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

Good morning, and welcome to this update on the mesdopetam project. My name is Gunnar Olsson and I'm CEO of IRLAB. With me today, I have Nicholas Waters, Head of R&D, and we will take you through this presentation. Mesdopetam is a great opportunity in an area of very large unmet medical needs. It is anti-dyskinetic, has anti-parkinsonian effect and this coupled with an excellent safety and tolerability profile. On top of this, also significant differentiation versus available treatments for LIDs. We've identified the dose for Phase III, the 7.5 milligram twice daily. We have an excellent IP situation. We have potential for exclusivity into the early 2040s. And this is a product with great opportunities for life cycle management. The first run will, of course, be the treatment of LIDs. Second line could be optimizing of levodopa treatment without driving LIDs. Third line could be prevention of levodopa-induced dyskinesia since our animal data indicates also a preventative effect of mesdopetam. Other areas is Parkinson’'s disease psychosis and toward dyskinesia. The type of dyskinesia we see in patients with long-term treatment with neuroleptic, a very large population. It is not just us in IRLAB that believes that we have a fantastic potential. Here, I have a quote from one well-known opinion leader in the field, Karl Kieburtz and I read his quote. “"I think the mesdopetam data package is one of the most compelling available in the symptomatic treatment of Parkinson’'s. Mesdopetam has the rare ability to both improve dyskinesias and improve parkinsonism and, at the same time, appears to be well tolerated. I expect it will have both clinical utility and commercial success." Karl Kieburtz who used to be the Chairman of the U.S. FDA Advisory Committee for the Peripheral and Central Nervous System Diseases. So what is the basis for the great potential of mesdopetam? I think it's the clinical data package that we have now. With all the good data on safety and efficacy, and it comprises of the full analysis of the Phase IIb study data. We have the 3 studies in Phase I that Ipsen ran. And the studies that we have previously reported, the Phase I/Ib and Phase IIa studies. Secondly, we have a precedent regulatory approval of treatment for PD-LIDs. And our data from the study is in alignment with that approved product profile. And thirdly, we have a very strong IP position. So with this as a basis, we have worked out this agenda for today's presentations. Nicholas Waters will take us through the mesdopetam Phase II data, and he will also discuss the Phase I studies performed by Ipsen. I will then come back and talk about differentiation and commercial positioning of the future product with mesdopetam. I will also take you through some considerations regarding regulatory precedents in PD-LIDs and how this is important for us. Then we'll come to way forward with the project and we will end with a Q&A session. So with this, I hand over to Nicholas. Nicholas, please tell us about data from the Phase IIb study.

