Egetis Therapeutics AB (publ) (EGTX) Earnings Call Transcript & Summary

[Audio Gap] Please begin.

Thank you, operator. Good afternoon, and good morning to everyone. Welcome to PledPharma's investor and analyst call that will focus on an update regarding the press release issued earlier today concerning the clinical hold in the U.S. of the Phase III POLAR program. Before starting the call, I would like to refer you all to the standard forward-looking disclaimer that can be found in our general corporate presentation on our website. As introduced, I'm Nicklas Westerholm, the CEO of PledPharma. And with me today, I have Stefan Carlsson, Chief Medical Officer; Christian Sonesson, Vice President, Product Strategy and Development; and our Chief Financial Officer, Yilmaz Mahshid. During today's call, we will give you an overview of the situation at hand and leave ample time for question and answers at the end. First, let me begin with providing an overview of the global Phase III POLAR program for PledOx to put things into context. The POLAR program consists of 2 double-blind, randomized, placebo-controlled trials, POLAR-A and POLAR-M. POLAR-A is conducted in Europe and Asia in patients undergoing adjuvant chemotherapy treatment for colorectal cancer and was fully recruited in December 2019. POLAR-M is conducted in Europe, Asia and the U.S. in patients undergoing chemotherapy treatment for metastatic colorectal cancer and where the recruitment still is ongoing. Let me be clear, safety of patients in our clinical studies is paramount to us as a company. What that means for our patients in the POLAR program is that we have an independent drug safety monitoring board, a so-called DSMB, who conducts regular reviews of all available clinical data from our studies to ensure the safety of patients. The experts in our DSMB Committee represents the key fields of the relevance for the POLAR program, i.e., oncology, neurology and statistics. Today, we announced that the U.S. FDA has issued a clinical hold in the U.S. on the POLAR program for our lead candidate, PledOx. The implication is that recruitment and dosing of patients in the POLAR-M study is halted in the U.S. The decision by the FDA is due to safety reasons based on a few numbers of observed adverse events. The independent drug safety monitoring board, i.e., DSMB, for the POLAR program has reviewed exactly the same adverse events and information and has recommended that the POLAR studies can continue as planned without modification. Furthermore, to ensure the safety of the patients in our clinical trials, PledPharma has also conducted an extensive review of all available clinical and preclinical data. To date, in clinical studies, approximately 2,700 doses of calmangafodipir have been administrated in about 500 patients. In addition, the molecule of calmangafodipir has been commercially available and used in more than 240,000 patients where clinical data is also available. Our review of this data supports the continuation of the POLAR program. And as mentioned, our review is shared by the DSMB. Thus, both POLAR studies will continue to improve and dose patients as planned in Europe and Asia, allowing for additional data to be collected on the benefit-risk profile of PledOx. It is important to recognize that adverse events are very common in this fragile patient population we are studying PledOx with, i.e., patients with cancer that are ongoing treatment for the disease where key safety endpoints in our POLAR program are progression-free survival and overall survival. That said, the safety of patients in our clinical studies is our most important responsibility. As a drug development company, we will, therefore, of course, continue to work with the FDA to provide the necessary information to lift the clinical hold as soon as possible to allow the recruitment of U.S. patients in the POLAR-M study to continue. Other regulatory authorities involved in the POLAR program will be informed about the U.S. clinical hold. In essence, we are confident in the overall safety profile for PledOx, which supports the continuation of the POLAR program, and both studies will continue as planned in Europe and Asia. With that, we can now move into questions and answer. Operator, if you would, please.

[Operator Instructions] And so we go to the first question, which is from the line of Klas Palin of Redeye.

My first is just for clarification. The FDA decision, is this based on observation in the PledOx arms? And have there been any similar adverse events in the control arm? And my next is also about these adverse events. Have they surfaced just recently or have they been ongoing in the -- during the trial?

Thank you very much, Klas, and great questions. We can't comment in detail on the adverse events as such. As mentioned before, there are a few adverse events that has been the concern of the FDA and mentioned also before that the patients in our clinical studies is an incredibly important responsibility for us as a company, and hence, why the independent DSMB for the POLAR program had reviewed exactly the same adverse event as the FDA and had recommended that the POLAR studies can continue on plan in addition to us as a company as well. And I don't know if our Chief Medical Officer, Stefan, if you would like to comment further.

