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

[Audio Gap] Please go ahead.

Thank you very much, operator. Good afternoon and good morning, and welcome to PledPharma's investor and analyst call that will focus on an update regarding the press release issued late last night, concerning the decision to place the dosing of patients in the PledOx POLAR program on hold at all sites in all countries. Before starting the call, I would like you -- to refer you all to the standard forward-looking disclaimer that could be found in our general presentation at our website. As mentioned by the operator, I'm Nicklas Westerholm, and I'm 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 an overview of the situation and leave ample time for questions and answers. 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 their colorectal cancer and was fully recruited in December 2019. Up until the clinical hold issued by the FDA on the 22nd of January 2020, POLAR-M was conducted in Europe, Asia and the U.S. in patients undergoing chemotherapy treatment for metastatic colorectal cancer, where recruitment is not completed. It is important to recognize that adverse events are very common in this fragile patient population we're studying with PledOx, i.e., patients with cancer that are ongoing treatment for their disease. As we announced on January 23, the U.S. FDA issued a clinical hold on the POLAR-M study, after which we informed all regulatory authorities in countries participating in the POLAR program about the U.S. clinical hold. On February 19, we received the formal clinical hold letter from the FDA, including the rationale for the clinical hold, stipulated as concerns about a few observed adverse events in the CNS area. This letter has also been shared with other regulatory authorities. The fact that the FDA put the program on hold, 3 good questions for most of the other regulatory authorities during February, the company has responded to all such queries. The independent Drug Safety Monitoring Board, DSMB, for the POLAR studies consisting of experts in the fields of neurology, oncology and statistics, has continued their regular reviews of all available clinical data from the studies to ensure the safety of the patients. On February 14, 2020, the DSMB for the POLAR program recommended that the POLAR studies should continue as planned following their review of the accumulating data from the POLAR program. At the end of last week, the French regulatory authority requested and reviewed the latest unblinded safety data from the POLAR program. On February 28, they expressed the same concern as the FDA on a few numbers of adverse CNS events and requested that recruitment and dosing of patients should stop in France. The safety of patients in our clinical studies is our most important responsibility as a drug development company. The conduct of clinical studies are guided by globally accepted ethical and scientific quality standards and governed by national regulatory authorities in their respective jurisdiction. The current situation with 2 major regulatory authorities in 2 of the major regions, the FDA in the U.S. and the French regulatory authority in Europe, requesting us to stop the dosing of patients in the POLAR program is a major challenge for the program itself, especially considering that the French regulatory authority has requested and reviewed unblinded safety data. Note of importance is that the sponsor cannot have access to the same unblinded data since that would risk the validity and integrity of the studies, and hence, we are not in the position to evaluate that data at this point in time. All together, based on the views of the U.S. FDA and the French regulatory authority, PledPharma has taken a decision to place dosing of patients in the POLAR program on hold in all countries. To continue the studies in other countries without first solving the issue at hand with FDA and/or the French authority risks that we will have further clinical holds also in other countries. All regulatory authorities, ethics committees and participating clinical sites involved in the program -- POLAR program will be informed today about the change of status of the POLAR-A and the POLAR-M study. The next step is to work with the FDA and the French regulatory authority to clarify the right path forward for the POLAR program as we continue to believe that nerve damage associated with chemotherapy remains a substantial unmet medical need. In the U.S., we are preparing for a Type A meeting with the FDA to further clarify their requests for information, as described in the clinical hold letter. In France, we have already today requested an interaction with the regulatory authority to clarify what type and amount of information they would require to change their opinion. In the POLAR studies today, about 600 patients have been dosed with active treatment or placebo, of which more than 400 patients have completed 6 cycles and about 200 patients have completed 12 cycles. For the time being, both POLAR studies will continue to collect data on the patients currently enrolled to ensure that these studies will provide valuable data, both on efficacy and safety of the compound. With that, we can now move into questions and answers. So operator, if you would, please.

[Operator Instructions] And our first question comes from the line of Klas Palin from Redeye.

My first question is related to the adverse events. And if it's possible to share further details about these adverse events? And also just for clarification, the French authorities, they have -- it's the same numbers of adverse events behind the decision from the FDA? Or has there been new adverse events in this data set? Yes, we could start with that.

Yes. Thank you very much, Klas, for your question. And as mentioned before, the events in question, both from the FDA and the French authorities, has been in the area of CNS. We don't specifically comment on the actual adverse event itself. What we can say, though, that the number of adverse events, again, that was in question from both the FDA and the French regulatory authorities were less than 5, as per the communication in writing to us.