Thank you, Gunnar, and thank you all out there watching and listening today. This is the first opportunity we have since we prepare or presented the top line results of the Phase IIb study that we performed previous years. We are extremely happy to be able to present some more in-depth information from that study. The design of the study, we've discussed that at several occasions before, but as a repetition, this was a placebo-controlled study where we had 1 arm of placebo and 3 arms with mesdopetam, 3 different doses, 2.5 milligrams, 5 milligrams and 7.5 milligrams twice daily. We enrolled patients in the trial who have troubles with dyskinesia and of course, Parkinson's disease as a diagnosis. We're looking at the functional impact of dyskinesia in these patients need to have a certain degree of complications. And then as a third important requirement, they should be on stable antiparkinsonian treatment. And that is usually a stable dose of stable treatment regimen with levodopa throughout the trial. So that we don't get any confoundings due to changes in levodopa treatment strategies. The study was a 3-month study. We had a screening period, which ran between 3 and 1 month. And then we had a run-in period where the patients were treated. All patients that were randomized were actually treated with 5 milligrams, the first 10 to 12 days in the study as a starting dose. And then they received the randomized dose that is 7.5 milligrams, 5 milligrams or 2.5 milligrams, of course, blinded. Between visit 2 and visit 3, in the study protocol. The patients and that is between 2 weeks and 4 weeks of the study. The patients were allowed to adjust their dose one time, and this was a down titration that they could do during the trial. These are important aspects when it comes to the analysis of the results, which I will show you. The objective here with the study was, of course, to investigate the efficacy and the safety, and further say build on the safety database for mesdopetam. We had a long list of endpoints in the study where we looked at the primary endpoint was good ON-time based on Hauser-diaries that we collect in the study where the patients actually fill in on a daily basis several times during the trial, the different motor-states ON with troublesome dyskinesia and without dyskinesia of and bad ON-time and sleep -- those are the 3 things that come out of Hauser diary. And then we use the Unified Dyskinesia Rating Scale and a number of other assessments were done during the study. So to analyze the data or in any clinical trial, what you do is you look at the -- what is usually referred to as the modified intent to treat population. In our case, we called it full analysis set. And the full analysis set was the data we presented in January, a top line result was based on the full analysis set. And these are patients who are randomized to treatment and receive one or more doses and then have 1 -- at least 1 post baseline data generation. And then -- and this is independent of the actual dose they have received during trial. So if they were randomized to 7.5 milligrams, they are assigned to the 7.5 milligram cohort in the analysis even if they actually reduce the dose to 5 milligrams during the trial. So that's an important thing to remember when we talk about the results. And then we have the -- we will show today some data on patients who are in the protocol adjusted dose set, which we call PS in this presentation. And these are patients that are compliant to the protocol during the study, they take the medication to a very high degree, at least more than 80% of the time -- or the drug that we've given, they take. And then they also follow a number of aspects of the protocol perfectly. And also, when one analyzes the data -- one analyzes the data based on the dose they actually took during the studies. So if they were assigned, for instance, or randomized to 7.5 milligrams, and took 5 milligrams, they will be assigned to the 5-milligram group in the analysis. Statistical aspects -- considerations are quite mainstream. We are looking at the least squares mean differences versus placebo in this trial using an MMRM model, which is the commonly used statistical models for this type of data. The full analysis set was based on randomized dose as I already told, and then we had the protocol compliance subjects were based on the dose they were taken and also following the protocol. When it comes to the primary end point, we published in January or informed that we actually did not meet the primary endpoint. And this graph here shows the full analysis set analysis on the primary endpoint, which was good on time, based on Hauser-diaries. The interesting aspect of the Hauser-diaries is that when we look at more refined populations in the study all the way to the protocol compliance studies, we see a consistent dose response of the drug, which was the purpose of the study. And we have a nominal significant effect at the 7.5 milligram dose, actually reaching about 1.75 hours improvement in good ON-time in this trial. So despite the fact that we missed the primary endpoint, we actually have an effect on the diaries in this study, looking at the patients who actually took their medication throughout the study and calculating based on the dose they took. A secondary endpoint in the study was the unified dyskinesia rating scale, which has been used in dyskinesia studies over the past decade. This is an endpoint which or a scale, which has been preferred by the FDA in previous trials and previous approvals. We do see in the full analysis set as presented in January, we do see a very clear significant effect on the UDysRS -- and the UDysRS -- I have to go back 1 step. The UDysRS is comprised of 4 sections, 1, 2, 3 and 4. The FDA advised the sponsors today to use only 1, 3 and 4. Previous approvals have been based on 1, 2, 3 and 4. Remember that when you compare the data we have here with other studies. So we had a very significant -- very clearly significant effect across the doses, 2.5 milligrams, 5 milligrams and 7.5 milligrams in the full analysis set. So already there, we have actually fulfilled the criteria for an anti-dyskinetic treatment. And then looking at the objective part of the scale, which is Part 3 and 4, these are physician-rated -- solely physician-rated parts of the scale. We also see a significant effect. And this is important -- the regulators across the globe wants to see the UDysRS in total 1,3, 4, but then broken down also into the subsections, and they want to see efficacy there as well. Looking at the PS dataset, we see then in an improvement in the size of the effect. We see a clear dose response pattern across the doses that we have administered during the trial. And