Thank you. Well, it is actually what Nick has said here. We cannot sort of comment further on the type of events and so on. And again, I think it's very important to state that we have the DSMB position and we share the DSMB position, which in conclusion then gives us the confidence in saying that we don't see any issues in the safety profile of PledOx.

Okay. Is this confidence also built upon the mechanism of action of PledOx?

Yes, yes. Of course. And I don't know if all of you on the call knows the history of calmangafodipir and PledOx where it actually initiated the first investigation of PledOx as a new chemical entity, what was in the cardiovascular space, for example. So we have been looking very broadly across both clinical data as well as preclinical data. And based on the mechanism of action, we don't see any issues in the safety profile as referred to by the FDA. Christian, do you mind commenting from your perspective as well?

Yes. Thank you, Nicklas. Yes. So in short, your question alludes to the mechanism of action of PledOx. Based on the observed adverse events and our investigation into all clinical data, we see no reason to believe that the adverse event observed is due to the mechanism of action on PledOx.

Our next question is from the line of Erik Hultgård at Carnegie.

I just have a few one, and I think they're sort of adding on to what we touched upon last. So can you just sort of also please highlight how common it is for DSMB and the FDA to differ so much in their opinion given the fact that the DSMB has given a clear decision? And just to what extent does FDA and DSMB differ in terms of how much data they could look into?

Okay. Thank you. I think I struggle to comment how usual it is that DSMB doesn't align with their view as the FDA. So I don't have any data supporting that. So I can't comment, I would say. So I think that's the first point. With regards to second point, Stefan, would you like to comment?

Sorry, can you repeat the second point, please?

Just regarding sort of how common that is, but maybe we could just move on sort of to the next question that I have. While looking at sort of the definition of FDA putting a full clinical hold, there must be some severity related to these adverse events. Is there any chance of FDA looking at sort of the overall survival or progression-free survival occurrence to see that those 2 divert, that that's sort of the reason for a clinical hold? Or is it related to something else?

So the answer then -- I'll let Stefan in a second. The simple answer is no. They are not privy to any data and trends around progression-free survival nor overall survival.

No. We should -- recall that this study is -- those studies are designed to look into the prevention of CIPN. We are using the overall survival and the progression-free survival as sort of a safety measures after we have followed for 12, 24 and 36 months. So at this stage, it cannot be the reason.

Nicklas, this is Christian. May I just add to the response there?

Please.

Yes. So Erik, you asked if there was any difference in how much they, so the FDA and the DSMB, have access to -- and I think it's important to note that the DSMB has access to all data points in the -- all safety data points in the POLAR program so that the DSMB has access to more data than what the FDA had. Secondly, the DSMB, in their review, have also the opportunity to split the data -- all data in the program between PledOx and placebo and build their view based on that. In that essence, also they have more information than the FDA has. Both of them have access to all relevant information from previous studies as well. So that, if anything, in terms of information, the DSMB has access to more information to build their opinion. Your second question related to the overall survival and progression-free survival. Again, I would like to point out that the DSMB has access to overall survival, progression-free survival in the -- both files. They have not indicated any difference between the treatment arms there.

So I think -- I hope that provides a clear answer to your question, Erik. And to build further on that when it comes to adverse events, FDA, in the same way as all other regulatory authorities involved in the POLAR program, have access to exactly the same information. And obviously, this is a decision based solely by the FDA rather than other regulatory authority.

Okay. That's great. So just one last question sort of regarding on timing here for the POLAR-M study. I mean, this might be hard for you to answer, but since you don't have received the letter yet. But could you just -- so your best guess on how much the POLAR-M study will be delayed? And just sort of walk us through the process of submitting a complete response letter and sort of the response time from the FDA.

Yes. So let me start with the delay question first, and I think it's important to put it into context. We have 2 studies, POLAR-A and POLAR-M. As you know, POLAR-A is fully recruited, which we announced in the middle of December. POLAR-M, that is conducted across Europe, Asia and U.S., are -- where we have recruitment ongoing, is what's in concern here. It's premature to speculate in potential delays as of now since we don't have received the formal letter from the FDA and fully recognize what the areas are to address. So which leads us into your second question, Erik, around, how does the process of clinical hold works. So you can summarize it, in essence, very shortly that we were notified through a telephone conference last night from the FDA that we are put on clinical hold in the U.S. FDA then have 30 days to provide its written formal explanation to the clinical hold. Once FDA issues its written explanation to the clinical hold, we can expect more detailed information about the cause and the information activities that needed to lift the same. A clinical hold can then subsequently be removed after we, as a sponsor, submit a complete response letter to the issue identified, and then FDA should respond in writing to our so-called response letter within 30 days. Having said that, though, based on the call yesterday with the FDA, we, of course, have a view on the issues at hand and the things we need to address. So we're not waiting for the formal written explanation to the clinical hold from the FDA, but rather work together with, for example, our external expert in DSMB to further assess the adverse events. I think that explained it, the process.

