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

Ladies and gentlemen, welcome to the AB Science web conference. I will now hand over to Alain Moussy, Christian Fassotte, Peter De Veene and Olivier Hermine. Gentlemen, please go ahead.

Good evening, good afternoon and good morning. My name is Alain Moussy. I'm the CEO and Cofounder of AB Science, and I welcome you to our web call that will give some explanation about the voluntary hold in the clinical studies of masitinib. I'll let you read the disclaimer and I will explain you how this presentation will be structured. The medical and safety team of AB Science will present these explanations and give you more information about this voluntary hold. And also walk you through what we received in terms of questions, which are the most frequently asked questions. And at the end, we will also let you, the possibility, to add some questions, some more questions if we have missed some. So with me, Dr. Christian Fassotte, the Chief Medical Officer; Dr. Peter De Veene, Global Safety and Pharmacovigilance Director; and Professor Olivier Hermine, the Chairman of the AB Science Committee. I will let them introduce themselves and then walk you through this presentation. Christian?

Yes, good evening. My name is Christian Fassotte. I am indeed, the AB Science Chief Medical Officer. I'm a physician with a specialization in pharmaceutical medicine. I spent more than 33 years in the pharmaceutical industry, mainly in medical and regulatory affairs and R&D in groups such as Roche, where I spent 9 years and more recently, Sanofi, where I spent 20 years, among which as Regional Chief Medical Officer and member of the R&D Board.

Good afternoon. My name is Peter De Veene, and I'm also a medical doctor. I've got a little bit more than 20-year experience in total, of which, 18 years in pharmacovigilance and drug safety, including roles in Alexion Pharmaceuticals, Grünenthal, Daiichi Sankyo, and 10 years in Roche Pharmaceuticals.

Olivier? Can you introduce yourself?

My name is Olivier Hermine. I am a professor of Hematology at the University of Paris, Head of the Department of Hematology in Necker Hospital. I'm leading research laboratory on physiopathology and treatment of hematological malignancies. And I cofounded and I'm a coordinator of the National Reference Center of Mastocytosis and Mast Cell Disease. And I'm a co-founder of AB Science and Chairman of the AB Science Scientific Committee.

Christian?

Okay. So next slide, please. No, yes this one. So to start with, I would like to say that as part of its mission, AB Science is strongly focused on improving patient's life. And therefore, we believe especially as medics, that AB Science has taken the right decision to voluntarily put a temporary hold on recruitment and randomization in the ongoing studies. So that being said, let's go to the situation in order to set the scene for our presentation and further Q&A. So the safety data that we are talking about have, of course, being shared transparently and consistently with regulators and investigators. Starting, of course, with the so called investigator brochure, which includes a lot of data, but also already some comprehensive data on the potential risk of cardiovascular events as a whole. In addition, some mitigation measure, precautionary measures are implemented in all protocols to mitigate the potential risk. And up to recently, we weren't able to evidence any additional facts or evidences that have emerged to corroborate this potential risk. So what happened is that after the unblinding of the latest Phase IIb/III studies with masitinib, which in the whole represents a high number of patients. We also run multiple safety analysis as a continuous, let's say, standard effort to detect pharmacovigilance and safety signals. And in one of the analysis, when we pooled a subset of some of these studies together with a subset of some of the patient population, we have noticed an imbalance of events of so-called ischemic heart disease or IHD. So ischemic heart disease is basically, as you know, the term given to heart problems caused by narrowed heart arteries and reduced blood and oxygen, which is called ischemia. Ischemic heart disease is also called coronary heart disease or coronary artery disease and can cause chest pain and discomfort and can lead to, in some cases, heart attack. The main cause of arteriosclerosis -- by the way, it's known to be arteriosclerosis. And so this IHD were seen in imbalance between masitinib and the control arm, which might be interpreted, of course, as a signal of increased risk of IHD. As a consequence of this signal, the company consulted with external experts and decided to perform a meta-analysis on all the available data, so not only on the subset of those studies, but all data from control and blinded study data. So based on these current results that are available to us today, no evidence of an increased risk of cardiovascular events, including the ischemic heart disease in question is observed, which, by the way, lowers the probability that there is a risk behind this signal. These results were shared, obviously, as well with national competent authorities worldwide and the French competent authority, ANSM, requested some additional analysis and data. So out of precaution and because, as I said previously, patient safety is our priority and because the latest analysis provided did not allow the agency to draw definitive conclusions, we have decided that AB Science to hold inclusions in ongoing studies, pending completion of these investigations. So as a company, AB Science believes that it has made the right decision for the patient and is ready to resume enrollment, of course, once the remaining investigation of this risk is completed. Next?