the effect that we see is clinically meaningful in the sense that doctors around the world has investigated what is the clinically meaningful effect, and we actually passed that bar with mesdopetam, which is, of course, were reassuring. If you look at the objectives core, the same thing happens there, slightly larger [ effectively ] setting the full analysis set, but also a significant effect across doses. So on the UDysRS scale, we can be quite confident that we have a clear and unprecedented, I would say, efficacy with Mesdopetam. Another very important aspect of trying to develop a compound for the treatment of dyskinesia, in Parkinson's patients is that you do not want to hamper other symptoms of the disorder. And one problem that is the Parkinson's patients experienced during the course of the disease is OFF-time, increased OFF-time over the course of the disease. And OFF-time must not be increased by a treatment to treat dyskinesia. That's a requirement. In fact, what we see in the full analysis set is the contrary. We do see an improvement or a reduction in the OFF-time up to roughly an hour in the full analysis set that did not reach statistical significant in the past. However, it's a clear dose response that we see there. And looking at the protocol compliance subjects, in the study, we actually see a significant effect at the highest dose 7.5 milligram and the size of the effect is on par with what is perceived as clinically meaningful reduction in OFF-time. And we've seen approvals actually back in history of anti-parkinsonian drugs solely on circa 1 hour of improvement in OFF. So already here, we have an effect which is really valuable. Another aspect of drug development and perhaps one of the most important is the adverse event and safety profile that the compound has and introduced here a flow chart of the different doses and the -- how many patients who came through in the different cohorts. And for those interested in mathematics and doing that, we'll see that the frequency of dropouts during the trial is similar across all those arms from placebo through to the highest dose of 7.5 milligrams. So we have a similar number of completers in each treatment arm in this study, which is reassuring from a safety tolerability perspective. Looking more into detail of side effects. And here, we're looking at effects that were reported at more than -- a frequency of more than 5% or incidents higher than 5% in the study. And also here, we can simply say that the effect of Mesdopetam on the side effects side of the analysis indicates that there is no difference from placebo whatsoever. And actually, at the highest dose, the incidence is significantly appreciably lower than we see in the placebo group. So from a safety and tolerability perspective, the drug is really -- really usable in this population. So some strong conclusions that we can draw from the Phase IIb study is that we do see dose response and clinically meaningful anti-dyskinetic efficacy across the endpoints that we have studied in the study in the different scales. We see improvement in unified dyskinesia rating scale, nominally significant and clinically meaningful. We have improvement in good ON-time across doses, although we did not meet the primary endpoint. We have a consistent dose-response pattern in reduction in OFF across different analysis populations which indicates that the drug besides being an anti-dyskinetic also has to put potential as an anti-Parkinsonian drug. We don't see any hampering of normal motor function. We don't see any increases in PD symptoms, Parkinson's disease symptoms. So no increase in Parkinsonism with the drug which is, of course, necessary to be able to move this forward. The safety and tolerability profile was on par with placebo at all doses studied. So we have a quite wide dose range here where we can actually treat patients without any risk of side effects or adverse events. The plasma exposure, which I didn't show on the slide here, but in principle, it's linear and dose dependent. And this is in line with what we have shown before in Phase I studies and published. One of the most important aspects of a Phase IIb study and the dose finding study is to actually achieve the main goal to find a dose to study in further trials. And we have achieved that goal, the 7.5 milligram BID dose, which we think is the best dose going forward with the product. During the course of our collaboration with Ipsen, which was a collaboration that was really, really professional and very, very efficient in terms of generating data during the 2 years of work with Ipsen. And Ipsen performed 3 -- besides developing the CMC, besides producing drug product and API -- they did a lot of interesting studies and necessary studies which are necessary for submission of Phase III studies. They did a comparison between an Asian population and a non-Asian population in terms of pharmacokinetic properties. This is a thing you need to do in drug development. And then the conclusion is that the pharmacokinetic profile of mesdopetam is similar in these populations, which is reassuring. There is also a necessity to study drug-drug interactions and that is how does one other drug that patients take in the population affect the pharmacokinetics or the plasma concentrations of your test substance in our case mesdopetam -- and we will see -- the conclusion is there is a very low risk of drug-drug interactions. And this is really important, but this suggests for the further development that is no need for additional clinical drug-drug interaction studies. And perhaps more important, no restrictions on the patients that we can include in the studies in the further development. So we have a broader set of individuals with PD that can be included in the coming trials. Then a very important study, the mass balance study, that is a study where you're really in detail evaluate where a drug goes and which pathways it takes into the body and out of the body, if it stays in the body or if it's eliminated fully, and the total conclusion from this study was that there was no signs of risk of drug accumulation at all in the body. All drug is excreted over time and there is no risk for accumulation. So these studies are important pieces of the big puzzle of building a file for future MDA. The implications, as I've already alluded to, is that we have predictive PK with low degree of variability. And we have -- we anticipated a very simple and uniform dosing that is perhaps the 7.5 milligram dose which allows for a low risk of dosing errors since we have such a tight variability in the plasma concentrations after a given dose. Gunnar, please come back and talk about the differentiation and commercial positioning of the compound.