Okay. And also, if you might comment on these adverse events. Do they accumulate over time? Or do they -- do you see them from the first dosing?

I think as mentioned before, we don't go into comments on further details about these specific events, but I will invite my Chief Medical Officer, Stefan Carlsson, to maybe give a brief overview on our current position of the safety profile of PledOx.

Yes. So based on information, we are -- have accepted today. And based on our latest December review, which was in mid-February, we still have not changed our position on the, say, for the product. About this CNS event, we do not consider them being -- increased with the PledOx product.

Okay. So they should not be viewed upon as maybe related to manganese accumulation in the brain?

No, there's no indication that the mechanism of action of a product should actually be related to accumulated manganese in the brain.

[Operator Instructions] Our next question comes from the line of [ Juan Linares ] from Pareto Securities.

First one, could you remind us about the process and the timelines ahead? There will be -- you will obviously have a formal response to both FDA and the French authorities. Could we expect that to be coordinated to be the same material and what's time lines?

Thank you, [ Juan ], for your question, and I will invite Christian to respond to that shortly. But I think to start off with, as I mentioned, when it comes to interactions with the FDA and the French authority, that is obviously at the top of our agenda. In the U.S., we are preparing for a Type A meeting with the FDA to further clarify their request as they described in their clinical hold letter in France. As I mentioned, that already today requested an interactions with the agency to further clarify what type of information and amount of information they would require to change their opinion. But Christian, do you mind elaborating a bit on how you see the time lines going forward?

Yes, sure. Thank you. Yes. So for the FDA, the process is very formal. We think that the best way forward is to request the Type A meeting, as Nicklas mentioned, to have the opportunity to discuss with the FDA more around their requirements as expressed in the clinical hold letter and what their requests are in more detail. Such a meeting is granted according to their standard time lines within 30 days. After such a meeting, then becomes the time to actually prepare a complete response in writing from the company to the FDA. After that is sent to the FDA, the FDA has another 30 days to review and respond to the company. So in the U.S., that's a fairly straightforward process in terms of time. And if you start adding those time lines together, we end up with the best case scenario of around 3 months from now where we could have a response from the agency in the U.S. In terms of France, they have not stipulated what type of information or amount of information that they are looking for. And therefore, as Nicklas said, we have requested further interaction with them. And therefore, to say anything about the time lines and where that could end up with in terms of France, it's more difficult to say.

That's useful. And what about the -- given that whatever type -- time it will take, anything between 3 or 6, for -- just, for example, not that, that would be necessarily the case. But given that study, as an example, could start within 3 to 6 months' time. How should we review the interim? I mean there -- will that be based on less patients given the situation now? Or will we -- are we more likely to face delay accumulating a similar amount of patients as originally planned? Or is it too early to consider future scenarios.

Thank you, [ Juan ] for your question. And as I mentioned before, let me start with that, that, of course, both POLAR studies will continue to collect data on the patients currently enrolled to ensure that the studies will provide valuable data, both on efficacy and safety of the compound as it stands today. I think it's premature to comment on the specific delay as such, since we -- as we mentioned before, the next step is to work with the FDA and the French regulatory authority to clarify the right path forward for the POLAR program. I think in parallel, of course, we will work internally to further understand what options do we see going forward with existing patients into the program versus, for example, adding further patients into the program in the future. So when it comes to delay, [ Juan ], it's probably premature to comment on that as of now.

And finally, should we review this sensitivity for those few less than 5 events against the background with different formulation and previous issues with accumulation in the brain, even if it would be no actual bearing on PledOx?

No, we don't see that association at all. Any further questions, operator?

Yes. Our next question comes the line of [indiscernible], who is a private investor.

Thank you, Nicklas, and team to take this call, very valuable for us, investors and shareholders. I recognize it's a very key piece of information from one of your colleagues that you don't see the adverse events increase due to PledOx, but no indication that adverse events would worsen due to PledOx. So to me, this is a view it's still, as I say, product. So if one goes back to the former PLIANT study and so forth, it was basically no adverse event. So this is kind of surprising, even though it's just 5 -- less than 5 out of 500 patients that you put in the release. So I'm curious about how can one define the adverse events that for sure comes with the chemotherapy of oxaliplatin for the whole reason for PledOx right to exist, so to say, to reduce these very bad adverse events. How on earth can one potentially then explain, if you don't see that the adverse events that FDA has picked in these less than 5 individuals are not due to PledOx, but maybe then due to the other regimes of the very sick cancer patients undergoing chemo. How can one go about that? And then I just also wanted to then confirm that I got it right, you don't see any manganese accumulation in the brain. So that is not part of the adverse events that's on the table.

