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

And good morning, and welcome to PledPharma's investor and analyst call, that will focus on an update regarding the press release issued this morning, concerning the decision to close the pivotal Phase III program, POLAR, for PledOx, targeting a data cutoff by the third quarter this year. I am Nicklas Westerholm, the CEO of PledPharma. 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. Slides presented during this call can be found on the webcast. Operator, next slide, please. Before starting the update, I would like to refer to the standard forward-looking disclaimer, you can find on this slide, Slide 2. Operator, next slide, please. During today's call, we will give an overview and update of the POLAR program for PledOx, describe the path forward for Aladote, briefly mention our financial situation, and leave ample time for questions and answers. Operator, next slide, please. As a reminder, the POLAR program for PledOx consists of 2 double-blind, randomized, placebo-controlled pivotal Phase III studies, POLAR-A and POLAR-M. The program was initiated in the end of 2018, with the ambition to randomize a total of 700 patients. Today, we announced the joint decision, taken together with our Japanese partner, Solasia, to close the POLAR program. The decision was taken after a recommendation from the independent Drug Safety Monitoring Board, DSMB, that the program should be stopped due to severe allergic reactions, which has been observed in the studies after repeated dosing with study drug. This decision follows the communication in early March, where PledPharma decided to place recruitment and dosing of patients in the POLAR program on hold. This previous decision followed interactions with the French regulatory authority and the clinical hold issued by the U.S. FDA in January, which was due to a few number of observed CNS-related adverse events. Please note that the decision communicated today is not related to the few numbers of observed CNS-related events. PledPharma maintains its position that these CNS-related adverse events are not related to PledOx, a position which is also supported by the DSMB as well as by an additional independent external evaluation of these cases. The patients currently enrolled in the POLAR program will continue with their scheduled study procedures, although not receiving study drug until a data cutoff targeted for the third quarter this year. The totality of data generated will enable a robust efficacy and safety evaluation and an assessment of the benefit risk of PledOx. This evaluation will determine if future activities to find the path forward for PledOx to treat nerve damage associated with chemotherapy are motivated. I will now hand over to Stefan Carlsson, our Chief Medical Officer, to elaborate on the allergic hypersensitivity reactions and the DSMB recommendation, and then to Christian Sonesson, Vice President, Product Strategy and Development, to elaborate on the next steps for the POLAR program.

Thank you, Nicklas. Operator, can you please move to Slide #5, please? The safety of patients in our clinical studies is our most important responsibility. For the POLAR program, we have had an independent Drug Safety Monitoring Board, DSMB, consisting of experts in the fields on neurology, oncology and statistics. The DSMB has continuously monitored designated data since the start of the studies to ensure the safety of patients. Allergic hypersensitivity reactions are not uncommon in relation to platinum-based chemotherapy and in 1% to 2% of patients treated with oxaliplatin experience severe allergic hypersensitivity reactions. However, the DSMB recommendation to stop the POLAR studies implies that such a risk is increased in patients treated with PledOx. At the time point of the DSMB evaluation and recommendation, there was a total of 8 patients with advanced severe allergic hypersensitivity reactions observed in the POLAR studies. There are 4 things I would like you to note about these events. First, there is no reason to believe that patients previously treated with study drug is currently at risk. Second, that all of these severe events were transient and result of the treatment. Third, that all events occurred during the administration of oxaliplatin or study drug. Fourth, that all events occurred after the PET dosing of study drug. There has been no severe event observed before the sixth cycle of dosing. Together with external immunology experts, we are currently working to aim to understand why these allergy hypersensitivity reactions occur with PledOx, and that is why they occur with co-administration of oxaliplatin and why they occur after repeat dosing. With that, I now hand over to Christian.

