order to mitigate it, the infusion related reaction, which is particularly seen as the main, let's say, side effect In the first in men study, the monotherapy study. And so all the, the maximum of patients receive KANO4 As a dose of 5 milligram per kilo and for gemcitabine tax, abraxane as a standard dose. We defined from the monotherapy study that in order to mitigate the infusion related reaction to start that with a timing Dose of 0.5 milligram per kilo, let's say minus 7 and before to go to the combination for the amount of the patient at 5 milligram per kilogram. Another possibility in the and Mean to mitigate this division related reaction was seen with this kind of a drug is to increase also the duration of the infusion. So you can see here, we have 36 patient registered, but there are 3 patient not By chemotherapy or withdrawal concern.
And so we have only 33 patients evaluable for efficacy. And you can see here the patient characteristics for the our study, our cohort and the COMFOUR trials. And we put it here just for comparison, but only to remember for one of the pivotal trial of cemcitabine and Abraak Sein to this by Van Hoef in 2013. And basically the patient characteristic in the first line setting are Similar, except in our population, 15% of the patient received adjuvant chemotherapy. At this time, at the Venov presentation, There are no central adjunct therapy at this time.
So basically the patient characteristic as you can see from this slide are similar. So the patient receives it, the combination of chemo can offer Evaluated every 2 months by CT scan. Of course, as you know, CA19-nine is a tumor marker in pancreatic cancer and we follow this as also used in the clinical practice. And I will go directly to the main conclusion at this time from the combination of Kano4 And KEYMO, we observe responses as we expect with this kind of combination KEYMO and here in combination with Acono4, which were durable and I will come back to that later. Promising PFS and overall survival result.
And interestingly, we saw What's called in the immunologic field, immunotherapy field. And that's unexpected for pancreatic cancer For immunotherapy, as you know, immunotherapy didn't emerge as a treatment in pancreatic cancer for many reason. Not here to explain, but basically no responses and even no pseudo progression and no pseudo progression described in pancreatic cancer as a whole When we go to the literature and basically we observe at least in 5 patient, 5 well documented patient, pseudo progression like response And interestingly, which predict longer follow a longer progression free survival. Let's go a little bit more on details. Here, you can see here the evaluation of Tumor shrinkage by the investigators and you can see we have 27% objective response rate As you can see here in this slide, it's important to say also this is by local evaluation.
And by some alternative view, we observe nearly the same, but this evaluation is still ongoing. Only to remember what's been pseudo progression in the immunotherapy era field. So this patient, When you received checkpoint inhibitor, for example, they progress at the first evaluation, for example, before that the tumor shrinks later on. And this is explained simply, but I think it's a simplistic explanation, but surely correct. There are probably is a result thing from immune cell cells infiltrating the tumor.
And this is the reason why instead of resist the criteria was developed, what's called iResist To consider this further progression possible situation observed with checkpoint inhibitor. And to our knowledge, This not described in pancreatic cancer too so far. And you can see here the patient with the pseudo progression like response In 5 patient, you can see the really the figures are really the same. At the first evaluation, we see that By CT scan, the tumor progress. And sometimes we have a new lesion before the tumor strength.
And we can see in parallel to that, the CA99 decreased significantly. And that's a 2 for 5 patient in our 33 patients, which is really an important number of patients for a small cohort of patients, which suggesting strongly this phenomenon of So the progression like response. And to illustrate this by CT scan, you can see here in one patient with liver met, which After the first evaluation, there are increase in the target region before to decrease 3 months, 7 months and 12 months and you can see in orange here the evolution of CA-nineteen-nine. Exactly the same picture from another patient with pancreatic cancer and liver metastasis. You can see at 2 months An increase of the target lesion by 25% which decrease at 4 months you can see the lesion is a little bit Shrink and to shrink much more at 5 months and you can see the evolution of CA19-nine which should become became normal in this patient.
So if we summarize here, The objective response rate by investigator, we have 9 partial response 27%. We have a pseudo progression In 15% of the patient, we have a disease control rate of 72%. And it's important to remember here, Because this is really important with in pancreatic cancer as well in all the free tumor, the median duration of response in median here is around 7 months. And you can see that the range is from 2 to 14 months. By reference, I put here in the right part of this A slide, what was observed in the Abraxane, gepitabib alone trial.
You can see here the progression of free survival by IR Assist. Why IR Assist was used is to simply because also we saw this 5ks Of further progression like response and you can see the median IPFS is 7.8 months. You can see the internal confidence here with 15% 55% of the time. And you can see that's and that's more important That, DFS according to IRIS is at 6 months 62% of at 1 year 19%. And this evaluation is ongoing.
In my opinion, because as you know, here, of course, we are getting chemotherapy And immunotherapeutic agent, as you know, by using immunotherapy alone, for example, PFS is not really the good Outcome to study and important to look what's happened at the survival level. And at this time of the evaluation, the Cutoff for this data is in April of this year, 2021. The median overall survival is around 13 months With 42% of overall survival event, you can see the 6 months survival rate is 71% is not bad. 1 year, 55 percent and of course we need some maturation before to conclude about this small cohort of patient. Here, once again, to remember this information and to put it in the context and the benchmark with EMPACT trial, But I think we cannot compare for the PFS.
But for overall survival, we can say it seems there are something interesting happening In this combination with KEYMO plus can offer a particularly true with 1 year survival, 55% for pancreatic cancer metastatic stage 3 and mainly stage 4 disease is something of interest to follow in larger cohorts or larger randomized trial. Let's move now to the safety. We can say that as expected from the Phase 1 infusion related reaction and this was Observe in other drug is the same class was seen with AKAN-four and neutropenia and neutropenia related event, particularly fibrillaneutropenia. We observed mainly with the timing dose of 0.5 milligram per kilo up to 44 percent Of the patient developed mild to moderate infusion related reaction. We saw us manage the spray medication and prolonged 1st infusion when we go to the combination.
More importantly, we observed more neutropenia compared to what Would be expected from the pivotal Phase D trial of Abraxane and gencitabine and the grade 3 fibrin neutropenia was Sir, in this combination of KANO4, chrisabraxane and gepsietabine in 17% of the patient. And of course, this could be managed with GCSF and of course, those modification. And you can see here one example of patient. You can see in 2 patient, GSSF seems to decrease The deeper of the needle of neutrophile in a patient, for example, presented here at the right part Of this slide. So the brand neutropenia seems to be present, higher than expected 17% of the patient And that could be, of course, as you know, mitigated by GCSF and eventually in a further cycle, in subsequent cycle By those, a reduction of the chemotherapy, Asia.