Yes. Thank you very much, Christian. So I'm Peter De Veene. I'm the Head of Safety at AB Science. And I will take you through a few slides that are a little bit more technical in terms of signal detection and the activities that we performed to date. So that's why I think it is important to put up a slide on definitions really to set the scene because we talk about signal, we talk about potential risk, we talk about risk. And just to make sure that we have the same language. So a signal, as defined by WHO, is essentially a hypothesis over risk with a medicine. So we have some data that showed something, but we need to investigate this further. This can be based on quantitative methods. So we did a statistical analysis, which, in case -- in this case, we did, and it showed an imbalance in some of those studies. And it can also be based upon qualitative methods where you apply medical judgment or you review events that come in. In conclusion and evidence -- in conclusion, the evidence around the signal is not conclusive. It is -- there is a lot of uncertainty around it. So it is an early indication, but we need to investigate, right? So that's the signal, and that's what we're talking about today. A potential risk and that's what we have with masitinib and the -- already identified earlier, we have a potential risk of cardiovascular events because we have the cloud effect of the TKIs as well as signal in one nonclinical study. And therefore, we have already, as Christian mentioned, implemented some risk mitigation measures in our protocols. So that's the terminology. Signal is something that we need to investigate a potential risk. Again, there is uncertainty and has not been identified as a true risk with the product. Next slide. So what has happened so far? As already was alluded, we perform -- once we unblind data from studies and in this case, there were a number of studies that were unblinded, we performed as part of our pharmacovigilance activities, drug safety activities. We performed analysis on those data to see if there is a signal that we need to investigate further. And we do that in an improved manner. So we put all the data together. And preferably, of course, we do that on the unblinded data to make sure that we know as it was masitinib or placebo. In one of those exploratory analyses, we found this imbalance of events of ischemic heart disease between masitinib and the control arm. So I've said it before, this is a signal, not a risk, but a hypothesis. Based on that, the AB Science conducted a large meta-analysis based on relative risk calculation. And based on the methodology, which is published under the Cochrane Library. So really the golden standard according to experts. And based on that analysis, there is no evidence of an increased risk of cardiovascular events, including ischemic heart disease. Now we did communicate this also to the ANSM, the French competent authority and other competent authorities. And the French authority came back to us and said that they could not draw a definitive conclusion yet and requested additional data and analysis. Based on that feedback, AB Science took the action to voluntarily hold the inclusion of -- pending the investigation. So we suspended inclusion of new patients and also do not initiate treatment for patients already randomized. So that's where we stand today. And if we go to the next slide, this is what we expect to happen. So we will provide the ANSM requested data analysis. We will do that within the shortest possible time frame. The reason why they requested those data is because the authorities usually never rely on sponsors analysis and also always request raw data to perform their own assessment. And it typically includes quantitative data, so such as additional analysis that -- statistical analysis that we perform and also qualitative data, which is listing, narratives, release data that they can look at and read and make a judgment on the data. So they will receive the data in the shortest possible time frame that we can do. They will assess the data. And there are 3 basic outcomes of that assessment. Either the signal is ruled out, so there is no signal, and then we continue as is. The signal -- there may be a signal, right? But it's not confirmed. And then we may need to do additional activities to gather more data or to do additional risk mitigation activities or the signal becomes a true signal and then it becomes an identified risk. And again, then we are in a position to see if additional risk mitigation measures are appropriate. So we will, based on the outcome of the ANSM or the French authority's assessment, we will do an impact assessment for each study. And it can be that different risk mitigation measures can be adopted depending on the evidence that we have for the respective study. Next one? And I just want to -- this is a graphical slide showing a little bit of the landscape of risk mitigation. You can have the signal ruled out, there's no impact. You can have the signal identified as a risk. And then there are a number of options there. You stop one or more indications or study or you adopt a risk management plan. And as a company, AB Science already has adopted a risk management plan for the potential risk of cardiovascular events, including information to patients and investigators through the informed consent and the investigators brochure. We also reduced the risk by having some additional inclusion criteria, so we restrict the inclusion to protect patients potentially at risk. And we also monitor the patients while they are in the study. So this is a basic package that we already applied to the clinical program of masitinib. It is possible depending on the French authorities evaluation that we need to do some additional activity. Study monitoring happened throughout the clinical development program of masitinib and covers 2 aspects. For each indication study we have DSMBs, drug safety monitoring boards. And they come together frequently to -- and we provide them unblinded data to allow them to make a risk assessment. And we will also have a major adverse cardiac event expert committee that will review blinded data on ongoing studies to gather more information about the signal. So that gives a framework that we can work on. And I hand it over back to Christian.

