AB Science S.A. (AB.PA) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to the AB Science web conference. I will now hand over to Alain Moussy. Sir, please go ahead.

Good evening, and good afternoon for the ones who are from the United States. My name is Alain Moussy, I'm the CEO of AB Science. And I have the pleasure to run you through our web call on the latest safety results of masitinib in first-line metastatic castrate-resistant prostate cancer. The -- with me, there were 3 people -- experts in oncology who will answer the question that you will have in the second half of this presentation. There is a Professor Stéphane Oudard, who is Professor of Oncology at Georges Pompidou Hospital in Paris. Professor Theo de Reijke, who's Professor at the Amsterdam University Medical Centers. And Professor Olivier Hermine, who is our President, Chair of the Scientific Community of AB Science and Professor of Hematology at Hospital Necker. So prostate cancer is still an unmet medical need. Docetaxel was registered in 2004 by FDA with a level for metastatic prostate cancer progressing after hormono-therapy. There is many hormono-therapy registered, but when patients are eligible to chemotherapy, it's only docetaxel, and there has been no drug registered in combination with docetaxel in the last almost 20 years. And the median survival of patients with metastatic prostate cancer eligible to chemotherapy is around 2 years, and the final survival rate is around 30%. So masitinib is positioned in prostate cancer for as a combination with docetaxel. 4 patients who are eligible to docetaxel, which we call first-line treatment of metastatic castration resistant prostate cancer. And you can see on this slide, the list of drugs which has been registered, but before docetaxel or after docetaxel, but not in combination with docetaxel, although there are, of course, several Phase III ongoing. The masitinib profile and mechanism of action is to target 2 cells of the innate immune system. One is mast cells through 3 kinases: C-Kit, Lyn, and Fyn, and the other one is macrophage. Through macrophage colony-stimulating factor for receptor one. And those 2 cells play a role according to us, but also according to the literature in prostate cancer. And so I will leave it to Olivier Hermine for the scientific rationale.

Okay. Hello. So in general, we have a new view to think about cancer, which include not only the tumoral cells, but also the microenvironment. And we know that this cells and particularly, the mast cells and macrophages play a critical role in promotion of angiogenesis and tumor growth, and also contribute directly to tumorigenesis by suppressing the adaptative specific immune response against the tumor. And in addition, this test and it produce also some cytokines, which may use the survival and the resistance to chemotherapy. So in particularly, when you look at prostate cancer, it has been shown that the amount of mast cells, which infiltrate the human prostate cancer correlates with a poor prognosis. More you have mast cells, more you have a poor prognosis. Also, there is a strong correlation between the number of mast cells and the microvessels density in the tumor, and we know that this new microvessels by providing some nutriment and cytokines and also, they allow these cells to metasize outside the initial tumor. And we know that mast cells and they produce some androgenic factors like the EGF, for example. Also, it has been shown that mast cells in some models, may play a role more initially for promoting the proliferation of the tumor at the beginning. And then they may also promote the whole to unuse metastases. And at this stage, probably mast cells don't play any more role or less role because the cells become more autonomous cell as a beginning. And it has been shown also that in prostate cancer that mast cells modulate the expression of p53 and bisulphate mat kinase, which may play a role in chemo resistance in these tumors and mast cells and then promote chemo resistance by this pathway. And additionally, it has been shown very surprisingly that some prostate cancer bold tumors express the tyrosine kinase receptor, c-Kit, which may also promote the proliferation of the tumor cells. And finally, we know that mast cells, they also promote the differentiation of monocyte towards the -- and to macrophages, which may in turn favor the proliferation of the tumor and metastasis in contrast to M1 and one macrophage, which are associated to the better prognosis. So on the next slide, we have shown that masitinib indeed may play a role to prevent tumor progression in several models of tumors, including lung cancer, colon cancer, breast cancer and eventually, prostate cancer. In this model that we have shown is that in vitro, masitinib doesn't play a role to inhibit cell proliferation and to induce cell desks. But in contrast, when we engraft this tumor in mice model, as you can see on the right-hand side, we can see a very nice decrease of tumor proliferation in the presence of masitinib. And to make a long story short, we have shown in this model that is due to the depletion of mast cells and also to the whole programmation of macrophage from M2 macrophage, which induced tumor progression toward M1 phenotype, which reduce tumor progression. And in this system, masitinib has a unique role by blocking the kinase like c-kit, Lyn, and Fyn, which doesn't do other kinase inhibitors. So taken together, we do strongly think that by targeting mast cells and macrophages, masitinib may improve the prognosis of tumors in which mast cells and macrophages have been shown to play a critical role in their prognosis.

