IRLAB Therapeutics AB (publ) (IRLABA) Earnings Call Transcript

Welcome. Research company, IRLAB, have presented additional efficacy data to the Phase II study, REACT-PD. Along with us to present from IRLAB, we have CEO, Kristina Torfgard; and Nicholas Waters, Vice President of R&D. After the presentation, there will be a short Q&A. Viewers can ask their questions in the live chat, and we also are joined by 2 equity analysts. Hello, Kristina.

Hello, Mattias.

Welcome, and we are really looking forward to this new data that you are presenting today. So please go ahead.

Thank you very much. And can I have the first slide, please? So this is our disclaimer. And we are very, very pleased to be back and to be able to share some very exciting data that we have recently got through additional and further in-depth analysis on the REACT-PD study. So today's agenda, you have on the left side there, and I will, together with Nicholas Waters, EVP and Head of R&D, take us through today's presentation. So by that, I will hand over directly to Nicholas to take you through the study and the data.

Thank you very much, Mattias. Thank you, Kristina, and thank you all listeners for visiting us today again. Next slide, please. I just wanted to remind all of you why we have been working on pirepemat for the years we have so far and the background to that. And there was recently a publication that summarizes a quite substantial number of the publications that underlies the reasoning behind our choice to develop pirepemat -- or first of all, discover pirepemat and then develop it for this indication falls in PD. And that is, in essence, the fact that in Parkinson's disease, it's known that they rely very heavily on the cortical functions to compensate for losses of functions in deeper layers of the brain. And this is to remain postural control. And with pirepemat, we have a drug which activates cortical function and can also further compensate the losses these patients have in their neurotransmission in the cortex. And I just wanted to remind everybody about the background. Next, please. The pirepemat study, for those who have followed us and listened to our presentation on March 5, where we presented the top line results, the design of the study is an important factor in the coming slides here. We had a 3-month trial with a 1-month run-in period where patients are measuring the number of falls they are experiencing, delivering that through a system of diaries to the sites and then collecting it through the database. And then they are randomized either to placebo or a fixed dose of 300 milligrams or a fixed dose of 600 milligrams per day during the course of 3 months. And then we have a follow-up period as well. We managed to screen 146 patients. We had 104 patients that were randomized. This is the full analysis set. However, this includes a number of patients who do not follow through the full study. They take 1 pill or 2 pills and leave the study for various reasons. And we had 90 who completed the full study period. I'll come back to these numbers later on, why they are important. Next, please. Just a reminder of the participants that were included in the study. They are -- have an age between 55 and 84, so from quite young patients to older patients. The average age was 72 years. I can inform also that the average height of these patients or individual subjects participating in the study was around 167 centimeters, weighing around 70 kilograms in average, a quite homogenous group of patients. To be eligible to be part of the trial, they had to experience at least 2 falls during the preceding month before randomization, as we mentioned last time we spoke. However, the fall rates in this cohort that we have been studying was much, much higher. The average number of falls were somewhere between 18 and 22 actually at the baseline period, with a weekly fall rate of about 5 falls per week, which is a lot. Next, please. And then that illustrates clearly the problem with this issue. Next slide, please. Yes, sorry, I missed the flip. And we reported on the top line results on March 5. And those are data -- a small portion of the data that we receive quite soon after the database lock, which means that we have to go out and inform the market about them. We had a quite substantial drop in the fall rate in the 600-milligram group, which was -- the primary endpoint, sorry, was the comparison between the 600-milligram group and placebo during the last month during the trial. And that did not come out significant. However, we all saw that there was a quite substantial drop in the fall rates in the study. So of course, that gave us a lot of questions to ask the data. Next, please. One of the things that is prespecified in the statistical analysis plan, which is quite common, and that is that you want to assess the relationship between, of course, dose and effect. That's one thing, and that is what we have talked about before in press releases and in -- at the last presentation. However, there is also a requirement from many of the regulatory bodies across the globe to actually investigate the relationship between the exposure of a drug and the effect, i.e., the plasma concentration that a specific patient has and the effect in that patient. And that is a very important part of the assessment of a true effect of a drug. Sometimes, one uses the term PK/PD, pharmacokinetics versus pharmacodynamic analysis. So -- and that is something we had the chance to do quite a bit after we had