And interestingly also the observation, But still this is a small cohort of 36 patient that seems to be less fatigue, but fatigue as you know is subjective. But more importantly, in my opinion, less peripheral neuropathy compared to gamsinabibatroxen In the BRAHOV trial, which was around 17% and the fulforinox, where oxalitatin is neuroplastic drug was around 9%. So not described in the comfort cohort, in our comfort cohort. We can do a lot of hypothesis about that. Possibly, IL-one play a role in fatigue.
That's true. But peripheral neuropathy, possibly. And probably, we are mitigating here By modulating the IL-one pathway, IL-1RAP, Probably we are mitigating this problem of fatigue, peripheral neuropathy seen in other trial of chemotherapy based approach. So if we could conclude what we can conclude at this time, from this Pancreatic part of the CAMFORD trial that I think nadulonilumab can afford. Pujemplzitabine napaplitaxel In the first line treatment seems to give us promising efficacy in terms of response.
And this story, this observation, this funding of further progression like phenomenon, which is correlate really well what it was With what David explained to us about the ADCC, the immune, let's say, modulation, Because basically, this sort of progression like phenomenon in 5 patient, well documented, but wasn't described In other, with chemotherapy alone, for example, and we know checkpoint inhibitor alone didn't show a big or let's say breakthrough in the treatment of this disease. I think we cannot say a lot about PFS and maybe IPFS today And overall survival because these data are still need to be mature, but the early data seems to be promising compare what we know from historical control. But that's really, we can really give at this time same conclusion. What we see is clear that neutropenia is Seems to be more important in this combination. We have a little bit more neutropenia ready that mainly if you try Neutropenia, which should be mitigated by G CSF.
It's important to know that G CSF wasn't used As primary prophylaxis, that's truly secondary prophylaxis, those modification according to the protocol, mind to moderate infusion related reactions can afford mainly in the timing phase and which could be decreased was decreased by increasing, for example, the infusion time. And that was Documented already in the monotherapy arm, the first in men, for the trial. And That's important to follow because this is an important, less neuropathy. This is something cumbersome for the patient and less fatigue, which is more subjective. And that's I think there are rational to go to a Phase III trials combining this New approach, innovative approach, which are really targeting not only the immune function from one side, But also the IL-one pathway, 2 important pathway in solid tumor, particularly true for pancreatic cancer, but also For North Most Cell Lung Cancer, the North Most Cell Lung Cancer Court is still ongoing.
With that, I would like to thank you very much for your attention.
Yeah. We have a couple of questions to you Regarding your presentations and the first one is how could you clarify how many confirmed and Unconfirmed responses you have observed as there seems to be some sort of confusion about that.
I think we can say at this time, I think that what's really clear, there are at least 9 partial response. That's we can say, to my knowledge, to my evaluation, We have 9 objective response, which lead to 27% of the objective response rate.
And the other question is, how concerned are you about the new tropenia frequency ahead of Expansion into the FOLFIRINOX combination. To be honest, when
we go to For Inox, in my practice, what I saw from the reported result, there are no So important neutropenia related event, but from my clinical practice, we saw much more, let's say, So on and this is the reason why I am using for Forrenox mainly for young patient in order to not to have this problem. So, clearly, Cantofol seems to increase the neutropenia problem related to chemotherapy here. And I think it's important To use GCSF as prophylaxis, now the question, primary prophylaxis, secondary prophylaxis, You know, if we go to the algorithm about the use of GCSF of ESMO, for example, When we have less 10% or less, no GSF to be used, when we have 20% and more, this GSF Should be used. We are here in between. Of course, we this kind of patient are some to some extent are fragile.
So basically, I am not against to obviously just if we go to when we go to randomized Phase 3 trial.
I think there's time for a couple more questions. And what do you say clinically relevant overall Survival improvement in first line pancreatic cancer.
Sorry, Goran, I didn't follow well the question.
What do you view as a clinically relevant overall survival improvement in first line pancreatic cancer?
What is the my opinion About survival, what is could be considered, you mean, of importance, that's your question?
Yeah, I think that's how you should view the question.
Yes. You know, there are two things Here, in my opinion for pancreatic cancer and I am sure Doctor Hidalgo, which has a major experience also of pancreatic cancer, could comment on that later on. I think the media is something of importance of course, but what always for this kind of tumor in a met need situation, I'm looking also always the percentage of patients alive at 6 months, percentage of patient alive at 1 year. Because unfortunately, this group of patient is really bad in terms of prognosis. And personally, The median of 1 year that seems to be okay.
But what is more interesting to me, What was observed at 6 months and at 1 year, the percentage of patient is still alive. And I think in the Phase 3 trial, In my opinion, I don't know, to the exact goal what he think about that, should be one of the co primary endpoint percentage of the patient Alive at 1 year because this could be could give more information and more importance to the combination and the study.
Yeah. And could you share some light on the on what do you believe would be This sort of lowest level of overall survival rate in order for Can't afford to become a new standard of care treatment.
If we I will look If let's say, if we expect to have, let's say, 8 months from the standard chemotherapy and we can increase it By 50%, I think that's something of importance. Yeah.
And the final question for you then, could you shed some light on how representative the trial participants were of the overall first line pediatric
Normally, we cannot do what I did in one of my slide to put the patient characteristic of the Jean Ablak said pivotal trial head to head. I put it only to be sure that Our population are not different from the population of the pivotal trial. And basically, when we go Characteristic by characteristic, we are exactly the same, except for prior chemotherapy, which is not in favor of Can offer a chemo combination here because that's still not big percentage of patients receive chemo in the adjuvant setting or new adjuvant setting We have 15%. So is in my opinion is representative, but still we are here talking about the methodology of clinical trial. We cannot conclude from 33 patients, but that's give, let's say, good insight, in my opinion, To move ahead for two reasons.
The first reason is the data we, I presented. And secondly, the mechanism of action of this drug. The innovative approach of this drug, which is completely different from what we know in the immunotherapy field. We have checkpoint inhibitor. We have the antagonist.
We have the agonist. It is completely something different targeting at least Two different pathway. There are some interaction, of course. And I think that's a gift to this drug, in my opinion. So more, let's say, value to move it on In pancreatic cancer randomized trial, in any ways, if we ask for 50% increase, for example, in median survival or 1 year survival rate or whatever.
I think we do not need thousands of patient here. I think with some 100 of patient, These patients are available. There are no many competitive trial. We could have the answer very quickly basically about the value of Obviously, this study could be done very quickly. In my opinion, it's not really rare tumor.
The standard of care, of course, here is used. I think something in order to improve. And so I don't think we will have a difficulty to recruit patient in this kind of trial. And there are no, to my knowledge, many competitive trial in this setting.
Many thanks. I think we'll Keep the rest of the questions for the final Q and A session then. Thank you.