Thank you, Olivier. So we have here on this -- on Slide 9, the masitinib clinical development plan, which is made of 2 studies, a small Phase I/II where we tested masitinib in combination with 2 chemotherapy, docetaxel and gemcitabine. And this Phase III, on which we're going to deliver the results. The next slide. So on this slide, we confirm in this preliminary Phase I/II that masitinib is best associated with docetaxel and not gemcitabine. We tested up to 9-milligram per kg per day, but 6-milligram was better tolerated. And the internal confidence that we set up at 75%, just to see the PFS and the survival was in line with the historical data confirmed that we could continue the development of masitinib in combination with docetaxel in prostate cancer. Now we move to the key Phase III. So AB12003 study is the same design. It's a prospective, multicenter, randomized, double blind, placebo-controlled, 2-parallel groups, Phase III study, which also met with 6 milligrams kg per day in combination with docetaxel at 75 milligram per square meter versus the placebo masitinib in combination with docetaxel. It was randomized 1 to 1, and the main inclusion criteria was patients eligible to docetaxel, which were pretreated with hormono-therapy or aiming to directly be treated with docetaxel, which happens. And ECOG was limited to 0 or 1. The study was authorized by FDA. We enrolled in 15 countries in 67 sites, including, of course, 9 countries in Western Europe. That's FDA. Next slide. Next slide is the primary endpoint. The primary endpoint of the study awards progression-free survival, measured according to PCWG2 definition, which was the official definition at the time of the initiation of this study. And PCWG2 is a complex combination of 4 variables, which are radiographic progression. So bone and soft tissue lesion and also PSA progression, which has to be confirmed from the nadir, which is the lowest measure of PSA. And then the symptoms progression, which is a pain progression that we measure through a score called PPI ended because it's PFS. So it's earlier between progression and survival. But again, the progression is made of 3 sub variables. And the population analyses with mITT and not ITT. The difference being that 2 patients actually didn't take treatments, and they were excluded from this primary analysis. So mITT in just that patients needed to have one -- at least one dose of treatment. Next slide. Next slide is the other analyses. So we have sensitivity analyses of the primary analyses. The sensitivity analyses will include stratified log rank, cox model, ITT, care protocol, and investigator assessment of PCWG2. And the secondary analyses including subcomponent of the PFS, time to progression. So without the survival -- overall, survival response rate, quality of life and pain. So the design, this is important. This slide is important to understand and interpret the study. The primary analyses is test on the PFS, but the protocol tested in parallel to population, the overall population and a targeted prespecified subgroup of interest based on alkaline phosphatase kept less than 250 units per milliliter. And why we introduced this subgroup, it's because we thought that masitinib could generate a more favorable results in this subgroup, which detects, I would say, less advanced metastasis because masitinib acts to, I would say, present the transformation of the tumor into a more aggressive tumor. It's more [indiscernible] when it is [indiscernible] in early metastatic tumors. That, by the way, what we observed in pancreatic cancer for the ones who have followed the development of masitinib. So in line with this hypothesis, we introduced this subgroup. Then we control the extra risk by testing first the targeted subgroup and at 4% alpha level. And if positive, then we add back the 1% left to test the overall population with 5 person's alpha risk. But if negative, we're left with 1-person in the overall population, and interim analyses was planned that was using a peto function. And so it consumes, let's say, roughly 0.1%. So in fact, that the final analyses, we're left with 3.9% in the targeted subgroup and 3.99% in the overall population. And if the test in the targeted subgroup is negative, then 0.8% in the overall population. The IDMC recommended to continue the study, but in the targeted subgroup and to stop the recruitment in the OP subgroup, which we followed in terms of recommendation. Next slide. Now in terms of sample size, the initial protocol plan, 390 patients to be recruited in targeted subgroup, and 580 patients in the overall population. Based on the interim analyses, we stopped the recruitment in the OP subgroup and continued in the targeted subgroup. And the IDMC recommended a resampling to go