Thank you, Stefan. Operator, next slide, please. So now we are on Slide 6. So the decision communicated today effectively means that we will not continue the work to lift the clinical hold with the FDA and the French regulatory authority. This means that randomization in the POLAR program is completed, that no further dosing of patients with study drug will occur. The current status of the POLAR program is as follows. POLAR-A has been fully recruited, whereas POLAR-M is not. In both studies, taken together, a total of 590 patients out of the planned 700 patients have been randomized. In terms of dosing, 420 patients have completed more than 6 cycles of treatment with study drug and about 250 more than 9 cycles. This means that we expect that these patients randomized to PledOx have received a substantial treatment effect to prevent neuropathy. Our assessment is that the totality of data generated in the program -- POLAR program is sufficient to allow for a robust efficacy and safety evaluation and an assessment of the benefit risk of PledOx. Therefore, the patients currently enrolled in the POLAR program will continue with their scheduled study procedures, although not receiving study drug, up until a data cutoff targeted for the third quarter this year. This data cutoff is chosen such that all patients eligible for at least 6 cycles of dosing with study drug, as was originally intended in the study design, have completed a 9-month data collection of the primary endpoint. Following the data cutoff, data will be cleaned and the database locked. After which, data will be unblinded and analyzed. For the upcoming months of data collections, the company recognizes the challenging environment for conducting clinical studies during the COVID-19 pandemic and has therefore taken actions to ensure that data can be collected remotely according to issued guidelines from regulatory authorities. However, one should be cautious that the COVID-19 situation can lead to a higher than expected dropout of patients from the studies during this period. And it may also result in a longer time to clean and lock the database than would generally be expected. But in essence, the totality of data generated will enable a robust efficacy and safety evaluation and an assessment of the benefit risk of PledOx. This evaluation will determine if further activities to find a path forward for PledOx to treat nerve damage associated with chemotherapy are motivated. I will now hand back to Nicklas.

Thank you, Stefan, and thank you, Christian. Operator, next slide, please. I will now move into describing the position on Aladote and our financial position. As you have heard Stefan described, the allergic hypersensitivity reactions observed in the POLAR program have all occurred after repeated dosing of study drug. There has been no severe event observed in the program before the sixth cycle of dosing. For Aladote, this is reassuring, since in the case of reducing liver damage caused by paracetamol poisoning, we administer the drug as a single dose only. This means that Aladote is not affected by today's decision under recommendation by the DSMB. Thus, for the company, the focus on Aladote and the forthcoming regulatory interactions and clinical study remains. As previously communicated, the company targets one pivotal study with Aladote for marketing authorization application in both Europe and U.S., which will be further discussed with the FDA and EMA. Turning to our financial situation. We have a robust cash position with SEK 255 million at year-end 2019. We see that the current funding is taking us through to at least the end of 2021, including the initiation of the next Aladote study. Operator, next slide, please. And with that, we can now move into questions and answers. Operator, if you would, please.

[Operator Instructions] The first question we have is from Ulrik Trattner from Carnegie.

Nicklas, I have a few, if I may. I can just start off. So the initial comments that the clinical hold was issued based on CNS-related side effects. Why did that sort of occur? And what it's even related to? It's sort of the allergic reactions? Or is this sort of it's separate matter?

Yes. Thank you. Do you want me to start with that one first, Ulrik, and then detail on the ...

Sure, yes.

So based on our knowledge today, there are no relation between the CNS-related adverse events. We think we've been clear on that during this call as well, and the allergic hypersensitivity events described in the press release. I think the clinical hold obviously is based on the view and perception of the U.S. FDA as well as the French regulatory authorities, which, of course, I don't have any further insights to more than that was the issue that they have described and seen. And our position is that we don't have any issues. We don't see any relationship between PledOx and the CNS-related event, which was also confirmed by the DSMB as well as an external independent assessor. But I would also like to invite Stefan and Christian, if you want to comment any further.

No. You're quite right, Nicklas, that there are no reasons to believe that the CNS events are related to the hypersensitivity reactions. They are not these [ sims ] at all described related to those CNS events that we see with this hypersensitivity reactions.

