Ladies and gentlemen, thank you for standing by. Welcome to the Lundbeck Investor Telephone Conference. I'm Moritz, your Chorus Call operator. I would like to remind you that all participants will be in a listen-only mode, and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for a question at any time by pressing star and one on your telephone. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it is my pleasure to hand over to Johan Luthman, EVP Research. Please go ahead.
Thank you very much, and welcome everyone to this investor call, which is happening in relation to a readout that we had very recently with our Lu AF82422. It's an alpha-synuclein antibody. I will come back to the mechanism of action a little bit more in detail in the coming slide, but it's the disease-modifying approach to multiple system atrophy, and I will also describe the indication a little bit more. But before I go on, I'd like to remind you about the disclaimer, that this is, of course, a presentation of headline data from a very recently readout study. So, any forward-looking statements that I would have are made on behalf of Lundbeck, of course, but we have not gone through details of the data, and I cannot provide full granularity on what we have in from this study.
So just a few words about Multiple System Atrophy. It's a horrible disease. I think I can start by saying that it's a very rapidly progressing neurodegenerative disease. It has no treatment to offer today. Symptomatic therapies that are used are really primarily off-label use of various therapies. It's disease with many symptoms, but it's a disease that leads to degeneration on nerve cells in the brain. There are actually two forms of the disease, a cerebellar form and a parkinsonian form. The parkinsonian form is, as you hear from the name, more similar to Parkinson's disease and may actually initially be misdiagnosed. While the cerebellar form is, if anything, sometimes misdiagnosed with ataxia type of diseases. But both of them are defined by a very, very clear pathology at postmortem.
It's an orphan disease, but as I often say, it's a fairly common, rare disease. It's one of the more common diseases in the rare disease field, but it's, as I said, no treatment around, so it's by definition an orphan disease, viewed by most regulatory agencies. And I'd like to recall you that we already have this designation in Europe for the molecule, and we also have what is called Sakigake in Japan for this molecule. The drug, of course, is a disease-modifying mechanism, and I'd like to go through a little bit more in detail how we think this molecule works. This is based on many, many years of research on alpha-synuclein as a pathogenic mechanism in both Parkinson's disease and multiple system atrophy. In fact, multiple system atrophy is a more specific disease for alpha-synuclein.
Parkinson's disease often comes with more comorbidities. And in this particular disease, we have a pathology that's quite different from Parkinson's disease. The alpha-synuclein aggregates are actually affecting oligodendrocytes, which are the insulating cells building the conduction, sort of, myelination around nerve cells in the brain. And that by affecting those cells, you have a retrograde effect on the nerve cell itself, and it's dying off. What we're trying to do here is to basically mop up the release of alpha-synuclein aggregates. By binding with an antibody to those aggregates, we actually enhance the clearance by the phagocytotic system of the brain, the microglia, to clear away those aggregates that are decorated with the antibody. It's an IgG1, which means that it's actually actively helping the brain's microglia to clear the alpha-synuclein aggregates.
So it's an, has an active Fc region , which is another clearance mechanism shown to be quite important to really enhance the efficiency of the clearance. This particular molecule, Lu AF82422, was developed by Lundbeck, but it was initially a joint research, a collaboration between Lundbeck and Genmab. But the molecule has been taken through early research and development by Lundbeck. So this is the study that we just had a readout, the so-called AMLET study, which I'll need to emphasize, was a, or still is, because it's still ongoing with an open label arm, a small proof of concept study.
The way we like to do studies in Lundbeck, very challenging disease, of course, traditionally people do big studies for new generation, but we tried to define a study that was tailored to, in as small size as possible, give a decent signal of the molecule working. As you can see from the graph here, we enrolled sixty-one patients from sites in US and Japan. We had three sites in Japan, and the rest were in the US. The study had a design of one dose arm and one placebo arm, and it was imbalanced randomization, so we had forty patients or forty-one patients on the active arm and twenty on the placebo arm.
So a very small tailored study, but a fairly long-term study, with primarily looking at an endpoint at twenty-four weeks, but we went on forty-eight weeks and beyond, long-term study. So people actually were on the study for various lengths of time, while the endpoint was at the defined time point. The main readout here is UMSARS. UMSARS is a primary readout that has been discussed in this field, and we've been, of course, to the regulators agreeing to use this scale. But it's something that is fairly new to the field, of course, since people have not really gone into this indication much in the past. Of course, we have the inclusion and exclusion criteria, and sometimes people get this disease at a fairly young age. So you see the ranges from forty to seventy-five years.