Thank you, [ Eva ] for your questions. And I hope I understood the questions right as well. So please comment if I didn't. But starting off with your last question first. We don't see any issues with accumulation of manganese in the brain, whatsoever. What we have -- and when it comes to the adverse events of concerns in the CNS space, that has nothing we have seen in the PLIANT study either. So that's also one thing we can be very clear on. When it comes to the POLAR program and the events that FDA is referring to, obviously, it's always a challenging question to answer. And obviously, we as a company don't have unblinded data. However, we are heavily relying on the DSMB to look at unblinding data, and they don't see the concern in the same way as the FDA nor the French authorities have done with regards to these events in the CNS space. I would like to pass on to Stefan, maybe if you want to comment and/or Christian as well.

And in addition, we have had external consultancy also to look into this. And it's a very clear position based on DSMB on to extend our external consultants that they do not see relationship with these CNS events and our product.

Christian, anything further to add to the questions from [ Eva ]?

Yes. I mean I guess you really hit the hammer on the nail there, how can we really ensure that it is not related to oxaliplatin treatment in comparison to PledOx treatment. And I guess that's where the key difference between how the DSMB and our external experts view these events, and how FDA and the French authority currently use these events. And I guess that is really the key aspect of what we need to do moving forward to get FDA and the French authority to recognize the aspects of these events as we see them and as DSMB and our clinical external experts see them. So that's the whole issue moving forward for us.

So may I add just a follow-up question, Nicklas?

Yes, of course, please.

So in the PLIANT study, I was on the Board of PledPharma during that study, so I saw in detail the results of the study. And we were very proud that we did have basically no adverse events. What kind of weight could be put on that PLIANT study, to say -- I mean of course, there are severe adverse events, that's the whole point. But if this -- if somebody at FDA and authority mix the adverse events up between chemo and PledOx, that would be a heavy one, I think. So how much help could we have from a clean safety study from PledOx in this situation -- from PLIANT in this situation?

Of course, we can take help from the PLIANT data, and I think actually from all clinical data we have generated and we want to draw to the attention that we have close to 3,000 -- actually, around 500 patients that have been dosed with roughly 3,000 doses of calmangafodipir over the past decade or so, including the PLIANT trial, the POP study with Aladote and now the POLAR program. So of course, we are using all the data possible at hand to support our argument here. So of course, the PLIANT trial plays a role in this.

Yes, you pool the safety data. So when you -- to have this data...

You pool it. Okay. Very good.

Yes. You have that. That is what the company has. But then sort of authorities, of course, need to do their estimation.

So one last question. I mean this is like a little bit of the devil's advocate. I mean are we supposed to prove that adverse events that might come from the chemo does not come from PledOx? That is like you turn the right system backwards a little bit. I'm just curious, I mean how can we -- are we supposed to prove them that the adverse events that they allocate to PledOx that we are pretty sure it not comes from PledOx? How much proof do we have to give?

Yes. Yes. During the study, what we're doing, that is the possibility of the DSMB to look into which have access to unblinded data to consider the potential or not potential relationship with the PledOx or not.

And to build on that, we have -- in essence, the simple answer to that is, yes, as a sponsor now both agencies, the FDA and the French authority, have put their position. We can always argue right or wrong, but they have put their position. So we as a sponsor together with all the help we can get from the DSMB, from external experts, of course, we need to provide information and data suggesting else, something else.

Yes. I remember also that -- yes. So I mean it's really important that the people -- the authorities -- the key people of FDA really understands the adverse events from normal chemo because otherwise, it will be very difficult to understand what is related to chemo, what is related to PledOx. And yes -- so okay, I wish you, of course, all the best. But I mean some adverse events. The whole point is that the adverse events of chemo can be life threatening. So I don't know, I guess one could push that, but okay, whatever. All the best of luck, and thank you for being so transparent.

Any further questions, operator?

Yes. Our next question comes from the line of Bertrand Delsuc from Biotellytics.