Maybe I can then just move over to the answer further questions, but I'll start with a few. How come you didn't see this in the PLIANT study given that you had beyond 6 cycles of PledOx administered, same dosing, also oxaliplatin? How come you haven't sort of seen these sort of evidence in the Phase II trial? And the second one is that, you're obviously basing your analysis in the Q3 sort of cutoff on fewer number of patients. Just in terms of yours that have statistical analysis, how much reduction is sort of the study powered for? And what do you see sort of the risk there? And the third question is, now that it's quite obvious that PledOx induces the side effects related to oxiplatin, what type of efficacy in terms of production in PRO are you needed to show in order to have this drug approved based on a risk-benefit scale? Obviously, I'm assuming that you have some interactions with regulatory authorities or at least to your [ clinical years ].

Yes. Thank you. If you don't mind, Ulrik, we start with the questions on a one-by-one basis. And the first question, correct me if I'm wrong, was how come you didn't see this in the PLIANT trial and why do we see it now. And I'll start off and then I'll hand over to Stefan. During the PLIANT trial, we saw one event which was related to allergic hypersensitivity reactions in the study. So it has been seen before. As you rightly pointed out, we didn't see more than one event in that trial. So as mentioned by Stefan previously, we are investigating these cases more in detail, of course, and the course relationship between the same, both on why do they happen, of course, and second, why does it happen after the fixed dose and onward. But please, Stefan, please build on that as well.

No. I think it's very important that we get a clear picture on -- in trying to understand the difference with the PLIANT study, where, again, that we only saw one case related to what we see in the ongoing POLAR program. And that is, for sure, something that we are investigating thoroughly together with external expert immunologists.

Yes. Thank you, Stefan. If you then move to your second question, Ulrik, and here, you have to correct me if I'm wrong. You had a question around the cutoff date being in the third quarter of this year. And what data might that generate from a POLAR perspective, and also, of course, commenting on the benefit risk profile. So let -- was that correct, Ulrik?

Yes. It's correct. It's correct.

Perfect. So maybe we'll start with the first part of the question, which was around the cutoff and what the study hence will lead to. And here, I will actually hand over to Christian to elaborate further on how you see why we have chosen the cutoff as for the third quarter and how you see the sample size then and the data generated within that patient population, if you don't mind, Christian.

Yes. So let me start with the assumptions we made when designing the studies. And then the -- we assume that the placebo rate of neuropathy was to occur in 40% of the patients and on active treatment in 20% of the patients, which then means a 50% relative reduction of the occurrence of neuropathy. The design of the trials were to randomize 140 patients per treatment arm, which, in the case of a 20% dropout during the study, would result in 112 patients per treatment arm at the 9-month time point. Having data on 112 patients per treatment arm at 9 months would then result in an approximate 91% power for the assumptions previously mentioned. Now as you allude to, we did not randomize POLAR-M fully. We were fully randomized in POLAR-A. And the data that we are and the patient population we are looking for to focus on are the ones that, as I mentioned previously, were eligible to at least 6 cycles of treatment before we ended the single study drug in the studies, which actually means that the patients ought to have been randomized before the end of November last year, which then takes us to the end of August for the data cutoff 9 months later. Then as we know, patients can come in a little bit later than the originally targeted date, et cetera, et cetera. So that's why we say the third quarter. But that is how we think about the targeted patient population. Now the reason why we do that is, as we mentioned, in terms of the dosing, that we need to ensure that patients have been sufficiently dosed in order to have a sufficiently high expected treatment effect. And that's why we quote the numbers that we did in the slides earlier. So perhaps you -- was that sufficient answer to your question? Or do you want to have some further builds?

Yes. Yes, absolutely. And just in terms of -- have you had any discussions with sort of key opinion leaders based on this data or with the authorities regarding what could be an acceptable effect sort of reduction in PRO, putting sort of into context the -- that what seems to be manageable, but still severe side effects from PledOx?