You're welcome.
Thank you so much, Ahmad. And now I'm handing over to Manuel Hidalgo from New York, who will, let's say, present more about disease and then put the new data into context. So please go ahead.
Thank you. Good morning. I may have my slides.
Yes.
So what I thought to do this morning is to just give a brief overview of where we are in pancreatic cancer. I think a number of the questions Our sort of pertinent in terms of what is meaningful improvement in outcome, how do we design studies, What are the next steps came in the prior discussion? And I'll be addressing some of those as we go. And I will highlight You know, some of the ongoing therapeutics that likely or hopefully will impact the disease and then to spend A little bit of time on putting the data we just heard into context. So if I may have the next one, please.
These are my disclosures. Next. So this is the problem and this is recent data It's showing that really pancreas cancer, we have not made significant Progress in the past. And if you look at this slide, we're expecting that by 2026, which is around the corner, Pancreas cancer would be the 2nd cause of cancer related death, both in men and women, Yes, beside lung cancer. So a very significant problem.
Next. So far, we treat this disease by surgery. We are lucky to get it at early stages. Radiation therapy, which has a controversial role but with new technologies, hopefully, will be effective and helpful, Particularly in patients with the locally advanced or localized, more localized disease. And then traditional Chemotherapy, we heard about that and we saw the data from the EMPACT trial before, which is The main treatment strategy.
Neither precision therapy nor immunotherapy really has made an impact on this disease as of yet. And for that reason, the data we saw this morning about modulating the immune system and starting to see You know, responses that are durable is quite exciting because, again, we are not there yet. Next. So just to I'm not going to go over the entire spectrum of management of this disease, Just to highlight how little progress we have made is the only biomarker that we have At the moment is performing status, which has been around, you know, for 50 years maybe. And we classify patients in groups depending on that.
And if their performance status is good, and usually those are the patients that we treat in clinical trials, We can use either Gensitabine, Abraxane or FOLFIRINOX. Today, we saw data with GA. Data with for filperinox is being developed. Either one of these regimens are optimal standard of care First line treatment, there are differences in which one we apply to one patient versus the other, but they will never compare head to head. And the belief that fulfilling ox is more effective is based on non comparative data.
When you look at real world evidence, real world data In properly selected patients, they are quite comparable. So it's good to have data with both of them, but I think either one can be and move forward as a registration strategy. On the other side, poor performance status, gensitabine It's what we use, very ineffective. And the discussion, unfortunately, with these patients is best supportive care. And then the group in the middle, Reduced performance status, Karnovsky, greater than 60, the ECOG2, A very interesting group because it's a large group of patients.
We tend to use gensitabine or gensitabineabraxane. Actually, We published data on that showing that GA is tolerable. And that I think is when we look at the spectrum of the disease, One thing is to develop drugs for the good performing status, which is important and the first Step to get drugs into the market, but we need to also understand that many patients come to the clinic And I'm not candidate for those drugs. And therefore, anything we can do to improve either change performance status by early diagnosis, By better supportive care or applying these drugs to those patients is important. And of course, In advanced disease, we are not curing patients.
So it's eventually important that we move these drugs to earlier stages And that we diagnose patients at earlier stages. So by increasing the number of patients and moving the drugs in those situations, Likely, we will be able to save more lives, which is at the end what we want. Next. So multiple agents in development. This is from a review.
I just we just wrote with the Ignacio Garcia from the YAREDO, sorry, from the UTAD a number of years ago, very, very busy area. Many drags in early stages, very few advancing to late stages and really Nothing at the moment that you could say, well, this is really outstanding. It's going to change the panorama. So still, we need to continue sort of doing this early work as the one we saw today to identify new targets, new drugs That will have an impact on the disease. Next.
Now, 2 major areas. Precision oncology and the problem here, and I will be very brief, is that most of the cancers have RAS mutant. It's not the 12C, it's 12V, 12D, which so far we don't have effective drugs for this tumor type, for this oncogene. And that is a major problem for precision oncology in pancreas cancer. The other genes, p53, SMAD4, P16, the same.
They are not targetable as we speak. So a major area of research interest is to develop drugs that work In this genetic background. Next. But we have been able to sort of pick small groups that have actionable mutations. The largest group being the DDR, the DNA Damage Repair Deficient, Which may be up to 10% if you combine all the genes, BRCA1, BRCA2.
As you know, olaparib was approved Based on improvement in progression free survival, very important, because we're talking about how you move drugs forward. Usually, overall survival has been the predominant outcome or endpoint for registration. Olaparib failed in OS, was approved based on PFS because it helps In this selected group of patients to decrease chemotherapy is better tolerated and probably easier for the patients. There is a debate In the field, whether or not that is enough, but the reality is that the drug was approved. And then a number of a myriad of other mutations less frequent, But when you have them, and let's go to next, drugs work.
And this is an example recently presented For the red fusion, very rare, patient with red fusion, as you can see, baseline multiple liver metastases And then very good response up to 40 cycles with the cell percaptanib. So very interesting And I just want to highlight that those cases are out there and we need to do sort of genomic analysis to identify them. Next. And this is the data I just alluded to for olaparib that increased progression free survival and was approved first targeted agent to be developing pancreas cancer. Next.
So, one area, precision oncology, working on it. 2nd area, immunotherapy. And there, we face the tumor microenvironment that was alluded to before in the Early sort of mechanistic presentation, which creates this immunosuppressive tumor microenvironment. For that reason, Many or none of the immune active agents that have been approved in other tumor types have been effective in pancreas cancer. Next.
Some of the drugs that have been developed or are in development or already failed, we don't need to go over this, but I'm Going to make a couple of points. Checkpoint inhibitors, as we know them, they just don't work. So the progression free survival, the overall survival in these patients is very short. It's worse than with chemotherapy. It's about 3 months.
It does not improve The outcome of patients treated with chemotherapy and that kind of give us sort of the ground of what immunotherapy is doing in this disease. Of course, multiple attempts to overcome that problem. I'm going to I'll show you just three pieces of data from one of our recent studies using CXCR4 inhibition just to illustrate where we are and how difficult and complicated this is. Next. So, this is a strategy of making the cancer immune sensitive.
We do that or we try to do that by blocking CXCR4, which is a receptor that signals T cell to stay Out of the tumor, so the belief is that the tumor does not respond to immunotherapy for the simple reason these cells are not in Close proximity to the tumor, when you block that pathway, in this case, with when you block Fibroblast or eliminate fibroblasts that secrete the cytokines, and we heard about that earlier today, Secret cytokines that signals the T cells to stay out, T cells get in, and when you then incorporate PD-one active agents, You get a response. Next, we saw in biopsies taken in this clinical trial published last year, Before treatment and after treatment, in a trial that we did with a CXCR4 inhibitor, BL-eight thousand and forty Plus pembrolizumab plus chemotherapy, we proved that in paired tumor biopsies, you can get an influx of T cells. And of course, next, When you treat those patients, you start seeing response rate. In this case, in the overall response rate was about In this small cohort of 22 patients of 32% in the second line setting, this is probably the best Data that we have available, published data with immunotherapy in pancreas cancer, still It's not outstanding.