Okay. Olivier Hermine on the phone. So we would like to explain why we are so cautious on the cardiovascular toxicity with kinase inhibitors. Because we know that most of the kinase inhibitors which are registered and used in clinical studies and in patients now exhibit some cardio toxicities. And because we know that some kinases are critical for functions, for vasculature functions. And by blocking these kinases may induce some kind of cardio toxicity, like blocking of the EGF receptors may lead in some cases to cardiac insufficiency by blocking Abelson, which is a kinase, which is critical for the heart function and stability, may lead also when it is inhibited in some cardiovascular disease blocking some EGF receptor or MAp kinase pathway [indiscernible] may lead to some cardiotoxicity. So overall, most of the kinases may induce some cardiovascular disease and cardiovascular dysfunction. However, when we look at the profile of masitinib, none of the kinases, which are critical for heart function, are inhibited by masitinib. So we know that if we use very high dose in mouse model, we have shown a little bit of cardiotoxicity, but at dose which is far above what we use in human patients. And at the dose we use, we do not block kinases, which are known to be -- to have an effect on the cardiovascular system. So based on what we have seen in vitro and in mice model, we believe that masitinib should not exhibit a high profile of cardiovascular toxicity when you compare to other kinase inhibitors, which are already in the market.

Thank you. Christian, Peter and Olivier for these explanations. Now we move to the second part of this presentation, which is to answer, the most frequently asked questions that we have received, and we thank everybody who send us to prepare this session.

First question, Christian?

No, I think this is for -- you skipped one slide Alain, previous slide, please. Yes. So yes, I will take this one. So what happens for the patients under treatment? Yes, there are indeed some patients who already received masitinib in the ongoing indications. So patients already under treatment at the time of this decision can stay in the study at the investigator decision and providing that positive inhibitor with benefit risk is documented. And the request for this risk-benefit assessment has been approved by the French agency pending, of course, the completion of ongoing investigations. Next? So I think for Peter.