If you don't mind, Christian, I can go first. And I think it's 2 questions in one in that follow-up question, Ulrik. One is, of course, based on the regulatory interactions and discussions with the key opinion leaders, what is clinically meaningful from a reduction in neuropathy perspective. And there, we have seen that the discussions have taken us to at least 30% reduction in neuropathy is clinically meaningful. Then, of course, on the other hand, when you evaluate the drug, you need to look at both the benefit of the drug and the risk of the drug. And I think your second question was around benefit risk profile of PledOx. And I think there, we need to be clear, of course, with these allergic hypersensitivity reactions, that the risk of the drug has increased. That we can't shy away from. However, there is still an opportunity by reading out the robust data generated in the third quarter to look at efficacy parameters as well. And then there, it's a couple of parts that is very, very important. One is, of course, the patient reported outcome and how much reduction in neuropathy do we see, as well as other very, very important factors, such as, can we influence the amount of oxaliplatin a patient can tolerate is also a very important aspect to consider, i.e. the cumulative dose of oxaliplatin given in the PledOx arm versus the placebo arm. So sorry, Christian, to interrupt, but do you have any further builds to that to Ulrik's question?

No. I think you outlined it nicely, Nicklas. Thank you.

Great. So I just have 2 more questions. And the first one is, you -- obviously, in your last Capital Market Day, you outlined a sort of strategic view to expand into indication with other taxanes and platinum-based agents. Obviously, on the basis of this sort of news today, would limit your [ sort of ] possibilities into expanding this, right? And the second one is just on sort of your cash position and what you mentioned that it is -- or at least financed to the end of next year. But then is it ethical to initiate a pivotal trial if that one isn't fully financed? Those are my 2 last questions.

Thank you, Ulrik. And I think, yes, we mentioned that we have kicked off some preclinical studies with PledOx in the taxane space. We will have data from that within this first half of 2020, which, of course, we'll communicate to the market. I think it's premature to speculate would and can we take that forward, because it's all dependent on -- to some extent on the data readout looks like from the POLAR program. However, one should acknowledge that when it comes to taxanes, of course, compared to oxaliplatin-based chemotherapy, that has a different side of a side effect profile. So I think one should also consider that. So I think, again, it's premature to speculate on any further development activities with PledOx until we have the data for the POLAR program at hand. Your second question was around the financing and the ethical question mark around initiating a study in Aladote if not fully financed. It's a good question. And I think, to be very, very clear there, of course, the initiation of the Aladote study will be a separate investment decision made by the Board. When it goes -- so also related to study design. And we're looking at a number of different aspects there, with an interim futility analysis as part of the design package for this. So I think we need to look at all aspects into that context, of course, when it comes to the financial situation, Ulrik.

The next question is from Klas Palin from Redeye.

I don't have as many as Ulrik. But anyway, I [ as readily ] curious if you could just provide some further details about how you managed to follow up the patients during this COVID-19 crisis and -- to limit any further dropouts, and especially in the countries like Italy and Spain and France that has been heavily affected by the coronavirus crisis. And also, I guess these patients could perhaps be managed by telephone or something like that. But also, part of the endpoint is related to, you need to have some hospital visits. And how you will manage that?

Thank you, Klas, for your question. And I'll start on responding that and then hand over to Christian and Stefan. And -- but first, I would like to mention that this is, of course, a challenge, Klas, so I think rightly so that you point this out. It is a challenge for any clinical study to be executed in this current COVID-19 environment. From our perspective, we have been working and are working very, very closely with our CRO in question in order to make sure that we in the best and most pragmatic way can collect the data aligned to the newly updated issued regulatory guidelines from EMA and FDA, for example, in order to do this. But Christian and Stefan, please elaborate further in that in-depth discussions you have had with our CRO on this.

So there are, as Nicklas says -- has been a lot of guidances coming from different competent authorities in how we should deal with collecting data in ongoing trials. And we are doing that in a close collaborationship with CRO, where we will remotely, if possible, it changed the hospital visits to phone calls or also via mail or if email is possible. Also, we have been able -- are able to expand the visit in those also for the patients in order to make it flexible for the hospital staff as well for the patients to adhere to the protocol visits.

Okay. And this has been working fine by now? Is it -- have this been implemented by now?

Yes. Yes, it has been implemented in several sites already.