And in the second line, we will need to see what happens when we do this in a randomized a clinical trial, but it's positive in the sense that we were able to see some responses, but we still need to see whether or not that's going to be impacting progression free survival and overall survival in a randomized trial. Next. Among the many targets There are sort of important in the stroma. IL-one is one of them, both Alpha, in pancreas cancer, the most recent data, which suggests that beta is the most A significant one. And this is a very recent paper from Dana Barsaghi at NYU in which they showed that Indeed, IL-1 beta is needed and is produced by the fibroblasts, It's produced and it fits the tumor and you need to have it for pancreas cancer progression.
Preclinically, the IL-one pathway, I think, has been nicely validated and highlighted as a targetable or as a strategic target in this disease. Now, is alpha, is beta, Is that wrap? Those are things that, of course, we will need to sort out in the studies. But the strategy that you saw today, If you remember from the prior presentation, by targeting the receptor associated protein, It likely blocks signals from both alpha and beta. And I think that's important.
Next. So, we saw, and I'm going to pick up A few of the slides that Doctor. Awadha presented before, response rate, this is confirmed By risk is by investigators and you see a number of patients with disease control with partial responses. And of course, we now compare that This is using REST. We compare that to the standard of care.
It's 30 patients, non comparative, very difficult to say This is going to be sort of different if we were to do this in a randomized Phase 2 study, which in my mind should be the next step. But what was very interesting and unique in this study is the pseudo progressions. And as it was alluded before, We have not seen that with chemotherapy, of course, but not in the immunotherapy studies that we have run so far with checkpoint inhibitors. And this is taken from the prior presentation, a few patients that The tumor goes up, but the tumor marker comes down. And if you continue treatment, then they enter a response or stable disease.
And that tends to be durable, which I think is an important message. They are durable. If we were to do these studies using just RECIST Criteria, as we do with chemotherapy, many of those subjects would have been taken off study Yes, at the point of the disease progression. And that's probably what would happen in the next patient. And that was one of the cases that was shown.
If you can advance actually, I thought I have one of the CT scans, I don't know if I may have it in the next one. Probably not. But here it is. You see that this patient, by 2 months, 25% would have been taking off a study and then we would never know if there was benefit or not. But 6 months, 5 months later, there is basically a complete and stable disease.
The tumor marker has come down. It's very likely that these patients will enjoy this disease control for a while. The problem Or the limitation or how we need to be sort of innovative here is how do we build this into the design of a clinical trial. But I think we're there. We are there for a couple of reasons.
First, as I mentioned before, we got olaparib In the market based on improvement in PFS. So PFS is in the right setting Can be considered sort of a registration regulatory primary or secondary endpoint or maybe combined with overall survival. At the end, we want overall survival, but we need to sort of build these stage ways. But if you go to the prior slide, which I'm sorry I have them flipped, This is very interesting data. This is a recent paper published by the Canadian group In which they these are patients treated with checkpoint inhibitors.
And what they did is they monitor Cell free DNA at 3 months. And you can see here, out of 73 patients, There were about 30 patients that developed disease progression in blue and had increased Cell free DNA, they didn't do very well. But the 7 patients that had disease progression and decrease In Cell 3 DNA, in Orange, they did very well. They did as good or very close to the patients that had a racist evidence of response. So, The problem of a patient comes in, we have disease progression, what do we do?
We continue treatment or we just stop treatment, I think can be solved now by, of course, applying the CA199, but also by utilizing More sophisticated and innovative ways to monitor disease. So, these are elements That incorporated in the right clinical trial, I think will be helpful to move this agent along And to be able to capitalize and take advantage and to capture those patients with pseudo progression that still Benefit from the drug and should be continued on treatment. And likely, if you have up to 15% of those, That's going to increase your disease control rate in a manner that will very well show benefit as compared to Chemotherapy. I think this is my last slide. We already saw this one.
Thank you for your attention. I had a pleasure to review this data and I'm happy to take questions.
There's no specific questions related to your presentation, so I think we can proceed. So
thank you so much.
Thank you.
Manuel. And Maybe I don't know if sure if you have time to stay on, but if you have maybe a chance for questions later on.
Yeah, I can stay for a little bit longer.
Yeah, okay. So then I'd like to hand over to Ignacio Garcia Ribas, who is Chief Medical Officer and is going to explain how we are, let's say, advancing the Programme.
Hello.
Hello, everyone. I hope you can see my screen. I'm Ignacio Artyom, the Chief Medical Officer and Medical Oncologist by Framing. And I'm going to tell you about the current developments of, kind of 4, nadunolimab In the light of what the data that you have seen in pancreatic cancer in combination with Emcytovine and Abraxane. So I hope that now it's clear that we have promising data.
Obviously, it's very early what can you expect from single arm trial. But we are having hints that there is good hopes for having better efficacy compared to the standard of care. The reasons to believe is what we see first, durable responses that is not only the pseudo progression is those patients with response as Professor Laguarda show. They stay on response for double time that is it is published in Bonhoeffer's, the emcytobineabraxane trial From 3.5 months to 6.8 months. This is interesting, although obviously the numbers are very small.
And the second thing that is really what It's more interesting is this pseudo progression phenomena about which Doctor. Hidalgo Has discussed quite a lot because it is not response. What is going to be evaluated by regulatory authorities as relevant clinical benefit It's a time to event, in this case, progression free survival and overall survival. And this is something that is an interesting finding Because it's pretty obvious that if we can generalize this in this 15% of patient population of patients in this population, It can really impact the overall outcome of a registration clinical trial. We need to investigate this more.
This is not unexpected because the trial was designed to evaluate patients, but I've raised this criteria. So we were hoping kind of for to have an immuno oncology mechanism of action and it seems that This purpose is paying out now. The new clinical trials that you will see I'm going to present to the best possible way Also speaks for the chemosensitization hypothesis that we had it. We observed this in animals. We generate Non clinical data about it and we are seeing also some interesting results in this direction.
Obviously, we have CFFT side effects, the first one was first presented by Doctor. Rawada at ASCO 2019 is not unexpected. It's infusion related reactions. Today, we know that this is similar to many other commercialized monoclonal antibodies And it's not a risk for development. The second one neutropenia and febrile neutropenia is not unexpected.