from 390 to 468 patients, and we finally stopped at 451 because the COVID period started, and it was slowing down in terms of recruitment. So we increased the sample site almost up to the recommended target. And at the end, we had 714 patients in the overall population. So you remember that 2 patients didn't take the treatment. So from ITT to mITT, we just have 2 patients less. Next slide. Next slide is the baseline characteristic for the overall population. So it's balanced for ECOG, for Visceral Disease, for Gleason, for Halabi, for the ones who are not familiar with prostate cancer, these are analysis score measures the -- I would say, the aggressiveness of the disease and the prognostic of the disease. LDH is also more or less balanced. Alkaline phosphatase as well. PSA is -- it might be a little disbalance defense issue with the mean or the median. And Chromogranin is developed both in mean and median in this favor of masitinib. So we can say that more or less, the baseline characteristic on balance with maybe a slight disbalance in this favor of masitinib on Chromograninn. Next slide is the same slide, but for the targeted subgroup, which leads to the same, I would say, interpretation. So balanced on Gleason, Halabi, visceral disease, which is for prognosis factor. And some kind of these balance of Chromogranin and maybe potentially in PSA. This is the primary analyses. So remember, we test first the targeted subgroup which is the subgroup measure for alkaline phosphatase less than 250 units per millimeter. In the literature, this cut is predefined. That's why we use it. And in the literature, it's supposed to be 2/3 of the patients. So here, you can see what has been the p-value for this study. The p-value is 2.72%, so below the 3.9%, which is the threshold. So it's below. So we can conclude, the study is successful. Then when you look at the median, the median is an increase of 0.9%. So it's modest, but still. And the median of placebo plus docetaxel. So docetaxel is 5.4%. I would say, in line with what we know from the literature and masitinib increased at 6.3%. And you have other calculation statistical, which is hazard ratio of the cox model, and the hazard ratio is 0.79, which means that there is a 21% benefit of being under masitinib when you calculate it through the PFS. And you have the Kaplan Meier curves below on this graph. Then the next slide is the sensitivity analyses of this primary analyses as per protocol. So you remember that there was a stratified log rank. So the difference is not -- is from unified to stratified. So you introduced the stratification factors. The p-value is better, below 1%, and the other ratio is slightly better, but still consistent with the primary analysis. The ITT doesn't change nothing. Those 2 patients didn't take treatment. Anyway, the per protocol population slightly better consistent and the PCWG2 as calculated by the investigator. We used this [ thoughtful ] reading, and [ thoughtful ] calculation that calculated by the investigators doesn't change nothing. So all sensitive immunology are consistent. The PFS rate, which is also another way to look at the PFS. It's still in the targeted subgroup. So you can see, at month 6 around the median. So masitinib at 66% -- 66 percentage of patients which survive with the progression. Whereas, the placebo is at 45%, and it is already statistically significant. But then the difference is made, I would say, in the second year, between month 2 -- month 12, sorry, and month 24. And so you can see here that at one year, there are less than 20% of patients who are survived with a progression in placebo and almost 1/3 with masitinib. And then at month 18, it's 14%, 15% with placebo, but double, 28%, I would say, with masitinib, statistically significant. Same story at 2 years where you have 12% of patients who survived with progression with placebo is docetaxel, but 23% with masitinib. And then the percentage are reduced, but still in favor mathematically, of course, of masitinib, and it's significant at all-time points. So you can see that the median doesn't tell you everything. It's the way we design the study, so it's positive. But when you look at PFS long-term, you can see that there is a subset of patients which benefit from masitinib, I would say, more long-term, like 2 years and even longer. Next slide. Next slide is the remaining part of the primary analysis in the overall population. So adding the beyond subgroup, and you can see here that although masitinib is above for the Kaplan Meier curve, it doesn't reach any significance. So we can say that there is no benefit in the overall population, which was -- so the rest of the primary analyses. And it justifies the recommendation of the IDMC that says to stop the recruitment