Yes. So I'll take this one. So is this potential risk new? As we already stated, the potential risk of cardiovascular events is not new. But cardiotoxicity is an identified risk with certain TKIs, which was already mentioned by Olivier. So that, together with a potential or a signal in the -- in one nonclinical study, we had identified cardiovascular events as a potential risk at the beginning already of the clinical development program of masitinib. And as already stated, this potential risk is described in the investigator brochure and then full consent for the patient. So in terms of information to patients and investigators, we are -- have been very transparent. Now ischemic heart disease is a new signal that we have now detected and is currently not a potential or identified risk, and that needs to be investigated further. The next slide. So again, I will answer this one with this data reported from ischemic disease under masitinib. As Christian already mentioned, ischemic disease is a -- has categorizes a number of heart conditions, including atherosclerosis but also a myocardial infarction and, of course, can be fatal. So as consequence that I have from IHD has been reported both under masitinib and placebo. Some patients do present with comorbidities that can -- has a risk factor that can lead to ischemic heart disease and the course of disease itself and also when they enter a clinical study. So sometimes that can lead to major excess cardiac events. What we do on an ongoing basis is evaluate these events when they come in. We make an assessment. We make also an initial causality assessment. We analyze medical history. And we also look at other parameters to make an assessment whether or not there is a possibility that the drug is involved in this or other occurrences of the event. On the next slide. So the confiscation of the number of cases and the services of the cases, we already alluded to the fact that some patients died, either on masitinib or on the control arm across studies, but the number of cases and the differences -- are different between the masitinib and control. It varies between the studies. It also varies in terms of severity of seriousness. It can be grade 1, which is a term that is used to describe severity of events grade 1, and the lowest grade 5 is death. But it can be great bond such as chest pain or thorax pain that disappears after a while up to grade 5, which is death. And again, that has been seen in control as well as the masitinib treatment arm. The signal came to line because we build the number of studies in certain indications. I'll hand it back over to Christian.

Okay. Thank you. So I'll take the next one. So what additional analysis was requested by ANSM? Well, first of all, health authorities, including, of course, ANSM, usually do not solely rely on sponsons' analysis, of course, and request data to perform their own analysis and assessment before providing an expertise. And those data and analysis, typically include the whole data that we also use ourselves to generate the analysis, the listings. Some more qualitative data is described by Peter, which are, for instance, the narrative of the adverse events and some sensitivity analysis. So we are obviously cooperating in more transparency with all agencies, including ANSM, but not solely. And of course, we will timely provide the requested information so that ongoing investigations can be smoothly completed in parallel. We are also keeping on working. And of course, also keeping on consulting external experts to provide more insight on those points. Next? Okay, I'll take that one as well. When will we know the conclusion of the investigation of the potential risk? This is obviously a tricky question or a difficult one. And in order to be conservative, we do not provide forecast. Of course, we will communicate when investigations are completed. That being said, and as previously mentioned, we are working already in relationship with ANSM and some other agencies. And our current expectation is to be able to address rapidly the request from the French agency. And last but not least, I think that agencies like AB Science are clinically patient-driven and reactive on this topic. They know that there are patients, as we know that they are patients behind. And there is high unmet medical need in most of these indications. Okay. Next? Okay. So given the nature of this potential risk, does it modify or prevent the benefit risk in nononcology indications to be positive? So first, to say, of course, that we don't have the position of the agency to know if this senior role is confirmed as a potential risk or not and what is the magnitude of this signal. Second point is that there is, of course, a clear expected benefit in each of the indications pursued. We will cover them later due to the positive results generated by our clinical program, Phase IIb/III results, and also for COVID 19, based on expected mechanism of action. So we are 1 stage behind in COVID with Phase II trials versus Phase III in the others. Therefore, if this potential risk is materialized, an assessment will be done indication by indication. And they are very different. Moreover, the risk mitigation can also be specifically adapted indication by indication. Next? So safety was the strength of masitinib, that in the program jeopardized. Perhaps we could use the present time instead of the past in the statement because the expected benefits are unchanged today and still present. So I mentioned previously, the positive results of Phase IIb/III studies. So what is at stake today is not the benefit, but to determine if there is some increased risk and how to protect the patients in face of this eventual increased risk, including risk management measures such as exclusion criteria and guiding with preventative measures during the studies, which we already have as part of the risk mitigation measures as detailed already by Peter. Next one? What is the probability that the studies do not restart? So there will be, as I just said, probably a specific decision for each study. So it will be a case-by-case and indication-by-indication approach. The decision to restart each study will depend, obviously, on the conclusion of the investigation of this risk, but also on the risk benefit ratio that will have to be analyzed based on these conclusions and eventually a new setting. Separately, as I said, for each of the current but also for the future development programs, meaning the Phase III [ dose study ]. So this benefit/risk analysis takes into account presence or not open of a new risk. The risk management plan that we have in place and can be expanded, the medical need and the benefit based on the existing generated results. Next one. Peter?