And, as obviously clinical diagnosis, it's a possible or probable MSA diagnosis, and the diagnosis was made according to new updated criteria for the disease, quite recently published. As I said, this is a fairly rapidly progressing disease. So, during this time period, we anticipated that we would be able to detect some effect on clinical progression, and that is really what we've been looking at primarily with the endpoints, but we also had endpoints related to biomarkers, and here you see this lot of different readouts we had: from disease progression with the UMSARS readout, various parts of it, functions, global impression, CGI-S, et cetera, and then we looked at autonomic symptoms, global disability, various disease milestones, speech, swallowing, et cetera, and also how people progressed on the disease to a later stage diagnosis.
Health-related quality of life measures and MRI biomarkers, as well as two different sets of biofluid biomarkers, of which NfL in blood and also CSF was taken. And then obviously, we took a look at the pharmacokinetics of the compound. So a rich set of different readouts in the study. So, when we looked at these different readouts, I think I actually skipped this slide. I'll go to the next slide here. I think it's important that we look at the baseline characteristics of the study. Obviously, with such a small study, you can be prone to small variabilities in inclusion having some effect on the readout. But looking at the group of patients we included, it looks very well balanced. We have obviously people with the MSA-C form, the cerebellum form.
That is a dominating form, which is also dominating the study, but we also had patients with the MSA-P form, and we will not talk about this today, but obviously we have possibilities to look at various subgroups here, but please note the small sample sizes here. In terms of sex distribution, it was very much the expected, about an even split. Race, yes, you heard that we had several sites, three sites in Japan, so we had a national contribution to the study, but otherwise, it's quite dominated by Caucasian individuals in the study. Again, the diagnostic criteria, we're following the probable or possible diagnosis. Fairly short time since diagnosis, we tried to get people into the study as early as possible.
So you can see that it's not a very, very long time with symptoms or of course, with diagnosis, which obviously, with this, little complicated disease, may take a little time from symptoms to diagnosis. You see some measures on baseline, data on NfL, et cetera. The disease stage was reasonable, severe, but since we were aiming for early-stage patients, it was not a very, very advanced stage of the disease. Many patients had orthostatic symptoms, problems. You see here about 30%- 40% of the patients. So, what have we seen with this study? Obviously, we got the data just, early today, to really look over, but I think overall, I would say it's encouraging. We did miss on the primary endpoint, but that was trending in the right direction.
And I think it's important to emphasize that we also had a number of other measures that are listed before, and all the measures we look at generally are trending in what I would say, the right direction, including biomarker endpoints. We will come back to details about this, so you have to apologize. I'm not going to go into the details of the secondary and biomarker readouts in this call. We like to analyze this more in detail, and we like also to primarily address the scientific community with those data moving forward. And of course, we are also looking forward to discuss this with regulators moving forward. But I think it's also important to say this, this was a very tolerated therapy. We really didn't see anything of concern here.
So some of you may know about this ARIA-E and other things you may see in other indications when monoclonal antibodies addressing pathology of protein aggregation. We have not seen any safety signals of any kind similar to that. So overall, a very, very tolerable treatment. We do emphasize, of course, that we're looking at progression of disease. And what we're looking here is really the UMSARS total score over time. And that's where we saw a trend of slowing the progression of disease, which is, as I emphasized at the beginning, fairly rapidly progressing disease. So we had within that time frame, a decent possibility to see effect on disease progression, and that's what we see with the trend data.
So with that, I'd like to summarize the finding with this first-in-class antibody, which has, if you look at this, profile in vitro and preclinical data on this molecule. We have pretty strong data on that. It has a good binding, high-affinity binding to alpha-synuclein, and prevents, in animal models, the aggregation and progression of disease. Now we're moving forward with this study testing the proof of mechanism and also proof of concept for this molecule. We believe that we have definitely solid proof of mechanism, and it looks like we have a clinical signal here that encouraged us to move forward in the development with this molecule. That brings, of course, hope for patients with this disease, but we have, again, to be very, very careful with this.
It's an early study, small study, but it's enough for us to say that we most likely are going to progress with MSA soon with this molecule in further development. So with this, I'd like to hand over for Q&A.
Ladies and gentlemen, at this time, we will begin the question and answer session. Anyone who wishes to ask a question may press star followed by one on their touchtone telephone. You will hear a tone to confirm that you have entered the queue. If you wish to remove yourself from the question queue, you may press star followed by two. Participants are requested to use only handsets while asking a question. In the interest of time, please limit yourself to one question. You may then get back in line for any follow-up. Anyone who has a question may press star followed by one at this time. One moment for the first question, please. And the first question comes from Xian Deng from UBS. Please go ahead.
Hi, thank you. It's Xian from UBS. Could you hear me all right?
I hear you fine. Thanks.
Yeah. Thank you. So thanks for taking my question. So just one, please. Understanding that you might not be able to give a full data today, but just wondering, could you give us a sense about the possible next steps here? If I say, you know, I give you, let's say, you know, for the three possible scenarios, say you will start another phase II, or you progress directly into phase III , and then just for the sake of, you know, completion, even let's include a super blue sky scenario of let's say, accelerated approval. So just wondering, how do you think about those potential future steps? Thank you.