It can be seen as pharmacologically driven And what we are learning is how to harness this. We have now GCSF, FigaStream. It's Now generic and is used in many situations. So if you can show that your combination makes good benefit and I has a good outcome. This should not be a barrier for treating patients.
And there are Other potential benefits that I would like to highlight now, and we will need randomized trials for this, but it's interesting the possibility of nadunolimab to control the Abraxane or maybe the Oxaliplatin neuropathy, which is a big problem And the discontinuation of patients with grade 3 neuropathy in the case of pancreatic cancer, even patients who are receiving benefit. And also due to the anti inflammatory properties of Canophore, it would be or we hope to see a good impact in cancer related Thank you. So this is the overview of the current development status. As you can see, we have made good Progress, we have a number of trials that are prepared are ongoing or in preparation for 2021. In non small cell lung cancer, I'm going to Present one slide of information that was previously disclosed.
I can say that recruitment is ongoing and we plan to offer results in Q3 this year. For pancreatic cancer, we are, the data presented by Professor Agwada corresponds with R and D That was completed in October last year, but we have an extension phase ongoing. We are investigating other doses And not only for safety reasons, because, well, you know that now regulatory authorities require at end of Phase 2 meetings and before starting registration trials to discuss with them the dose selection strategy. So we will go with enough Information on several doses to agree with the agencies and the best dose on the schedule. We have another ongoing trial in the U.
S, the IND trial combination with pembrolizumab that may open the door All the future combinations with pembrolizumab and immunotherapy is enrolling well. And I will tell you a little bit more later. We have the 2nd trial in pancreatic cancer, the other first line with modified for free NOx. And The protocol is approved. It has been submitted and the regulatory review is ongoing.
We expect to have a first patient in this Quarter. Cripple negative breast cancer with gemcitabine and carboplatin, we are doing, this is the first trial that we planned, that we are going to do in collaboration with the Spanish Breast Cancer Group. They adopted KANO4 and we are working with them and we expect the submission in also in this quarter. And we have another trial that we call Basket Trial with 3 parallel indications, colorectal cancer for 4 folks, biliary tract cancer With Jim said, renal cisplatin, non small cell lung cancer with docetaxel. We also expect to submit this quarter.
So here is a little bit of non small cell lung cancer combination. So here is not this information was Disclosed in September last year. Obviously, we have more data that we cannot disclose today. And these patients, as a reminder, is business most of them with metastatic non small cell lung cancer that are either first line chemotherapy Or have progressed to pembrolizumab and then are eligible for a platinum tablet. We are seeing, as you can see here, 6 out of 9 available patients at that time show objective response Versus a historical control with gemcitabir and cisplatin alone of 25%.
We have well, probably the only thing I want to say because you have seen this before It's the only effect that we are seeing again is neutropenia with a higher frequency, but we are treating this in the same way As seen the pancreatic cancer trial. So this is a little bit of information about the pembrolizumab trial. The first patient started in 2020 and the enrollment is running according to plan and we expect to deliver results in the second half of this year. So this trial is for patients who have received previous pembrolizumab. So we are trying to break the acquired resistance to checkpoint inhibitors.
So And obviously, the first intention is to investigate the safety of the combination. It's novel combination. So we need to learn about that we are not having any other safety issues. And with this trial, Once we have it, it will be the obvious building block for future combinations, the doublets of pembrolizumab plus Nadunilumab and chemotherapy, for example. We are going, we're including You know, typical tumors for immunotherapy today, low to small cell lung cancer, head and neck cancer, melanoma, heart cancer, And it's now up to 18 patients.
We have 3 sites in the U. S. And you have more information in clinicaltrials.gov. These are the trials To be a start that I announced in my 3rd slide, the first one is for free NOx in pancreatic cancer. It's going to be, this is It's closed already in clinicaltrials dot gov, 30 patients initially.
We are going to do dose escalation. We are using a modified FOLFIRINOX that is less intense. It produces less neutropenia than the original for 3 knocks from Conroy. And we are going to open 9 sites in France and And we plan the 1st patient for 2021. I mentioned about the Basket trial, the 3 combinations in non small cell lung cancer, CRC, Ambulatory Threat Cancer.
I will give you in my last slides information about the rationale for the indication selection. So I'm not going to stop myself here. And again, submission is planned for this year. And the triple negative breast cancer that I mentioned for the combination of gemcitabine and carboplatin in collaboration with JACAM. So why these Indications and combinations.
As you can see in our early development plan, we are trying to do many shifts in goal. We are going to explore several Different indications that likely are going to give us a good variety of information about the safety and potential efficacy Of the KANO4 in combination, colorectal cancer is an obvious place to go. I mean, it's a huge unmet medical need, It's the 3rd most common tumor. You have patients after the first and second line of chemotherapy plus Sebastian, plus cetuximab. They are in good shape And they don't have clear options.
The options that they have available as monotherapies, they don't produce responses, they produce marginal survival benefit. So clearly it's an unmet need. Oxaliplatin among the cytotoxies is cornerstone in colorectal cancer. Immunotherapy testing to work for 90% of the colorectal cancer and we have data. I mean, we it seems that kind of 4 lights platinums.
So it's a place that we want also to further explore the convenability of nadulonilumab with Oxaliplatin, same as we are doing in the for free NOx trial. There is also data speaking for the importance of IL-one, IL-1 beta in the colorectal cancer. So we hope also to have this dual mechanism of chemosensitization And at the same time, changes in the tumor inflammation. Biliary tract cancer is a small indication. It's a smaller than pancreatic cancer.
So why Going into this, well, 1st of all, because the standard first line is the MCYTAV analysis. You've seen the interesting data in lung cancer with MCYS In terms of responses, almost every patient is having some tumor reduction. So why not coming here? It's in the met need. Recently, Only the IDH inhibitors, there is one that has been approved for an IDH mutant intrahepatic cholangiocarcinoma.
This is just 10% of ulcerative cancer. Many of these patients progress afterwards and in the end most of them will be candidates if they are fit enough who received the CYTOPAINT and CYSPlatin. So this is an interesting option for us. There are some studies, I mean, it's easy to find where IL-one has been also implicate this pathway in the promotion Of the ABLIAD Tract Cancer. Well, in non small cell lung cancer, we want to cover the field.
So we plan for, you know, it's a small proof of concept arm in this basket trial for the combination with Taxotere. So this is, as you know, docetaxel is in the end a common 2nd, 3rd line in patients with non small cell lung cancer. So based on our chemosensitization hypothesis, this could be an interesting Interesting opportunity for nadulinumab and we would like to take it. There is no question that the IL-one system Has been well described, its importance in non small cell lung cancer development. And finally is this triple negative breast cancer.