We now go to Pareto Securities and Johan Unnerus, please go ahead. Your line is now open.

Largely already addressed, actually. But to follow up then, especially on the last one, the -- in conclusion or the impression you get is that we're talking about a delay in sort of a positive scenario, at least 2.5 months, thereabout, depending on activities and so on. Is that reasonably correct?

Thank you, Johan, for good questions, fishing for a bit more information here. As you can imagine, I won't be able to speculate on if it's 1, 2 or 3 months, et cetera. What we believe in, we are -- we have a firm view and a good view on the issues at hand and what the FDA is expecting for us to provide additional information on. That will be -- and we start to work with that ASAP, of course, as you can imagine, in parallel with awaiting the formal response letter from the FDA. And of course, we do our utmost to submit a response to that. Again, the priority for the companies are very, very clear, it's finalizing the recruitment of the POLAR-A -- POLAR-M study, sorry, as well as solving the issue at hand with the FDA.

Yes. And we have 2 30 days period at least. Of course, it might take shorter, and then the work in the processing between. So yes, maybe 2, 3 months or at least or thereabout. And then more of a clarification, which is perhaps self-evident, but the term adverse event, the fact that it has been put on hold rules out the very, very mild adverse event, but there is nothing in that, that qualifies if it's very severe, moderate or whatever. It's just adverse event. Is that correct?

I would summarize it, as Christian mentioned before, that there is a handful -- a few adverse events that has raised the concern of the FDA. The data safety monitoring board have reviewed the unblinded data for these events at hand, of course, but also the overall study that they review regularly from a safety perspective. And in addition, out from our perspective, we have reviewed all the clinical data and preclinical data. And yet again, the conclusion that we are very confident with is that the safety profile of PledOx is good.

That's useful. And also because these observation are based not only on U.S. patients or centers, but also the others in this POLAR arm, is it possible to say anything about the likely number of patients that have been sort of advanced enough to form the base of this? Is it like 70 in 200 or more than 100? Or is it impossible to say anything? We know that it's a handful event, but is it out of 70, 100 or 150 or is it possible to say anything on that?

Maybe I don't fully understand your question, Johan, but let me try to answer, and then I'll let Christian build on this question and a previous question as well. So if you think about how many patients that has been randomized, as you said, you're absolutely right that all agencies are privy to adverse events no matter what country it is and no matter what region it is. So you can start with understanding of the POLAR-A is fully recruited. So there, we have 280 patients that have communicated that has been recruited into that study. And then, of course, we went through the recruitment of the POLAR-M study. So in total, there are quite a few patients that have started randomization. Then I can't to give you a number. I won't give you a number of how far they've gone in their randomization, et cetera. But that's a starting point, Johan. That's a fairly big sample size. Christian, do you want to elaborate further on this question as well as another question around the delay Johan asked?

Yes. Yes. I mean, again, coming back to the fact that Nick mentioned earlier in the call that this is, of course, such a fragile population that we are talking about in both the POLAR-M and POLAR-A studies. So you would expect a number of adverse events in this population to be relatively large compared to many other populations. So of course, what we observed in the study are many adverse events reported. So when we indicated there are a few that the FDA has put their lights on is -- it's of course on a few of many adverse events in [indiscernible] patients or many patients [indiscernible] So that gives you some perspective of what we're talking about. I also would like to just go back to the question you had before around the delay, and you mentioned a number of 2.5 months by just looking at the review process time line for the FDA. It's important to remember that recruitment is ongoing in Europe and Asia in POLAR. And so even if recruitment is halted in U.S., it does not mean that there are no new patients coming into the POLAR-M. So it's a little bit more complex picture than just looking at the review times of the FDA.

So we now go to the line of [ Magnus Pernier ] at [ Direct News. ]

I have a couple of questions. First, since you can't recruit patients in Europe and Asia, is there any possibilities that patients in Europe and Asia could replace patients that would have come into the study in U.S.? And I also would like to hear a little more about how far you have come in the recruitment. As Johan said, maybe you won't say so much more, but is it fair to say that you have a good share of American patients already in the POLAR-M study?