Thank you, Nicholas, for that good presentation. I will now talk a little bit about commercial aspects, and I will focus on differentiation and how we see a future positioning of mesdopetam as a product. I'll start by just recapitulating the accessible market. And you see here from some key markets that about 5 million patients with Parkinson's disease. We see that a proportion of those will develop PD-LIDs. And a proportion of those with LIDs will get treatment. But I think that the 2 key take-home messages from this, that is that the prevalence of PD-LIDs is in the range of 25% to 40% of the Parkinson's population. And if a patient develops LIDs, then there is a high likelihood that, that patient would want active treatment and also get treatment for the LIDs 80% roughly. Now to differentiation. I know that this is a slide with lots of data, and I will take you through it step by step. Here, we compare our mesdopetam Phase IIb data with your safety and tolerability with amantadine ER that is GOCOVRI -- so actually, the amantadine table here, the right hand, that is taken from the labeling text in the United States approved by the FDA. We start here by looking at the placebo groups in the 2 sets, the mesdopetam placebos and the amantadine placebos. And you see very low rates of reported AEs or side effects. That to me, indicates that we are dealing with pretty similar populations in these 2 different datasets. If we then go to amantadine ER, we see a very frequent set of side effects. 1 in 5 of the patients cannot continue treatment, has to withdraw. 1 in 5 will develop hallucinations and we could continue the list down. But let's instead look at the mesdopetam active treatment column. Here, you see it as described by Nicholas that our safety tolerability profile is on par with placebo, a very marked degree of differentiation. And then we should understand that today, amantadine ER is the only approved drug for treating PD-LIDs. We have here summarized some important characteristics or properties of a treatment and I won't go through every single box here. I think that when we leave the slides on our homepage, anyone could study them in detail. But I wanted here to just make you aware of the fact that when we look at this, we see mesdopetam ticking all the boxes in a positive way. When we look at amantadine, as you see in most of the fields, we see that the drug doesn't match what we think is the ideal position for a drug. So we do have a very marked differentiation potential for mesdopetam, opposite the available treatments for LIDs. So the ideal profile for LIDs medications will actually be a clear anti-dyskinetic effect, a good safety and tolerability profile as well as no signs of increase of Parkinsonism. But this is really the profile that you heard being described by Nicholas, when he went through the data from the Phase IIb study. So when we put this all together and we think about what would be the positioning of mesdopetam as it hopefully comes to the market. Well, we see that this is a first-line treatment of levodopa-induced dyskinesia. It has anti-dyskinetic efficacy, anti-parkinsonian effect, excellent safety and tolerability profile, and it is simple to dose, and we can use it in the broad PD-LIDs patient population because of the predictable PK, no known drug-drug interaction and no contraindication. Leaving the commercial aspects and now moving into regulatory considerations that we, of course, have been discussed and evaluated as we now see Phase III coming up. Then of course, we have then spent time looking into all available -- for us, available regulatory documentation from the approval of amantadine ER in the U.S. What we can extract of it, that is the endpoints that was of importance in the product development and that was then later on approved by the FDA. As primary endpoint, UDysRS Part 1, 3 and 4. Key secondary endpoint UDysRS Part 1b and 4 -- and the safety endpoints OFF-time can't accept that being worse, MDS-UPDRS Part 2, again, should not be worsened and "Bad ON"-time shouldn't increase. And then as an optional secondary endpoint "Good ON"-time. So this is what we have been able to take out from the precedent with regard to approved product for PD-LIDs in the United States. So let us now see where does the Phase IIb data fit into this. As you see here, we have the UDysRS Part 1, 3 and 4 be ticking the box. And we have the safety endpoints, the OFF-time, the MDS UPDRS Part 2 and "Bad ON"-time also ticking the box. And that means that already now on the past data, if we can replicate that in a Phase III study, we actually fulfill what we believe will be the requirements for registration of Mesdopetam. If we now look at this and we take the PS analysis into account. We actually see that we are ticking all the different boxes. So the task for us now, that is with all the knowledge and experience from running these type of studies. We will build that into the Phase III program and we will aim to reproduce what we saw in the Phase IIb study. I think that this is time to also have another quote from another well-known key opinion leader that we have consulted and discussed our data with. And this is Professor Warren Olanow. And Professor Olanow is a key clinical researcher in the field of Parkinson disease with a very special interest in LIDs. And he just summarized his view in one short sentence, "This is a really important drug". So now -- we have taken you through new data that we now after the agreement with Ipsen, we've been able to communicate, and we are very pleased to do so. We have already now, of course, started to think about what is the next steps forward. And as you all understand, we are now working together with Ipsen to have a rapid transfer of all different parts of the mesdopetam project to IRLAB .And we are preparing for an end of Phase II meeting with the FDA, and that is to define how we should design the Phase III program in detail. And to do so, we are now starting to prepare a briefing book -- and that briefing book, we are bringing together in collaboration with regulatory and clinical advisors. And we also have support from Ipsen to do so. When we have that document in place, and I should stress here that we now have all the information that needs to go into the document. So we don't need to produce new information. We have it now. When we submit that to the FDA, then we can also ask for a meeting and hopefully, we can get a meeting time then decide it upon. In parallel, we will, of course, capitalize on options for financing of the Phase III program. And here, we will look into all options and possibilities. We will, of course, look into capital market routes. We will, of course, look into business development and partnering routes and at this early stage after having the project back. I can't give you more details than that, but we definitely will work on seeing the different options and see what is the best an optimal way forward for us. I should also comment upon the right side of this slide. Just a reminder, next week, is the MDS conference in Copenhagen and then additional data will be presented with regard to the Phase IIb study addition to what you have seen here today. Before I open the question-and-answer session, I just wanted to remind you about some key characteristics of IRLAB as a company. We are developing a portfolio of products that we aim to transform treatment of people with Parkinson, change the life of the Parkinson patient. At the moment, we have 5 products from preclinical development up to Phase III ready project. We are addressing the great majority of different complications and symptoms that an individual with Parkinson may have during the full course of the disease. So we are addressing things in the early Parkinson individual as well as in the late-stage -- disease stage. In IRLAB, we have pioneering biology and the unique ISP platform for identification of new candidate drugs. And all this is building on the profound knowledge base that has been build around the research group around the Noble Laureate Professor, Arvid Carlsson. Our strategy is very focused. We have the very deep understanding of Parkinson and we are now developing drugs that will help the Parkinson patient. We have validated our model. We have taken -- I shouldn't say, we have taken -- we've discovered a few molecules that we have taken all the way to now Phase III readiness. We have a broad portfolio. And I would actually dare to say that I think we have a world-leading portfolio within Parkinson's disease. And we are an organization that is positioned for success. So with that, I think it's now time to open up the Q&A session, and I invite Nicholas back here on stage. We will now have the Q&A session in the following way. You have been able to send in questions through e-mail. We have Tove, who is the receiver of all your questions, and she will now address the questions and read them out loud, and then Nicholas and I will see that we are responding to the questions.