This is a separate trial. I think it could be a great opportunity for us. Breast cancer is a huge health problem, thank God. Now the incidence of metastatic breast cancer is going down. Still It's the most common cancer in women.
And triple negative breast cancer, that is a phenotypic definition, so tumor does not express estrogen or progesterone receptor or HER2 is still 15% of cases. And it's probably one of the worst today because affects younger women. It's more aggressive in general and it's associated with BRCA mutations is a highly moving field, but it's the breast cancer Type 1 IL-one rubber has the highest level of expression. So it seems that makes sense to test IL-one inhibition here. And interestingly, among all the breast cancer, in triple negative is the only place where the oncologists are happy To give polychemotherapy rather than single agent and the platinums have shown A clear anti tumor activity is the only place in breast cancer where platinum is used.
So the gemcitabine carboplatin combination It's used as a standard of care for many of these patients. So why not is an excellent opportunity for us to explore this scenery. And this is my last slide. So we are happy to take questions from the audience. Thank you very much for your time.
Yeah. There's one question related to this and that is concerning If it would be interesting to study the response on a sub cohort of patients with high I'll let IL-1RAP and compare that efficacy data with survival in this sub cohort.
Yeah. And definitely, it's a good idea always to try to identify or to verify if there are different Efficacy, high versus low. I mean, the IL-one route is a very novel target. So for the moment, we don't have data To separate, to make a cut off and separate high from low, definitely it's a good idea.
Thank you.
Okay. Thank you, Ignacio. So now it's time to leave the cancer area for a while and jump into autoimmunity and inflammatory disease. So I would like David to Take the stage again and present latest on Can10.
Thank you very much. Okay. So let's see here. There. So let's leave oncology for a little while then.
So, Canten He's, of course, the little brother of Chem 4. But it's a project that aims to harness the potential of Now in inflammatory and autoimmune disease, where there are obvious, maybe obvious advantages. So and I'm happy to do this, because I think Canton has advanced really well in the last years. We are in this project focusing on 2 indications, myocarditis and systemic sclerosis. These are Different diseases in many ways.
Myocarditis is an inflammation of the heart that can be fatal. It's characterized by an acute inflammation that leads to fibrosis and loss of heart function. Systemic sclerosis is a disease which is a chronic autoimmune disorder that leads to fibrosis of the skin and internal organs. And often, The cause of death in this disease is lung disease and or heart disease, actually. So even though these are quite different, there are some connections.
Vascular inflammation is important in systemic sclerosis and heart failure is one reason for death in this disease. And in myocarditis, then fibrosis of the heart is the reason why you lose contractile function. So the rationale for Canten is now that I1 RAP, as we talked about before, it interacts and is crucial for signalling From IL-one alpha and beta. But actually, IL-one RAP can also interact with the IL-thirty three and the IL-thirty six receptors. So in this way, it's required for signaling through 3 different signaling systems.
And these are all Exploited by different approaches, so there's drug development in these different systems. But the opportunity for us then is, of course, that if we can find an antibody that binds I1 wrap in a way that blocks all of these pathways, We can do something more, and this is what Canton does. So we've developed an antibody, which is a potent blocker of all of these pathways, Like kind of 4, you see to the right there is a part that binds i1 wrap and inhibits signaling. And the other part that we amplified with CHAN4 is Here now, silence. This is a pure blocker.
It does not kill any cells. Okay. So We've done some conceptual studies with Canton just to try to understand the potential of I1 wrap targeting. And this is a simple inflammatory mod. You basically inject, MDSU crystals.
This is monosodium urate. This is what creates inflammation in gout, for example. So you inject this IP in mice and what happens is you get inflammation, you get cells into the peritoneum, which is the left trough, and you get cytokines as well that you can measure as a sign of inflammation. And what you see here then, we've compared here to anakinra I1 RA, which is a I1 alpha and beta blocker. So If you look at to the left on neutrophiles entering the peritoneum, you see that I1Ra has an effect.
And Kanten or murine surrogate, and Antibody targets murine I1, it does the same thing. So we do get an anti inflammatory effect. We see effects in cell infiltration into the peritoneum optimized. At the same time, we see as well a reduction in certain cytokines. So G CSF, for example, we talked about is reduced both by IL1R and Cantem, IL6 as well.
But you also see that for IL6, IL-five and eotaxin, 3 different cytokines, you have a stronger a much stronger effect by CAN10 compared to I1 RA. This was very important for us to look at this because this shows that I1 wrap blockade is not the same as I1 blockade. It has additional value, and it's a stronger anti inflammatory treatment. The fact that we had A similar efficacy as Anakinra as well on, for example, G CSF nucleophile is also good because Anakinra is a very potent Taiwan blocker. This is another set of data I'll run through, but we also this is also a conceptual study.
So this is A psoriasis model. And the reason we looked at skin is because in this tissue, you this is where you find IL-one, IL-thirty three and IL-thirty six, it's all been described and it's all been described as relevant for, for example, psoriasis, but also for other skin inflammation. And here, we see that if we take, for example, the graph to the left, the orange bar is anti-one rep treatment. We compare here to anti-1 beta, which is in green, which has no effect. But again, if we use our antibody, we do see a good effect On the C score.
This model is a bit different. You have topical administration, so you basically Put Imiquimod, an irritating agent in the skin of the mice, and you measure redness and flaking as you go along. The control here is dexamethasone, so that's steroids applied to the skin directly every day. So it's a different control, But we see after 7 days, we have a similar effect. So this again shows that i1 wrap Inhibition is a potent anti inflammatory treatment.
Okay. So, The reason we chose systemic growth in myocarditis is we did an exercise with a company called Cello Health to run through, I think it was 154 different indications looking at disease severity, medical need, patient populations, market size, Regulatory feasibility and so on, going through loads of parameters to select a few because we realized we need to Focus. And this turned out as the best indications. I won't mention about System sclerosis at this time, since the data we have presented now concern myocarditis. But I'll tell you that In the systemic sclerosis, you find clear connections between all of these I1, 33, 36 cytokines to the disease Flu fibrosis.
So, that's certainly not an issue there. The models are quite difficult. There's no really good model for systemic sclerosis, We are working with both human tissue and animal models and this is something that we will present at the scientific conference at the later stage. Now when it comes to myocarditis then, I think it's quite clear that IL-one is involved in this disease. So IL-one beta Lokeid has been quite extensively investigated in cardiovascular inflammation.
Also, a Kindra I1 RA has been tested. And the reasoning here is A bit similar to what I described before in the tumor that you have dying cells in the heart that release IL-1 alpha That's a danger signal. And this is processed by macrophages, for example, in the tissue that release IL-1 beta. And this leads to an enhanced inflammation, more cell death and a vicious circle that propagates this inflammation. So by blocking them with anti IL-one, you can alleviate this.