in the OP subgroup. By the way, I forgot to show you in the previous slide that the percentage of patients in the targeted subgroup, if you can go backward, yes, one more slide. When you look at the percentage, well, you don't take here the percentage, but the percentage of -- sorry, the targeted subgroup is roughly 2/3 of the patients at the detacher side. We go back to the remaining part of the presentation. Next slide, yes. This slide is interesting to see the impact of alkaline phosphatase on the interpretation of this study. So we prespecified the subgroup with a cut of 250, which is in the literature. But what if we went a little lower to try to take patients even fairly or, let's say, with less aggressive tumors. So we run different cuts to 50, 200, 150, and 100. So it reduced the percentage of the population for roughly 2/3, 63%, as you can see on this slide. And then at 200, for instance, where 50% of the population at 250, 1/3 of the population roughly and then at 200, it's 20%. And you can see, the median difference. And again this one Increased from 0.9 to 1.3 to 1.4 to 2.1 and the risk-benefit increased also mathematically from 21%, which is the primary analysis to 27, 37, and 47. So what this slide tells us is that there is a pattern which is the earlier you take masitinib in a metastatic prostate cancer and the greater will be the benefit of the patients, even though, of course, the percentage of patients and the population reduce. But it's perfectly logical and gives a lot of strength, I would say, to the -- and logic to the demonstration. Next slide. Next slide is the survival. We don't see in the targeted subgroup a benefit in survival. We don't know how to explain it because we did not measure the subsequent line of treatment. And you know that there are 4 products which are registered after docetaxel that might have kind of modified from one arm to another, the survival, but we just observed that there is no benefit on survival. Next slide. Next slide is the overall population just for one piece of information that's important, which is the thankful progression, radiographic -- the radiographic measure the soft issue and the visceral metastasis. And here, in the overall population, which is negative, in terms of PFS. But if you take one piece, which is the radiographic time to progression, you can see that masitinib generates a benefit because you can see the Kaplan Meier curve, which is above the docetaxel alone, and it is statistically significant, okay? So it means that masitinib, in fact, acts already on the tumors. It will act also on the PSA and the targeted subgroup. Less actually in the overall population, mainly because the tumors are actually in differentiate after, but masitinib has this ability to slow down the progression of the metastatis, visceral and soft tissue, even in the overall population. And here, because there are no feelings, it's statistically significant. Next slide. Next slide is the safety. So the safety is the following: the number of fatal AEs slightly lower in the masitinib group as compared to docetaxel alone; the number of AE is increased. We don't share here in detail, but it's increased mainly due to grade 4 neutropenia, the docetaxel generated neutropenia and masitinib also adding them will increase the non-fatal SAE rate, which was expected. Severe is also increased, but it's spread through different shocks. And you have also a higher rate of parent discontinuation, which is due to this neutropenia expert protocol because at some point, you have to stop treatment, so that was expected. But there was no other signals, except that use hemato, I would say, toxicity of neutropenia, which was expected. Then next slide. Next slide is intellectual property situations. We have been delayed in delivering this presentation because we wanted to take a new patent, which we did. And this patent, if granted, could protect us -- could protect masitinib in this indication until 2042. We have also saw some compassion of natural pattern that protects that [indiscernible]. So it was necessary to find this new patent. And next slide, so our last slide, is the market. So the market is significant. We are talking only about patients who are eligible to docetaxel. We're not talking about the whole market of prostate cancer, including our monotherapy. And according to literature, there are 75,000 patients eligible to docetaxel in Europe and 50,000 in the U.S. We just put there the price of products which has been registered in prostate cancer. And so we can conclude, it's a big market, obviously. And that ends our presentation and now we can open the sessions to questions that you can formulate only by writing. And the experts will, of course, will be there to answer your questions.