Yes. So I'll take this one, why you did not see this potential risk in previous studies. And I think we already answered the question, but I think it is important to understand that when you run a study, you -- before the study starts, you predefine some analysis that you want to do to look at safety data from that study. For each of these studies, separately, those predefined analysis were performed and did not identify a signal. But due to the fact that a number of those Phase IIb/III studies were unblinded, a large number of patients and data of those patients became available. And so it was decided to do some exploratory analysis where data was pooled but also to look at some subsets of studies and patients. And one of such analysis, the -- and the subset of studies and subset of patients, this signal was seen of increased risk of IHD, which we're now exploring. We did a bigger meta-analysis on historical data and the new data to look at all cardiovascular events and also including IHD and other elements of cardiovascular events, and we could not confirm the signal at this time. Next slide. So this potential risk comes from the ongoing study. So we currently have ongoing studies in ALS, mastocytosis and COVID-19. And just to confirm that the signal did not come from these 3 studies. It did come from this retrospective analysis of completed controlled unblinded study. All right. Next one. Christian?

Yes. So I'm not sure about which precautionary measures we are talking about because they are twofold. Obviously, there are already precautionary measures taken, as we mentioned, specific dilutions in the protocol to address cardiotoxicity as a whole. Now I guess the question is addressing the decision -- voluntary decision to hold the ongoing trial. So on that one, the opinion of AB Science based on the current analysis and, of course, on expert opinion that were considered is that masitinib does not seem to have a clear liability in terms of cardiac safety probably from most of the reasons that have been described by my colleagues. But yes, ANSM requested additional data and analysis. We concluded that some level of uncertainty remain and therefore took the decision. Next one.

Okay. I'll take this one. Yes. And it comes back to a little bit why we are seeing this now and not in the past. The cardiovascular event has been a potential risk and the start of the clinical development of masitinib. And [ historically ], at least on a yearly basis, if not more frequently, the -- all the available data have been screened and analyzed for cardiovascular events for all studies in the past. [ Applied ] cardiovascular events included ischemic heart disease have occurred in masitinib clinical studies, and though data have been analyzed, but no confirmed risk have been identified. So again, this potential risk or signal -- this potential signal comes off the unblinding of the large number of patients that were added to the safety database. Okay. Next one.

Okay. I'll take that one. So does the situation affect the data of the past -- previous studies? The reply is no, the efficacy and safety data of completed studies and results from those study remain unchanged, of course. The benefit/risk of masitinib will be and will need to be reassessed in each indication if the signal is confirmed and depending, of course, on its magnitude. So it will be, again, as I said, a case-by-case, indication-by-indication review and assessment. Next. So I'll take that one as well. Suspension of inclusion or discontinuation of patient will be delayed by how much the program. First, I have to correct a little bit because the patients are not discontinued if they are already treated, as I previously said, pending the documentation by the investigators of the benefit/risk ratio. So what is on hold are the new inclusions to the studies or the randomization and the treatment of already screened patients. And we expect that the development program will be extended by the duration between the hold and the restart of each of the programs. Next one. So what is the position of other agencies apart from ANSM? I have to say, because we shared all analysis with them the same way we did with ANSM, and so far, we did not receive specific remarks of [indiscernible]. So we cannot comment at this stage. All right. Next one. Okay. So I think we have covered most of the frequently asked questions. So it will be one of the concluding slides. Just to remind the audience about what is at stake in terms of masitinib portfolio, it's a portfolio which is major. As you understood, most of the studies have generated results in Phase IIb/III except COVID, and some of them are already in confirmatory pivotal Phase III trial. This is the case of ALS and also mastocytosis. I think what is important is the high unmet medical needs. A couple of examples. Perhaps ALS is obviously a deadly short-term disease, [ actual term ] disease, as I said. So in progressive form of multiple sclerosis, there are very little alternatives and treatment possibilities. Pancreatic cancer and metastatic prostate cancer do not offer -- or need all the therapeutic options. So they are really -- we are already developing masitinib in indications and platforms of indications, neurology, inflammatory diseases, oncology and viral disease where the unmet medical need is high, meaning potentially, the benefit of the compound is also high. And perhaps Olivier, I guess, would like to comment on this and on this statement.