There's also an ongoing clinical Trial here with Anna Kindra in patients with acute myocarditis. There's less known here about IL-thirty three and IL-thirty six. There are papers saying that putting IL-thirty three here and having a role in my colitis as well, but it's not necessarily described. So I think One of the main questions for us was to show that I1 wrap has an additional benefit to just I1 blockade. Here, we have good models.
This is an experimental autoimmune myocarditis. Basically, what you do, The blue bars in the top, the day 0 and day 7 is that you immunize the mice with heart protein. So you create an autoimmune reaction to the heart You get a peak inflammation about 14 days after the first immunization. And then after a while, you get fibrosis And the heart function deteriorates. And you can measure this, as you see in the lower left, by doing echocardiography.
You measure, in this case, the main parameters is left ventricular ejection fraction, how much blood the heart pumps out. And as you see here, if we start treating, this is from day 7 with our antibody, which is the orange line. We see in this experiment, we hardly lose any in the function in a heart function, while The control is going down. And you see anti al beta in the green is not as good as well here. So we seem to have an additional benefit here as well.
It's the same data from day 42 there to the right, showing that our antibody is actually superior to anti beta in this case. And the reason why we get this effect is that we decrease inflammation. This is To the left here, we see fewer cells infiltrating the heart. And to the right, you see that we also decrease fibrosis. So this makes sense from an anti inflammatory treatment.
What's also good about these experiments here is that it's actually treatment from day team. So here is when you have the massive inflammation, we don't start treatment until then and you still have good effects. There's more data from this on the poster, but what we say there is that Canton blocks And not only IL-1 alpha beta, but also IL-thirty three and IL-thirty six alpha beta and gamma. So 6 different cytokines that signal through IL-1RAP. Blocking I1 RAP then is a potent anti inflammatory strategy.
And importantly, it is qualitatively different from pure I1 alpha and beta blockade. So, it's not the same thing. IL-one replicate counteracts inflammation, fibrosis and the decrease in heart function And has additional value compared to IL-one blockade and actually prednisone as well. Those data on the poster, but comparing to even on AKINRA or prednisone, We have a better effect with our antibody. So, the model, I think, has to be adjusted a bit.
So as we saw before, dying cells release IL-one alpha, but they actually can release IL-thirty three as well. And the cardiomyocyte, at least on RNA level, Endothelium and macrophages can respond to this, produce IL-one beta as before. Endothelium actually responds to IL-one, but also to IL-thirty three. So, if you have both of these cytokines there, you will have a stronger signal. Infiltrating cells like granulocytes, if it's eosinophiles, they will also react to IL-thirty three and participate in the inflammation.
So by blocking IL-1 alpha, IL-thirty three, IL-1 beta, And possibly IL36. We believe we have a more potent effect here also in myocarditis. So where is Canteen now? Well, we're doing CMC development and we're doing production, but for safety and clinical studies, and that's ongoing very well. We will, during this year, complete the safety program.
We communicated that we did the first tox assay already showing Now, it's just up to, I think, it was 50 milligrams per kilogram. And we will do further studies during the year to prepare for the clinical part. We will also have interactions with health authorities to go through our clinical program. Next year, then, we will have the CTA submissions And we will start the clinical studies. And this and then we will also prepare for further clinical development then in my conduct is And system is Cubasis.
So that was my last slide with this presentation. So thank you very much.
Yeah. And there's one question related to your presentation, David. And it It helps around if you're able to elaborate on why IL-one RAF blockade Would it be superior to MTTF in the proposed indications?
That's a more difficult one, but it's a good question. Anti TNF, it's a more Specific molecule, so it interacts and it's amplifying inflammation in a way. But the IL-one, IL-thirty three and IL-thirty six will be much broader. IL-one will induce TNF, for example, those often goes hand in hand. But if you reduce TNF, you will still have IL-one there and you certainly will have IL-thirty three and IL-thirty six.
So again, this would be a broader effect. We may imagine that by blocking I1 wrap, we'll have reduced TNF levels as well. But I don't think it would be the opposite.
Thank you.
Okay. So if I understand correctly, there are no more direct questions to Kenten. So then I think we have reached the end of the presentations and we now have some minutes left for additional questions and answers. If there is Anything that has come in here or if there's anything that anyone would like to ask?
Yeah, just a couple of questions. One is regarding if you will be able to identify methods To pre test patients that will react positively for the treatment and also identify non reacting patients in order to sort of make the treatment more successful.
Yes, I think In the cancer field, so I guess this is for pancreatic cancer, definitely, it seems that This phenomenon of pseudo progression could be something predictive. And obviously, one of the attempts that we are trying is to identify Clinical factors to potentially enrich the patient population to increase the success rate.
Thanks. And regarding the PDAC study, And this is a specific one regarding how many were defined That's in stage 3 and how many in stage 4?
Yeah, 90% of patients were in stage For metastatic, just where a few items in very few, a couple of patients were at stage 3 unresectable.
Yes. And then follow-up Questions to that would be, do you think there's any value for Cano 4 in early stages of Oh, Pentarchy, cancer?
Well, it's early to say, but you know that the normal development, for example, gemcitabineabraxine Was first registering metastatic pancreatic cancer that is the majority of patients and then it's moving to And neo adjuvant or adjuvant treatment. So this could be the natural development path.
Yeah. And there's a couple of questions regarding the future plans for PDAC. And They are mainly focusing on whether you will apply for a Phase 3 study in the near future or if there's any other plan for this indication going forward?
I can start and then you can fill in if you like. But obviously, what We are, let's say, very encouraged about what we've seen so far. And obviously, we're going to take this program forward. And as Ignacio said, there are some, let's say, aspects like we need to have more data on various dose levels before we can going to Phase 3. It's things that were that are ongoing right now to let's say fill that gap.
And we are recruiting patients. We expect the last patient to enter This part of the trial within a few months from now and then we are ready for, let's say, having complete discussions with regulatory authorities. And in parallel, we are doing everything we can to prepare Our files and let's say, have a suggestion for them. But I I think we need to, let's say, be humble to say that next steps is not really controlled by us. It is really an interaction with regulatory authorities Fink.
So we can be clear that we are definitely going to advance this program and then Exact details we need to come back with, but we have no, let's say, desire to sit and wait And let time go by, we understand that there is a time pressure here to advance the program.
Thank you so much. Is there anything you would like to add on that, Ignacio?
No, no. Thank you.
Thank you. I'll move on to another question then. Do you believe you will need to show an OS benefit from the Phase 3 trial For approval or will you do believe a PFS alone benefit would be sufficient, providing that only Quality improvements.