the top line results actually. We started this analysis quite recently. And in that work, we, of course, needed the plasma concentration data, et cetera. And to assess this, we have assessed the plasma concentration, and we have divided the plasma concentration range into 3 similarly sized aliquots in terms of number of patients. So we have participants with the highest concentrations. Those are 19 into the high group, participants with the medium range of plasma concentrations, the 20 there in the middle and then 20 patients with the low exposures. So this is not based on any full data or anything like that. It's just a division of patients into how high their exposure has been. Next, please. And this is the outcome of that analysis. And we see here, and I'll try to take you through this. And on this slide, upward direction is improvement versus baseline. So what we see is in the low range, we have a slightly lower -- we get less of an effect or a small worsening, you could call it, although not statistically significant, of course, versus baseline or versus placebo. And this is placebo corrected, I should say. But in the medium range, we see a very clear and very strong signal of a dramatic reduction versus placebo, 31% less fall rate or lower fall rate than we see in the placebo group. And at the high dose, again, there is less of an effect. And this represents a biphasic dose response curve or an inverted U-shaped dose response curve is sometimes mentioned or called. And this is not an uncommon phenomenon in CNS or for other indications for the matter, well known and especially for drugs which act through the cortex, lots of publications around this. And it seems that we have actually hit that exact plasma concentration range, which defines that bell-shaped curve in this study. Next slide, please. This is the same data, same population of individuals but showing the different strata here in the divisions here. So the gray line in the middle is the placebo effect. And we've talked about that. We've had a very large placebo effect in this study, much, much larger than has ever been published before for any fall study. Patients dropped from 100% that is the baseline. Every individual baseline set to 100% or 1. And then you see a drop down to about 70% of baseline during the course of the 3-month trial in the gray. And then we have the light green, which is the low concentration or low exposure group, which goes to around 78%, not different from placebo. And then we have the medium in the middle green color, the medium plasma concentration group, which goes down to around 50% or actually lower, 51.5% below baseline, which is a dramatic effect, clinically meaningful and significant versus placebo. And then at the high dose, again, we see that those patients at a very high concentrations, they are more similar to placebo. And this illustrates, but in another dimension also with time, the progression of improvement you see in this trial and the dose or concentration-dependent effect as well. Once again, a biphasic pattern. Really, really interesting observation and indicating that we, in this trial, actually have been able to achieve what we wanted to learn from this trial. We come back to that. Next slide, please. So the basic conclusions concerning the data is that we have gained information, clear information about the therapeutic window or the concentration range, where patients should be to have a good effect of pirepemat and the benefits at that concentration range. We've also learned a lot on how to define the inclusion criteria. I don't have time to go into that today. We'll come back to that issue, but it has to do with the balancing the baseline and understanding a little bit more about how to design further trials. We've learned a lot based on the REACT-PD study. We've learned how to run-in patients. We know how to stratify patients to the different arms by now. We have a new strategy for that. And we have also developed during the past week or weeks, we are working on developing a strategy for reaching this specific dose range or plasma concentration range in as many patients as possible in the next trial. Kristina, do you want to come in?

Sure. Thank you very much. So as Nicholas has alluded to, we strongly believe that there is really a way forward for pirepemat now. And our aim is really to move forward and to develop pirepemat for a really large unmet medical need, which fall is indicated for. So we will present more information and more disclosure, the results at upcoming scientific meetings as well as in scientific journals. So the next slide will take us through what's happening next week because already in next -- in the middle of next week, we are participating in the International conference for Alzheimer's and Parkinson's disease, which is held in Vienna. And at the meeting on Friday, Joakim Tedroff, our CMO, will have an oral presentation about the cortical enhancement. And he will also include, of course, information and data on the pirepemat study, the REACT-PD study. In addition, on April 4 and 5 in the middle of the week, Susanna Waters will present also a poster, and that's based on the PD-REACT study, where we have information about both the fall rate cognitive measures, UPDRS-subscales and apathy scales. There is an analysis performed on that, very interesting. So you will hear more from the coming week. And also, I'm sure we will report back on that. So with that, I think it's time to hand over back to a Q&A session.