[Operator Instructions] We have now a question from Derek McFly.

This is Kay [indiscernible] who called.

Good morning, Kay.

I want to ask the KOLs. Two questions. One, what is their view of the strength of the study results, let's start with that. Any areas of concern about the strength of the data that you're showing here.

If you want, I can start. So you asked another question about what are the positive issue regarding the data from this study? So first of all, the main endpoint of the 3 was positive based on the advertises so far based on the combination of masitinib and docetaxel. So you've seen that there even though we have a lot of negative study, especially past 3 trials, seem that in this study, based on the design, which looks at patients with low tumor burden or lower, I would say, low volume of metastatic disease or operation with low-risk disease, I would say. It seemed that the combination seems to be active, specifically regarding those patients. So -- and it has been shown regarding the data looking at phosphatase alkaline or ALP, of less than 250. And if you see based on the data regarding the APL (sic) [ ALP ] of less than 250 or 200 or 150 or 100 and so on you have an increased efficacy regarding the primary endpoint, which is composite PFS. So it seems that it's quite logical to have this data according to the -- again, the hypothesis, which look at that and try not to go for a study just to compare 2 drugs compared to 1 drug and taking into account all the patients based on high volume, low volume, high-volume disease and so on and so on. So it seems that based on the fact that masitinib is a immune checkpoint, I would say, a kind of re-initiating the tumor based on the immune system. It may promote the disparition of bad macrophages moving from macrophages type 2 to type 1 and maybe to restimulate the immune system in combination with docetaxel.

I think if I may add, one of the strong points of the study is that in both arms and active drug was used docetaxel, which is indicated for this patient cohort. Addition of masitinib gave these results and as it looks like, low volume metastatic CRPC. One of the things that we have to take into account, if I recall it very well, is that conventional imaging was used in the study. So bone scan and MRI and/or MRI. And nowadays, I think we would use [indiscernible] test scan to better determine the volume of the disease. Please correct me if I'm wrong, if other imaging was used there.

No, they were. Yes, both.

Also PH and AFS?

Bone scan and MRI were used.

Yes. So that's underestimate, so I think, the metastatic extent compared to nowadays imaging. So that has to be taken into account if we interpret the data. One other thing is, we talk back to Slide 18, please. If -- can we see Slide 18. What is interesting for me is, if you look to the 2 curves, the splitting of the curve starts at month 4, month 4 or something. And it would be interesting to know what is the difference between these patients at that time. So that's that is what would interest me at least? Or do you have an explanation for that?

Okay. I -- yes, maybe the -- I completely agree. Maybe the fact that the curve begins to split that for 4 months is that we need maybe some time to reinitiate the immune system based on the masitinib activity. And we're looking at the curve, there is no plateau at the end. But the difference is still there with the p-value of 0.02. We had an increased rate of 21% of delaying in PFS with the combination. So yes.

But for me, it would be interesting to see if there are different characteristics between the patients that respond and do not respond.

Yes. I completely agree. Yes.

After month 4.

Yes, I agree.

Because, of course, this is an active drug combination as it turned out from the well-designed study. But still you treat a lot of patients that do not benefit from the combination treatment that we have to find for markers and perhaps, immunological markers based on at whatever test we can do to identify those specialists who will have the highest chance to benefit from the combination treatment.