Yet traditionally in pancreatic cancer registrations Until the power inhibitor has been based on survival, among other things, because Unfortunately, the survival event happens very quickly. So it's not one of these tumors like ovarian cancer or pancreatic cancer That PFS is an accepted registration endpoint among other things because the disease is very long. Patients have many lines of treatment. So there is kind of Lot of confounding factors. Traditionally, in pancreatic cancer, it has not been like this with, you know, a median survival time shorter than 1 year.
I believe, but this is just my personal opinion, that still survival is going to be The registration endpoint, maybe, you know, in the case of PARP inhibitors, when you go into very small, very focused targeted At treatment, when you have already a clinical proof of concept in indications in breast cancer, in ovarian cancer, I would say that regulators should feel, you know, Comfortable by doing so, but I'm not so clear that this is going to be generalized to every drug. In any case, as Joran mentioned before, our plans are still are going to the regulatory authorities with these kind of questions.
Thank you. Moving on then. We've recently seen other companies with ILO1 targeting assets, initially in clinical trials for pancreatic cancer. Could you please elaborate a bit on the differences Between those studies and the study you have been conducting.
Yeah, I can start then, and then if you'd like to fill in. So we're well aware about, let's say, the study that Manuel Hidalgo presented earlier on showing the relevance of interleukin-1 beta in the context of enhancing PD-one active anti or PD-one reactive antibodies in this field. So there are trials ongoing where PD-one or PD L1 antibodies actually combined with Chemotherapy and an IL-one beta antibody is being tested in the first line setting. And then we're also aware about second line trials using an interleukin-one alpha antibody, which are just starting. But to, let's say, be very clear, we are well ahead of those development programs right now.
And we clearly believe that Our competitive edge is around, let's say, the chemosensitization and counteracting chemo resistance. So We believe that we have big advantages even though we have full respect of those programs.
Thank you. Moving on then, the fact that you've been using a different protocol for the pediatric study And compared to historical data that you've been benchmarking against, do you think that that Could be a complications when interacting with regulatory agencies?
Well, I'm not sure if I get the question about the protocol.
It's concerning the resist criteria.
Okay. Now I get it. Well, obviously, every novelty requires new regulatory So we don't know to what extent in other indications with other drugs, FDA or EMA or national Authorities have been discussing the situation. Definitely, it is for the good. It is not really changing the endpoint.
Imagine if the endpoint is going to be survival that is the classic is not affected by this directly. I mean, it's only the conduct of the trials. But we all understand that in the minds of authorities and everyone is to maximize the benefit of participants in the clinical trial. So here it will be even an ethical dilemma to say that you need to discontinue patients that may have prolonged benefit as we are showing. So, it's a discussion that I'm happy to take.
Thank you.
And this, I think it That you were able to present yesterday evening, are you happy with the results?
We can, all 3 of us can join to say that, I think it's been pretty clear that we're very happy.
Yes. That was my view as well. Going on Do you see any early Hypothesis is generating biomarker from biomarker signatures that could indicate some patients that are more likely to benefit from 1,004 than others.
Yeah, well we I don't know, maybe David should explain what we're doing in this field.
Yeah, so this is something that we're Looking at and what we're doing is 2 things. First of all, we're measuring soluble serum Biomarkers in there, so we can look at factors and we can follow through treatment, how they change. That's something we're going to do, of course, all that we are doing. And the second one is to look at biopsies from tumors. There we have for patients, we have Biopsies before and after treatment.
There we're of course looking at changes as well to follow. But we're also looking at how do the biopsies look when the patients go into study And how which patients then respond best? And if we get any Clear data of that, that will tell us, it will guide us. We'll see. But it's some really interesting analysis that's ongoing now.
So we will look at that definitely.
And do you have any time plan for when you will be able to sort of Disclose more information on that.
Joren, one second.
I think we need to come back, there has been, Let's say, logistically, it's been more complicated to, let's say, you say, to validate all these analysis and then we plan for regionally. And also since patients are still on treatment, we're getting more and more information. So we need to come back on that.
Yeah. We want to have all
the information. But again, we like to be transparent. So whenever we have something which we feel is robust, we will Communicated.
Thank you. And getting back to the Phase 3 Ishu, could you give any sort of flavor on the potential design and the dimensions of a Phase 3 design within this field.
Ignacio?
Yeah. Well, this Obviously, this is a Phase 3 is something that at least with FDA you go to an end of phase meeting and you negotiate because It's quite clear and transparent. But there are some unique things that are necessary. 1 is the discussion about The dose, what to do with these patients with sort of progression, the follow-up of patients, the safety management, things like this. So far, The Phase 3 design in pancreatic cancer has been relatively simple.
Unless You've been selecting patients for some very well defined mechanism of action as PARP inhibitors. So it's a randomized trial, 2 arms, 1 to 1. And normally, it has been classically 400 patients in total. So this is what is published for others. I don't think that there are reasons To think that FDA or EMA or competent authorities are rising the bar For efficacy with hazard ratios more stringent than the old ones of 0.75 Because still, I mean, these disease, most drugs fail.
So it has been it's a field that has been difficult to advance, as you all know.
Thank you. And finally, could you say something about The first in men study within KANO10, will it be a trial in healthy volunteers or Do you have any thoughts on that?
Should I start and then you can fill in, David? Basically, there are a few different options on the table now. So Since we're now, let's say, addressing autoimmune inflammatory diseases, it's not like cancer where you automatically go directly into patients. So healthy volunteers is one option. You can have some kind of patients, all camera being a Different option, you can have patients with some kind of dermatological disease of relevance or you can do some kind of mixture of everything where you start with healthy volunteers and then let's say, bridge over to these type of patients.
So Notice the final decision has not been taken exactly how to do this.
Thank you. And we just got one additional question. Do you have any explanation on the deterioration in objective response rate, what was Announced in October last year about 40% and now showing 27% Great for that. I can
take that one. So it wasn't really deterioration. So what we announced was that we had 40% confirmed and unconfirmed. And it was 30% confirmed. Now it's 27% confirmed.
So I don't think there is a major and obviously there are some unconfirmed patients here as well. I think what has happened after that communication where we said there are more and more patients with pseudo progression Instead, so I think if you add responses and CO2 progression events, It's been fairly constant all through the trial.
Great. I think we have been running Through all the questions that have been coming through this afternoon. Thank you.
Well, in that case, I'd like to thank the audience for listening to us. And I hope this has been very rewarding. And I would like Thank Ignacio David and Ahmed Awada and Emmanuel Hidalgo for taking part in this and finally for the organizers who made this possible. So thank you so much.