Thank you so much, Kristina and Nicholas, for that presentation. We will start the Q&A by letting in Fredrik Thor, analyst with Redeye.

So my first question was about can you explain the kind of the mechanistic rationale for showing an effect specifically in this mid plasma group with a scientific rationale or mechanistic.

Yes. A very good question. It's been known since 40 years back, 35, 40 years back that when you activate the cortex, you have with -- if you increase the tone of monoamines in the cortex and the first studies were done with dopamine agonist, but this is known for norepinephrine as well. You get a -- first, you get a very nice response, positive effect, for instance, on cognitive function, but then you get over a hump and downwards again. So it's a known biphasic effects. And this is known, for instance, ADHD drugs, methylphenidates, amphetamines, they have this property clinically. More recently, there have been a lot of publications relating to cannabinoid drugs, which also seem to have this biphasic effect in terms of benefit for patients needing that kind of treatment, mainly for neuropsychiatric symptoms. And then also in -- for other types of this like seizures, for instance, there are lots of drugs which have this kind of bell-shaped dose response curve. So it's not a surprise that, that exists. For us, it was a revelation that we actually found this in Parkinson's patients at this specific dose range.

Got it. And the next question was about the balancing of background characteristics in this mid plasma group compared to placebo. How similar are they to the placebo group in background characteristics?

As I mentioned initially, there are clear similarities between -- there is no huge imbalance in the populations in the different dose arms or in the different concentrations arms that we have created. But there are subtle differences, which we are working on to look if that could have an influence on the placebo effect because the placebo effect is an interesting thing in this study, and we need to know more about it. And there are certain aspects which we are working on where we think we have some understanding of what may have been one or at least one reason for the large placebo effect, which differentiates it from the other treatment arms.

Got it. And maybe a final question about just anything about the time line or what's the next step? What would you want to see in the next stage to move forward and so on?

Do you want me to go?

I can take that one.

Yes. First of all, we need to complete all the analysis of the study. And what we need to do and what we are doing is adjusting the -- our development plan for pirepemat according to these new findings. From a development perspective, this is a really important set of data that we've generated. We have -- and we have actually achieved the goals that we set out with the study, although we didn't meet the primary endpoint as we have pointed out so many times. We have achieved the goal in terms of understanding which plasma concentration should we have, how should we manage these patients, how should we stratify these patients into a trial. So the next few months will be we will be working on the specific technique to reach this specific plasma concentration in as many patients as possible entering into a trial. And that's something where we have a very good idea and understanding of how to do that.

And I can just comment about this also, as a pharmacist by training, I can see that this has really the potential where we have defined the therapeutic window. It's really good that we could have really specifically targeted treatment for each of the patients, so to make sure that they all get a good response. So I think there are opportunities now with pirepemat so to say.

Yes.

Thank you, Fredrik Thor of Redeye. I will soon let the next person -- next analyst in, but there's a question from a viewer that I found very interesting, and it goes, "How does the plasma concentration correlate with the dose since there are both low and high plasma concentrations? Should the middle group be from both of the dose groups?"

A very, very good question, and that is correct. The conclusion drawn by the questionnaire is correct. In this middle plasma concentration range, we have patients who experience the lower range concentrations for the high dose as well as higher concentrations for the low dose. And the trick now for us is to develop a technique to get as many as low-dose patients into this segment of efficacy and get the high-dose individuals with high doses down into this group. And we think we know how to do that.

And even though it sounds complex...

It's not.