Yes. More data, of course, will come in subsequent presentations and hopefully, use presentations. And so this is the primary analyses, of course, and there are additional data, different cuts of alkaline phosphatase where the curves are better differentiated, if you lower the cost of alkaline phosphatase. So I would say, okay, to answer your questions, the data on what they are. And again, keep in mind that no drug in combination with docetaxel could prove an benefit in [ OS ] or PFS. Here, at least we have some activity and benefit. But whether we should reduce the level of alkaline phosphatase is one questions for masitinib, definitely. But alkaline phosphatase is an easy biomarker. That's the good news. It's not something which is complex. It's something which is a biomarker easy to do and validate it.

Maybe I can make a comment. Olivier, this one. Is it okay? Can you hear me?

Yes. Yes. Olivier go ahead.

Okay. So I think what we do see is the clinical response is in line with what we have seen in mice model. Is that earlier is the better because the drug is not intend to block the cell proliferation is the intend to modify the microenvironment. And probably, when you have a high level of alkaline phosphatase, many [indiscernible] the sign of bone metastasis. And we know that in bone, the microenvironment is less accessible, I should say, to immune response. So maybe it might lead you to some -- more you have a bone evolvement, less the drug would be efficient. Probably, it's one of the hypotheses. And as we said before, earlier, might be the better too.

I think that's -- one interesting things would be to look at the bone targeted therapy as well, such as Telefónica acid or denosumab to see this proportion of patient rule. We had there this bond targeted to roughly because maybe it's a synergies sticky with masitinib with docetaxel. So we need to know, as Olivier said that what is going on at the [ we call it a 1-month ] at the bone level. And bone targeted therapy play a role in maybe promoting and/or inducing the immune system and maybe by delaying disease progression. So...

But I expect [ Stefan ] that the number of patients [indiscernible] had bone targeted therapy in this study or not.

I don't know if you look at the study from the UFCC from the [indiscernible] it was surprised to see that most of the clinician, in fact, I would say, 1/4 forget to give to the patient bone targeted therapy, even though it was required by the clinical try, looking at the study with [indiscernible]. So we need to be sure that the clinician do not forget to use this combination. Meanwhile, yes.

Because according to the guidelines in mCRPC, we usually give bone targeting.

That's true, yes.

But it would be interesting to look at that in the -- another thing is did you do some -- perhaps, I think you do it yet, but some subgroup analysis, patients with [indiscernible] disease who have a much worse prognosis and look at the outcome of these patients.

Yes, it's a very good point. I think that you should look at those patients who have [indiscernible] without alkaline phosphatase relation. You see, if you have a huge number of patients with visceral met because we know that for those patients, they have a very aggressive disease. And as you said, as alkaline phosphatase is very easy and cheap to perform just about test that everybody can perform in daily practice. So it will be interesting if you have a good correlation between low alkaline phosphatase and the percentage of visceral Mets.

Thank you. Maybe we'll take another question.

Yes, so questions on the chat.

Yes, we have no more question over the phone.

By writing -- first question we had in writing regarding the patent. Why is there a need to find for patents related to this study when it was already in Phase IIb/III.

Because -- this is Alain Moussy answering. So because these data have generated some [indiscernible] that fits -- that are eligible for a patent. And if we had not been able to do that, then we would be in danger in case we need additional studies to register, for instance. So we are happy to report that according to our patent lawyers, this patent that we have just filed, there is all chance to be granted. And we cannot reveal, of course, everything, but we have formed more than one thing in this study that could be patented and is now time for the company to do anything which agencies would request for registration. So that strengthens our IP portfolio.

We have another question. When is masitinib expected to be approved in the U.S. for prostate cancer?

Well, it's a tough -- and maybe too early question because we have not talked to any agency about this data that we're confidential just before the web call. So these are just, I would say, topline data, first of all. As you have seen, the expert themselves with whom we share more than what you can see, but not everything require more data just to analyze the study carefully. So we need to go into more details. We need to do [ in Costa ] report, then we need to talk to the agencies. And the agencies -- of course, we will -- I can confirm that we will, and then we will report. What's next. So is it possible to register with this data, we don't know? Is new study necessary, we don't know. But we will report when we have the information coming from an FDA and EMA.