Right. So we'll start with some clarifications on the clinical results, and we have a question here on what was the main reason for the dropouts in the study?

They go across a number of aspects and not always known to us, but sometimes the patients have decided to leave the study and sometimes physicians have decided that the patients leave the study. And that's indicated also in the slides that will be more details on that in the MDS conference poster. But in principle, there's no single reason that really can be pinned out. And as I said before, the adverse event profile and the safety profile is similar. So there's nothing to do with adverse event or safety.

And any comment on the dose reductions that have been made?

Equally across the different -- the 4 different arms in the study.

Including the placebo.

Yes, the 4 arms.

Right. So going into the clarification around the full analysis set, you did mention that a patient assigned a 7.5-milligram dose, later got reduced down to 1 of the lower dose -- they would still be evaluated in 7.5-milligram group. How come?

That's the way you do it. It's the modified ITT, your full analysis set strategy that is used for all studies. So that's nothing different from what you see in any presentation or publication on the clinical trial.

Let me just add here. But in this particular study, a dose finding Phase IIb study, the key thing for us as drug developers is really to understand how does different doses correspond to different degrees of effect. And this is why you always need to do this type of -- we call it per protocol or PS analysis so that you really look at what does an actual dose give in terms of effects because this is really where we need to select the dose for Phase III.

And that leads nicely into the next question because I was just -- are the protocol-compliant subject set is those generated applying the same statistical analysis that you do there.

That's the same statistical model, everything is similar. The difference is that the patients are divided in different -- into the right dose cohorts or the right -- the dose cohorts, they actually have -- the dose they actually had, and that they were compliant to the drug treatment more than 80% throughout the study.

So going into the -- more of the Phase III and path forward here, what type of study size would be needed to replicate the Phase IIb data with a decent statistical power.

I think the Nicholas is...

We can go look at precedent, we can look at the statistics with the data that we have. And the good thing about the Phase IIb study is that actually delivered those response. We have a fair understanding of the variability in the different endpoints. And all this taken together indicates that at least 1 Phase III study would be of similar size that we have already done in the Phase IIb, similar number of patients. Although here, in that case, we will have less treatment arms, of course. And to remind the audience, we had about 150 patients in this trial -- in the Phase III trial.

And do we want to comment anything further in regards to how we are looking to run the Phase III study on our own or finding a partner.