Yes. So let's start with the first question, which was around can you substitute patients if I use the terminology between the different regions. As I mentioned before, of course, we will continue to recruit patients in Europe and Asia. Again, one of the top priorities is to complete the recruitment. With that, Christian, do you want to further build on the position?

Yes. So if we are talking about our regulatory strategy already when designing this, and the POLAR study, the 2 studies, which only 1 of the 2 are -- is being conducted in the U.S. Of course, we rely on putting together a global submission package that contains these 2 studies and that we do already, initially in the design of the program, rely on using foreign base collected in the U.S. -- in EU patients and Asian patients when we file in the U.S. So in that sense, you're correct in assuming that we can, up to some extent, replace, so to speak, U.S. patients that we would have anticipated to recruit during this clinical hold with EU and Asian patients. And that was what I was trying to allude a little bit with Johan's question, before that recruitment is actually ongoing in Europe and Asia. And it's important to note that when you assess what type of delay we could -- we should be thinking about there.

And then to build on your second question, Magnus, if I got that, right, it was on the progress of recruitment in the POLAR-M study. As you can imagine, I won't give you the exact detailed amount of patients that has been recruited and randomized in the POLAR-M study. However, you might be able to calibrate that by us having the announcement as we had in December 2019, where we stated that the POLAR-A study was fully recruited, and we expect the POLAR-M study to complete recruitment back then in quarter 2 this year. Based on that, you can draw the conclusions that we're quite far down the road with regard to recruiting in POLAR-M as well.

And also, I came over an article here about clinical hold and the median duration of the time that they are on hold. And so a time line of 8 months. Is this fair to assume that a delay would be something around that? I know it's hard to answer, but...

No. I think that -- again, I won't comment on the time line. So I think when you read -- review article like that, you have, of course, everything from 1 month to 20, 24, 25 months. And it all depends on the issue at hand, what the issue are, how confident we are in reporting or responding to the issue at hand, and how fast we can do that. And as I mentioned before, I'll take yet another step back that we are comfortable with the safety profile of PledOx. The independent DSMB for the POLAR program have reviewed the same adverse events as the FDA and have recommended that the POLAR studies can continue as planned. So we believe that we will address this as soon as possible.

We now go to the line of Dan Akschuti at Pareto Securities.

Most of the stuff has been answered. I just have one or two follow-up questions, so regarding -- you mentioned now and also in the press release that both the FDA and the DSMB have reviewed the same information, but the FDA was blinded to -- so they couldn't actually see that these adverse events were happening in, let's say, the PledOx group and not in placebo. So they don't actually know in which group it has happened, but DSMB does, is that correct?

That's not so fully correct, actually. So Christian, do you mind elaborating on this?

Yes. So the FDA -- so the DSMB has access to all data that we collect in the study. The FDA has access through the standard reporting procedures of adverse events in clinical trials to such events that are being reported according to those rules. Then FDA may request information in terms of the treatment allocation for specific types of events. So it's not 100% correct to assume that all information that FDA would like to assess is blinded.

Okay. Another question would be regarding the potential type of events. Did you see there a grade 4 or even 5 events? And -- or were they maybe more unexpected or rare ones?

As mentioned before, and let me start answering the question, and I'll hand over to our Chief Medical Officer. As mentioned before, one should recognize that, of course, the PledOx study and the POLAR program is in a very sick patient population. You have a comment that you have adverse events across the board. And Stefan, do you mind commenting a bit further on that?

Yes. We should be aware of that. Again, what Nick says here is that it's a fragile patient population. They have cancer, perhaps these cells creates adverse events, and so also, thus the treatment of the base oxaliplatin chemotherapy that actually are having here in the study. So you can have a quite wide range of adverse events based on the disease, but also based on oxaliplatin treatment.

Thank you, Stefan. Christian, do you have anything to add to that question?

Yes. Just to circle back to what I answered previously in terms of -- I think it was Class 1 or Class 1st -- a couple of questions. Were these events unexpected? Yes. It's not any type of event that you would anticipate based on the mechanism of action of calmangafodipir.

[Operator Instructions] And [ Martin, ] we'll go over to you now.