Okay. And another question for me, and this is related to the FDA interaction. And how this is progressing? Or is this put on hold for now?

As we mentioned, [ thank ] -- it's also, as we mentioned during the initial update that, that is for now put on hold. I think the imminent steps are, of course, to collect the data, and making sure that we get and generate as much robust data as possible up until quarter 3, and then have a readout. And that will then -- that robust readout on efficacy and safety will guide us forward for the future of PledOx.

The next question we have is from Dan Akschuti from Pareto Securities.

I have a few more. One, I would be interested to know a bit the nature of these allergic reactions. As you said, they are quite known from oxaliplatin. And the numbers you mentioned, there are also different ones, like how much [ Japanese ] studies up to 7%, had the severe allergic reactions to oxaliplatin. And so what is the amount of patients that you had experiencing these reactions? And if it's far off from what you would expect considering various studies on oxaliplatin, because the numbers vary quite a lot there.

Yes. Thank you very much, Dan, for your questions. I think, again, as we mentioned during the initial update of this call, it is 8 patients that have experienced these allergic reactions or allergic hypersensitivity reactions. Stefan, if you don't mind, if you can further elaborate on the nature of these allergic hypersensitivity reactions as well as how common they are during treatment of oxaliplatin, both in the early treatment cycles of oxaliplatin as well as the late treatment cycles of oxaliplatin, because I think that's what you're referring to, Dan. It is a difference between early and late during the treatment regime of oxaliplatin. But Stefan, please.

Yes. Thank you. So I can start off with the numbers. Yes. According to our literature, there are severe hypersensitivity reaction based by on oxaliplatin treatment. They usually come after a bit late, 4, 5 cycles. You can see it. And that can be explained that the patients are sensitized after certain time of exposure. The allergic hypersensitivity reactions that we have seen are rash flushing, and that is caused by vasodilation. And you also sometimes see hypothermia. However, this vasodilation can also cause hypertension. I should stress that the reaction we've seen in the study, they have resolved after treatment. And again, at the sites that we are conducting the study, this is not an uncommon response, so they are actually well known and actually can treat -- can have treat this accordingly to local practices.

Just a follow-up directly. So you didn't -- because [ one ] thought ahead, because some of these reactions can be respiratory, so patients are requiring oxygenation. So it could be maybe an additional concern in the current time of COVID-19. But you say you didn't experience any respiratory reactions, which are quite common in oxaliplatin treated patients. But you just had the rash, hypothermia and the hypertension, which you then treated with adrenal? Or what kind of medication did you use?

Yes. In some cases, the patients have received oxygen, that is for the comfort. And that is not an uncommon treatment that you give in parallel to the treatment. And the treatment itself, that is giving antihistamines and steroids. And the patients then [ results ].

Okay. And just to be absolutely sure. Again, these 8 patients, they were all PledOx treated? There was none in the placebo group?

Okay. Yes. I think we need to be clear here that, obviously, from a unblinded perspective -- sorry, from a blinded perspective, one need to assume, recognizing that this is common within oxaliplatin dosing of patients, but one needs to acknowledge that the DSMB recommendation implies that it's an imbalance between the PledOx arm and the placebo arm. We are not commenting on the exact details of how many in each arm. Of course, at least personally myself is not privy to that together with the majority of the PledPharma team. It's only the medical team within pharma -- within PledPharma that have been unblinded for these certain events.

Okay. And another question is, how this did not come up with the FDA? It seems like this should have been seen by the FDA as well. And it apparently wasn't a concern by them. And the -- why does the DSMB only come with this recommendation now and not much earlier since the study has been stopped for a while now?

Yes. I can start with -- thank you for your question, Dan. And I can start with the first part on the FDA. And then, Stefan, you can elaborate further on the DSMB interactions and the mitigating measures. So I think from our perspective, as you can imagine, Dan, it's very difficult to speculate why or why not did the FDA didn't raise a question around this. They have been very clear in their concern, and that was the CNS-related specific events that we referred to during the call we had in early March and also subsequently the press release we had. So it's very difficult from our perspective why didn't they comment on that in specific, which I hope makes sense to you. But Stefan, do you mind elaborating on the second part of the question, which was around DSMB interactions and mitigating measures and dialogue around allergic and hypersensitivity reaction?