This brings me to another question. The study was performed in 16 countries, 1-6 countries, I thought.

Yes, absolutely.

And did you discriminate Eastern, Western countries, an outcome of data?

We don't show data here, of course, but we measure the impact of countries, the impact of centers, even. But it was a stratification factor in this study. So thanks to the stratification factor, the impact of the region versus another one would be balanced. That's what we expect.

We have another question regarding the statistics. So could you kindly reexplain the statistical analyses and allocation of alfa value for the trial.

Yes. Laurent, you can put us on the slide, which is Slide 14. So as you can see, the test starts by testing the targeted subgroup at 4% level then we have 2 outcome, positive or negative. If positive, then you test the overall population, adding back the one person left, which means you test the role at 5 persons. And if negative, then you have only 1 person in the overall population left. It's called fallback design. And then you have to integrate the interim analyses impact. But all in all, the test starts at 3.9% in the targeted subgroup and we're below the 3.9%. So exclusive. And by the way, when you think about the -- what happened in this study, the interim analyses said continuing the targeted subgroup and do not recruit in the anti-targeted subgroup, which was reasonable. And they proposed a resampling, the IDMC, which is reasonable because the p-value is below the target, but not by far. So to minimize risk, I would say, to be in line with the calculation of the protocol, the IDMC logically recommended with something. So we think they really properly well-managed and gave a sound recommendation, and they did their job very nicely for this study.

We have one additional question. Is it possible to register based on this subgroup?

Again, and I will leave it to the expert after. In these questions, I see 2 different questions. First, the validity of the subgroup; and second, the strength of the data, as Kay said. For the strength of the data, I give it to the experts, and I give it to the agencies. But for the validity of the subgroup, we already asked the questions to EMA, long -- well, a couple of years ago long, in some interactions with EMA, and they validated the subgroup. So reglementary wise, the subgroup and the design, the fallback design is valid. Now is this study enough that is a good fair question that everybody will ask, given -- and me, I will not give you my opinion, but I will leave it to the experts, if they want to comment.

I can give my thoughts about that. I think that it's a kind of a study looking at asymptomatic and symptomatic patients based on the fact that if you look at alkaline phosphatase, if you have a high level, you may have some pain on both metastasis leading to complication. And if you are asymptomatic, you may have alkaline phosphatase, which is quite low. We should maybe look at that because you have all the data regarding the patient ECOG performance that you sent and pain and so on reported so far. So we will see in the different study based on [indiscernible] natural chemotherapy the Phase III trial were either addressed to patients with asymptomatic or symptomatic disease. And we know that based on that, the progression of the disease is completely different based on either progression, which is based on PSA progression or progression which is based on hydro lethal progression or progression, which is based on clinical progression with pain and so on. So -- and of course, the outcome will be different in terms of overall survival. So I think that now more and more, we try to look at volume of the disease, tumor load, and so on, and so on. But maybe this has an impact, especially regarding drugs, which have an impact on the [indiscernible] hormone. So it's a kind of first study looking at chemo with drug, which involved the [ equipment ] system and try to modify it at the end. So I need to see the data need to be, of course, our validation and so on and present to the NDA and to see what is going on. But I think that the hypothesis is interesting to look at the patient with low volume disease. And as you know, there are some drugs which are validated is high-volume disease, but not with low volume disease and so on. And it is new in prostate cancer, and that's why maybe it's interesting to look at the specific patient population. I don't know specifically the frequency of those patients with alkaline phosphatase of less than 250. Is it 20%, 40%, 60%, I don't know? So this needs to be evaluated by ambitions and to see according to country, what is the percentage of patients, who could benefit from this combination.