I just noticed on clinical trials that you had, concerning the POLAR-M study in the exclusion criteria, an item, which is any history of seizures. So I don't know if there is any link to these 2 events [indiscernible] that are in the CNS space. I just wanted to know if this addition was due to protocol change or to amendment, following what was observed by the FDA [indiscernible]? Or it was just an item that was missing right from the start? And coming back to the last question about your strategy to address this challenge, I would say. I guess you know the nature of these adverse events. You know the chemo regimen. I guess you already started to collect data with respect to this specific adverse events for this chemo regimen. So in a way, does this make you consider that you can address this challenge in a timely manner? Or do you potentially see some additional nonclinical studies to perform? So any more insight on the specific strategy, please?

Thank you very much, sir, for your questions. And let me -- I hope I got all the 3 ones right, so please correct me if I'm wrong here. Starting off with the first one. As mentioned, the concerns, the FDA and the French authority has had, has been an adverse event in the CNS space. As mentioned there, we don't specifically comment further on the details of these adverse events. When it comes to clinicaltrials.gov and updates on that, that's something we, of course, continuously update in order to optimize the protocol throughout the journey of the study. When it then comes to the way forward and general adverse events when it comes to chemotherapy treatment, I think it's very important there to recognize. And I think I mentioned that, that we have, again, as mentioned, the Drug Safety Monitoring Board in place to monitor the study throughout its journey. The Board itself consists of oncology experts, neurology experts and statisticians well aware about the side effects, the common side effects when being dosed or being treated with chemotherapy. So I think that's the two first questions. When it comes to the third, I'll ask Stefan to start off with and then Christian to build, if that's possible.

So what have been said [indiscernible] that the data we have access to today and based on the latest DSMB review of the program, we have no new concerns, actually. So again, talking about those CNS events that we -- that was referred to FDA and French authorities. We do not see that there's an increase for PledOx.

Christian, do you want to further elaborate on the performance?

Yes. So I think as you ask about the way forward there, and if there have been any and requests for, for example, new nonclinical studies by the FDA? Without commenting in detail around what the FDA expects from us, I think we can say that they are not, at this point in time, requesting any new studies to be performed in order to lift the clinical hold.

Okay. So currently, you believe that you can address both or at least the FDA request with what you have to end?

Yes. I think -- as we mentioned before, I think based on what we're seeing in writing so far, we believe that we're confident in the profile. [indiscernible] it doesn't pose an increased risk. Obviously, we need to engage in further dialogues through a Type A meeting with the FDA to have a better understanding of their request and data provided to them and in the same fashion with the French authorities.

Okay. And you did not start any new link to safety or [indiscernible] as of today?

No.

Our next question is a follow-up from [ Juan Linares ] from Pareto Securities.

The first one is on this aspect of proving whether they think that there is no elevated risk. Should we -- what's the measurement in this situation? Or is that something that will be clarified in future communication? Do you need to show that there is no increased relative risk or hazard ratio in terms of CNS risk? Or how should we view it?

Thank you, [ Juan ], for your question. Christian, if you don't mind, I'll hand it over to you.

Yes. Thank you, [ Juan ]. So I mean in general, as we just said that FDA has not required us to perform any new studies, just as you referred to, and the previous questions has referred to. Where we're going with the FDA is to provide them with as good as possible reassurance based on the studies that we have either conducted and concluded or from the ongoing POLAR program. So those are the basis for lifting the clinical hold as expressed in the written communication. Then of course, as is always the case, the agency is always looking for whether or not there is an increased risk versus being treated with placebo. And thus, it's reasonable to assume that this is the case also in this situation. Of course, as Nicklas has already mentioned, we are still blinded to the POLAR program data. And thus, we are in a slightly challenging situation in not being able to unblind those studies and work with the full data. But that is as expected, as we are currently performing those trials.

Yes. I was referring to existing studies. But of course, since it's not -- I'm -- since it's blinded, it's difficult. You can -- I guess you can mainly work with Phase II study and earlier studies to provide that relative risk assessment. And that...

We can -- yes, sorry, just to add there before your next question. Of course, we could also work with what we see on a blinded data in the POLAR program compared to what we would expect to see in this type of patient population based on what is known in the literature, et cetera, et cetera. So that is, of course, also possible for us. Sorry for interrupting you, [ Juan ].

That's cool. And also just a reflection, if there is, of course, a different baseline population -- patient population recruitment, these patients in the POLAR studies are in worse condition. And I guess there could be a case of the subgroup, which have -- are more prone to have more CNS risk and if you're lucky or random walked, those could not be evenly spread, and that could be more in the active arm of the subgroup than in the other arm, and that could, of course, be difficult to decouple from the active -- from PledOx.