If -- they have commented once on the allergy in early discussion. However, we have not heard any clear direction. As you know, they have only commented on the CNS-related events. And actually, no other further [ aids ] than that.

And do you mind commenting -- sorry, Stefan, I don't know if you misunderstood the question. But do you mind commenting on the DSMB interactions we have had around allergic hypersensitivity reactions as well as the mitigating measures we have put in place for the same, because I think that's -- correct me if I'm wrong, Dan, that was a second part of your question as well.

Yes.

Okay. So DSMB has continuously been looking into the data from the study. They have been looking to all the cases that can be -- severe case that can be perceived being allergy or hypersensitivity related. We have implemented in the protocol in January to give premedication, that would -- to be antihistamines as well as prolonging the infusion time. So that is the mitigation we have done related to the product. In addition, in parallel, the DSMB has in parallel since then, since early January, been reviewing all cases in an expedited manner to follow each of these cases. And that now had come to the recommendation of the DSMB for us to close the program.

Okay. And I also remember that one of the first trials that was published, I think, in 2012 with the -- [ manga for the peer ] in oxaliplatin treated patients, that, first, there were moderate allergic reactions. And only later on additional cycles, I think, cycle 8, severe hypersensitivity reaction occurred in one patient. Did you see similar signs? Maybe early signs that you can see that the specific patients is maybe going to react more severe earlier? And then for that specific patient, one could stop treatment of PledOx?

No. That is nothing what we have been able to see, but I'm still saying that we are investigating the program thoroughly.

Okay. So one last question. So you mentioned that the data cutoff will be in Q3. Can we also expect the top line data still in Q3? Or will this go into Q4?

I think it's very challenging to give you an exact month. That's why we're saying quarter 3. And it comes back to the challenges, Dan, around the COVID-19 pandemic. As Stefan and Christian mentioned, we have opened up the window to be a bit more flexible in how to collect data and when to collect data. So it's all about when can we see that they are coming in and reporting their last visit. So it's very difficult to give you an exact date when we can see data. It all depends on data collection.

[Operator Instructions] And we have a follow-up question from Dan.

Just one last question. Considering the scenario that it would be highly efficacious as you've seen in the PLIANT trial and no further safety concerns, would it be possible to file with just that trial data? Or would you need to run another clinical trial? Or is it different also for Europe, Asia and the U.S.?

Thank you for your question, Dan. Christian, if don't mind, elaborate on this one.

For me, the POLAR studies, as they are regarded as Phase III studies, and as such, they will be an important part of the regulatory package for submission in any region. However, we do expect that, based on where we are right now, we need to complement these studies before a regulatory submission.

At this time, sir, there's no further questions in queue.

Okay. Thank you very much, operator. Maybe I'll take the opportunity to summarize if no further questions, using Slide 8 as we have up on the screen. So today, we announced the close of the pivotal Phase III program, POLAR with PledOx, targeting a data cutoff in the third quarter this year, with a robust efficacy and safety analysis and evaluation to follow. The decision was taken after a recommendation from the independent DSMB to stop the studies due to a number of severe allergic hypersensitivity reactions. It is important to note that all such events were observed after repeated dosing and no severe events was observed before cycle 6 of dosing. The totality of data generated will enable a robust efficacy and safety evaluation and an assessment of the benefit risk of PledOx. This evaluation will determine if further activities to find a path forward for PledOx to treat nerve damage associated with chemotherapy are motivated. The company will now focus on Aladote as well, administrated as a single dose and not affected by the closure of the POLAR program. The next steps are continued regulatory interactions and finalization of the clinical study design. Our financial situation is that we have a robust cash position, with SEK 255 million at year-end 2019. That will take us up until the end of 2021. With that, I'll thank you all for your good questions and patience to join our call today. Thank you very much.