Thank you. Thank you, Christian. Yes, we -- as you can see, we -- AB Science is devoted to treat patients with real unmet medical needs for most indications. And first, I think it's very important to see that most of this indications trigger the senses, which is the mast cells, which explains why it seems so diverse. But all of them have in common [ this opportunity ]. The second thing, which is very important, is that all this indications have high unmet medical needs in which the mobility or the mortality of the disease is quite high. And the thing that we have detected in the -- potentially detected in ischemic heart disease is it must be put in balance with the benefit of masitinib. And we will assess indication -- the indication -- the benefit/risk of masitinib in all these indications.

Thank you, gentlemen, for this technical but useful explanation for our shareholders and potential investors. So I'll try to summarize in plain English to try to simplify. We have detected a potential signal in one analysis. There have been other analysis using other methodology. They do not confirm the initial potential signal. We discussed with the agencies in the world, but the ANSM agency told us that the [ dock ] remains. So there is -- we are not sure. And because we are not sure, we decided voluntarily to protect the patients and stop and pause the recruitment. To simplify, to pause the recruitment. Our press release should not be interpreted as a -- the fact that we abandon the program or discontinue any indications. We, of course, continue, but we protect the patients. Protecting the patients is the #1 rule in the industry. When such problem happens, we take it very seriously, and we do not hesitate. If you were the patients, you would appreciate. You are the investors or potential investors, more difficult to understand, of course. But it's the way it should be. We are -- those rules are extremely important. If we break those rules, we are not professional in this industry. So our expectation, of course, is that through collaboration with the agencies in the world, we will hopefully restart. We'll do it with all precautions, but we do believe that management -- and you have listened to the medical and safety team on the data that, of course, it's our intention but in collaboration with the agencies, of course. Now that we have told you our messages, maybe we can take additional questions. We covered lots of your concerns, but still there might remain some. I will take the first question that we received. Please do not hesitate to send your questions that remain on the platform. First question, each drug [ 3 years ] minor adverse events, especially the case for TKIs like nilotinib or ibrutinib. So is it surprising for you if medicines could trigger some cardiac events? Maybe, Olivier?

Okay. So as you mentioned, ibrutinib, which block, BTK and ITK and probably some other kinase, is associated to the high risk of 20% developing high blood pressure and arrhythmia, which is expected. And as you know also, some other drugs [indiscernible] are associated to cardiovascular disease, also ibrutinib to [indiscernible] stenosis. For masitinib because -- as I mentioned before, we do not see the inhibition of these kinases, which are more specific to the cardiac toxicity. So we do not expect to see [indiscernible] toxicity. However, as I said before, depending on the dose and maybe on some of target or low inhibition of some kinases, so we may expect to see some cardiac toxicity. Also, we know that most of the kinases may compete with some channel in the cardiac function, but we didn't see any signal for masitinib. So as I said before, the class of TKI are expected to see cardiovascular toxicity. Most of them exhibit some. And actually, it's interesting to see -- Peter has shown that masitinib is associated to the lower risk of developing cardiovascular disease. But we have seen that. We have to be focused very carefully to be sure what's going on.

Thank you, Olivier. Second question, when will you have certainty on the safety of masitinib? So maybe that's a question for Peter. When will you have certainty on the safety of masitinib?