Yes. Yes, that's absolutely correct. Since we are obviously working with a very few number of adverse events in a questionnaire recognized by the FDA and the French authorities, that might be the case.

Our next question is a follow-up from [indiscernible], who is a private investor.

So I have a question. Maybe it's too early for you to have done the analysis, but I think it would be very interesting to check into the literature and also the clinical trials of the chemo here, which is oxaliplatin, and check out the adverse events on oxaliplatin and see if they kind of compare to the adverse events that have shown up in less than 5 patients. Have you had time to do anything on that?

Stefan Carlsson here. So very generally, there -- as we have alluded to that, first, we have patients that actually are quite fragile and they're also given this oxaliplatin. And given, again, what we related -- discussed the -- sorry, the CNS event that we're talking about here is that we can say that there's no relationship with the [indiscernible], the product. This event that we are talking about may happen in patients treated with oculoplasty or being cancer patients. So that's why we can say that we do not see any direct relationship.

And then I have a follow-up question. Why is it so difficult that we don't have unblinded? So DSMB has unblinded. Now of course, the company does not have it. So Nicklas guided less than 5. So let's assume it's 4 because that's less than 5. Let's assume all of them have been dosed. That's 4 patients out of 500. What on earth can one draw from it? What kind of conclusions could anyone draw regarding anything from that number in a FDA perspective, so to say? Especially considering the fact that these adverse events are related either to oxaliplatin or just having cancer?

Thank you, [ Eva ], for your question. And I think you understand that it's difficult for me to speculate on what the FDA thinks and draw their conclusions on in the same way as we did for the French authorities. But obviously, it resonates what you're saying from our perspective.

Okay. Very good. I'm very happy to hear that you can see these types of CNS adverse events, either connected to oxaliplatin and/or cancer patients having cancer. So I think it would be very good to have a [ massive ] information about the connection between the 4 cases or whatever it is, the CNS, that have seen and connected to oxaliplatin and cancer, I guess, the key of the defense. And also, of course, the pool data of the safety of PledOx, which is massive. Because, I mean you're not so handicapped by being blinded, I guess, because it's less than 5, so it's 4. I mean you could just assume that all of them -- all 4 have been dosed with 1 of the 2 dose levels. And I mean what's new? Or suppose 1 did not get dosed, I mean it doesn't make a very, very big difference unless they say that they can prove that it has adverse events because 4 out of 500 [indiscernible] see a firm reaction that you also see in oxaliplatin and/or cancer patients. I guess that's a little bit of a strange case. So we show all this [indiscernible]. So could you say anything who is in charge of this FDA? Do they have the right competence? Do they have experience enough to evaluate this? I mean PledOx is a little bit of between. It's not really a cancer therapy. It's rather a adverse events lowering therapy.

Thank you, [ Eva ]. And you probably understand my question. It's difficult for me to comment on the competence and et cetera, within the FDA. That's solely to their discretion and...

But could you say what kind of area in FDA that has responsibility? Is it oncology area? Or is it some other area? Just this is a medication that will take away adverse events?

So the vision we are with when it comes to PledOx is the division of Anesthesia and Analgesia products, and that are reviewing PledOx.

So that I think is an interesting piece of information, which makes it even more important to explain to them the chemo effect, internal experts any time I guess.

And we have a follow-up from Klas Palin from Redeye.

And just a short one about Aladote and any implications you see on this decision or -- and how we are going -- progressing with that program?

Thank you, Klas. And I thank you all for recognizing for the people on the call is that even if it's the same API with PledOx and Aladote is obviously targeting a different patient population and with a different dosing regime. I can't say much more than, and we have the ambition to pursue the Aladote program as it stands. And that's something that's under further evaluation going forward in light of this, of course, as well.

Thank you. And we have a follow-up from [ Juan Linares ] from Pareto Securities.

Just very shortly, clarification more than anything else. Sorry, if it's been clarified before. Those few patients, CNS patients, are they all related to POLAR-M or could be in A as well?

Well, again, [ Juan ], as mentioned before -- sorry, yes, we haven't clarified this, but that's nothing we want to comment on specifically. It's within the POLAR program.

And as there are no further questions registered at the moment, I will hand the word back to you, Nicklas, for any final comments. Please go ahead.

Thank you very much, operator. I would like to take the opportunity to thank the audience for all the questions throughout. I hope you've got some further insight into the situation the company had at hand with full focus on working with the 2 different agencies and trying to clarify the path forward for the POLAR program. And with that, I close the call. Thank you very much all.