If I -- what is very positive in the study that the side effect profile of the drug seems to be very, very low. You show that there was no difference in the 2 groups. But I think it's important there are specific side effects induced by masitinib. And if they are present, yes or no. And the severity, of course. And the other thing that I think is very, very important is since it is study of this treatment that you do have to report on the patients reported outcome measures. And so what is -- what do the patients report about the treatment is a difference in quality of life between the 2 treatment times because this -- that is what the patient is benefiting from. And if he has a PSA rise and no complaints that something different than the PSA rises and complaints and all different aspects of that. So I think this is very important to take into account by presenting the data.

Yes. More data will come. We can immediately say, of course, that the benefit does not come on the expense of worsening of quality of life or worsening of complaints from the patients. So -- which is the good news. I would like to add one thing. In the efforts of registering a drug in prostate cancer, the other drugs or monotherapy or PARP inhibitor, they used to do 2 clinical studies, not 1. So that gives maybe some point of reference for masitinib. And the -- I would say, value of this study is that there is something that clearly shows activity of masitinib that you take it from the radiographic progression or the PFS, which is more complex. The PFS -- sorry, the alkaline phosphatase level, the logic of the alkaline phosphatase. So there is something, and certainly enough to do in -- if needed, in a later -- next, I would say, study. Something that will be more, I would say, striking to be in line with the expectations of everybody. So -- but there is something clearly because there is a logic of those results, the earlier, the better. The level of [indiscernible] et cetera. So that's the news for the sponsor coming to us that we see in this study. And then we need to discuss what's next. We are not magicians, and we understand the complexity of registration. But here, we see something. Masitinib does not increase the toxicity to a level where the benefit we see is contradicted by the additional toxicity. That's one thing. There is something and enough, at least to try to build the case for possible registration. Even if we need the study and that the agencies will tell us. There is one question. So verbally, maybe from some of the participants?

Yes. We have now a question again from [indiscernible]

Alain, you had the one slide where you showed the benefits of PFS cut by the different levels of ALP?

Yes.

And -- yes. And doing this subgroup analysis, did you also observe any benefits to overall survival for these patients with the lower ALP?

That's a good question, yes.

Yes. We do not report in this presentation. So you have to wait for publications/conferences. So I invite you to continue to follow that. We cannot give everything now. Obviously, we give the topline, but it's a fair question, of course. I tell you, a case. In fact, a trend of survival would be enough, okay? If you have PFS statistically significant, the trend of survival, probably, it would convince an agency, right? But I'm not the agency, so we have to ask them.

We have no more questions over the phone.

Okay. We use our time to address your question. Thank you to have attended this web conference about masitinib. For the record that the last clinical study is Phase IIb/III, I would say, where we're expecting the data. So this cycle, that's the end of the cycle, so to speak. And now we have to focus on the confirmatory studies in the program of masitinib. As you know, in neurology, where we developed it in innate in Alzheimer disease in the progressive forms of MS inflammatory where we develop it in mastocytosis, [indiscernible]. And oncology, where we have 2 indications, this prostate metastatic cancer, and also pancreatic cancer. For the record, in pancreatic cancer, the product masitinib increased survival and also PFS statistically significantly. In the population, which was locally advanced, but not metastatic, which means that masitinib in oncology is best as early as possible, even not metastatic would be even better. So in prostate cancer, nonmetastatic or early metastasis like hormono-therapy is available of metastatic also sometimes. But earlier than when they become eligible to docetaxel is another positioning that could be interesting for this product, although it's not the design that we have followed here. So let's see what we can do with masitinib in prostate cancer. But I would say, the strategy to target macrophage and mast cells in some cancers, as difficult as this one or even pancreatic cancer, can do something, can do something. So we'll continue the discussion with the agencies in those 2 cancers. Thank you very much for your listening, and thank you, everybody.

Thank you. Good evening.

Have a good day. Bye-bye.

Thank you. Good evening.

Ladies and gentlemen, this concludes the web conference. Thank you all for your participation. You may now disconnect.