I have a follow-up question here on what Stefan was riding on the fragility of the group. My impression has always been that the adjuvant group has been a harder group to get a Phase III study for, because you wouldn't accept that type of adverse events or that type of -- how should I say. It will not tolerate those kind of side effects, so to say. And that the metastatic group, they have longer progressed disease and they are more kind of -- excuse my cynical -- that's more terminal, so in saying that the acceptance of adverse event and side effect would be higher. And the fact now that you have recruited -- sorry, successfully recruited the adjuvant groups and now get hold on a metastatic groups, can it be something that the fragility of the nonhomogeneous group here, that they are more terminal are coming into these studies in a more, so to say, heterogenous status? And also elaborate on the acceptance of adverse events in an adjuvant segment compared to a metastatic segment? That's something I would like to elaborate on.

Thank you, and let us explore that further. I'll start off with maybe a general statement that has there, of course, been any concern prior to the start of the POLAR studies, both for POLAR-A and POLAR-M, we would not have started the studies as such. And of course, the regulatory authorities wouldn't approve them to start either. Stefan, do you mind elaborate more on the different patient populations?

Yes. But you should also sort of realize that what we also mentioned here is that the patients are actually on oxaliplatin, both the adjuvant patients and the metastatic patients. And it cannot be at all said that, that is not the reason for any adverse events. And that is why we're having the DSMB evaluation, for example.

And I think to reiterate that further, of course, that the metastatic patient population are sicker. Having said that, though, as Stefan mentioned, we have to be clear that the adjuvant patient population also are receiving chemotherapy. And of course, many of the adverse event drives -- is driven by the chemotherapy in both patient populations.

Sorry, [ Martin ], does that answer your question?

Yes, to some extent, but I was more -- I mean, you haven't -- I understand that the different trials have been designed and have got regulatory approval, of course. But I'm just thinking about if you get oxaliplatin and PledOx in an adjuvant setting, you are, so to say, at least to my understanding, earlier in the development of -- at an earlier stage in your cancer disease. And would it then be fair to say that in an adjuvant setting, you would not accept that much of adverse events or side effects of the treatment compared to in a metastatic setting? And doesn't that contradict what we've seen today?

Okay. Thank you. Let us further elaborate, and I'll hand over to you, Christian, if you want to respond.

Yes. Yes. To some extent, I understand your [indiscernible] question, Martin. So thanks for that. And yes, the adverse event is, of course, the tolerance for adverse events in a patient population that is regarded to be more healthy is, of course, lower than in a patient population that is in an M stage disease. So that is certainly fair to assume. On the other hand, we must also remember that any benefit that we see in an adjuvant population is, of course, in a sense, worth more when it comes to -- when it's delivered in a healthy patient population. So if you take both of those sides of the coin together, it builds a more complex picture. And the tolerance of adverse event depends, of course, on the totality of the benefit to the patient population itself. Because at this point in time, I think for PledOx and for the POLAR program and for the POLAR patient population, that's all we can say right now before the data actually becomes available, too.

Yes. That's clear. But I mean the FDA has not taken the end points into consideration here. I guess they have just looked at the adverse events. And you would accept -- how should I say -- more side effects or more adverse events in a metastatic setting compared to an adjuvant setting, if I said that, that was my point.

Yes. Okay. Yes. Correct. But please understand, the FDA's assessment is an overall assessment, not necessarily based here on one or the other patient population, though.

Gentlemen, at this stage, there are no further questions in the queue. So can I please pass it back to you for any closing comment? Sorry, I do apologize. One has just jumped in. So we're going back to the line of Dan Akschuti at Pareto Securities.

Just a follow-up question, not sure if you can comment on that. But in the PLIANT trial, you had, in the inclusion criteria, life expectancy of at least 3 months. And now in the POLAR-M trial, you don't have that. Is that correct? So could it be that you took in more terminally ill patients in this trial now?

Thank you, Dan. Christian, do you want to elaborate on that?

I think that we can discuss the small differences in inclusion criteria in the PLIANT versus the POLAR-M study. However, those, I would say, is not of any particular relevance for the adverse events that have been observed and is all FDA's concerned.

Okay. Sorry. So once again, I pass it back to you for any closing comments.

Thank you very much, operator. And first, let me thank all the participants for joining the call and also for asking the very good questions, which I hope you receive your response to. In essence, and as I mentioned before, we'll continue to work with the FDA to provide the necessary information to lift the clinical hold as soon as possible to allow the recruitment of U.S. patients in the POLAR-M study to continue. We are confident in the overall safety profile for PledOx, which has been verified by the independent DSMB, which then supports the continuation of the POLAR program, and both studies will continue as planned in Europe and Asia. Thank you very much.