Yeah, thanks a lot for the question. I mean, obviously, we kind of ask ourselves the same three questions. So there are three good questions here. You should never sort of be too detailed in your planning before data readout, but when you have it, you have to move fast and decide what you do. But we will be very deliberate what we do as next step. Obviously, this is a smallish study, but as I said, encouraging data, which in different ways require, and we are obliged, I would say, to have a conversation with regulators about it, to understand what next steps could be in their eyes also. But these kind of studies are often followed by another study. The degree of confidence in the data we have is, of course, a big factor here.
I would say, based on the data we have, which, again, are encouraging, this will definitely be more a development program next step, if that is what we agree with regulators, that will aim for registration of a product. It's clear from the kind of data when we say it's, there is a degree of de-risking here, that encourage us to move forward with a more dedicated program towards registration. The accelerated approval question, obviously, that is something that people always ask, and this is something that I think we leave for a conversation with regulators more in detail. This is a very, very big medical need area. Obviously, it's a tricky balance, how much data you need and how much support you need.
So this is definitely something you can also design into upcoming program, how you may take different looks and cuts at data. So there are many, many possibilities here. But all three questions are super good, and we're going through them ourselves, and we'll probably come back with more information when we're ready for it. But this requires definitely an interaction with regulators, that's for sure.
Thank you so much.
The next question comes from Charlie Mabbutt from Morgan Stanley. Please go ahead.
Hi, thanks for taking my questions. Charlie Mabbutt from Morgan Stanley. I guess I'd be interested to know how much of a delay in progression you believe you need to show to make the product clinically viable. And I guess, how long of a study do you think you would need to show that sort of benefit if you had not seen a statistical significant benefit with patients up to seventy-two weeks? Or would it just be a case of a much larger trial size? Thanks very much.
Thank you very much. Again, really good questions. Yeah, there are different rule of the thumb ideas about what is clinically meaningful. I mean, obviously, we talk about two things often in clinical trials, statistical significance and clinical significance, and there are various ideas about what is clinically meaningful here or clinically significant. Rule of the thumb has often been 25% effect, but it also depends on the indication, how aggressive it is, and what you can offer on different readouts. Because what you do, of course, in these trials are looking at symptomatic readouts as a surrogate for an effect on disease progression, so you, of course, need to offer something that indicate that you're slowing down the progression. The data we have definitely indicate that that's going on.
So to go to your second part of the question, how long study and how much you'd like to see and how big it is? This was as small as a study probably you can do to look at proof of concept in a chronic neurodegenerative disease with reasonable solid data set to make decisions on, and that's really how we like to do development here. So with this data in our hands, we have much, much more information. Prior to this study, we basically had no prior information. Very few studies done in this field, and very little information from any natural progression study. Now we're sitting on a much better data set to decide how big a study would need to be and what power we would look at, and what sample size we would look at.
But again, it's a small study where we have encouraging data, so it's a matter also about how strong the effect is. So yeah, 72 weeks was the longer end, the outer end of the study. We have patients that were between the primary readout and 72 weeks, and the data set is actually dropping off because several people did not have time to finish that part from the primary endpoint to 72 weeks. Now we're going to have data gradually on an open label part of this, when everyone is switched over to active drug, which will also help us a lot to see how well the drug can, at a later time point, switch over and have an effect.
We are looking forward to something in the ballpark range of 25%, and it's definitely a bigger study, but time-wise, I think we did a really good study in terms of the primary readout and maybe allow people to go on longer time. Did that answer your question?
Yeah. Yeah, thanks very much.
And the next question comes from Manos Mavrikakis from Deutsche Bank. Please go ahead.
Hi, thank you for taking my question, which is basically what mechanistic or clinical hypothesis are you already forming in your head as to what could be going on that could either explain the results, or in other words, help you see a statistical significance in the next study? And, for example, could neurofilament difference between the two arms, be responsible for part of that result? Because as far as I saw it, there was a little bit of an imbalance there. So can we get your thoughts? Thank you.
Yeah, thank you. Yeah, I don't think we have talked about the neurofilament and imbalance, but you mean the baseline data, I assume, in the baseline data of the neurofilament. Is that your question?
Correct. Yeah.
Yeah. Yeah, that's not a very big imbalance, I would say. And you really look at change from baseline on neurofilament. So it's the individual patients change that is really the most important one. But going back to your mechanism here, I think this, of course, is based on a theory that we've been working on for many years. And when I say we, it's the scientific field, different companies, different academic groups have worked on the idea that there is a seeding mechanism, and I went through that little bit in one slide. We believe that there is some aggregation, extracellular aggregation, alpha-synuclein, that is basically spreading like a prion disease or something like that, a pathogenic aggregate of alpha-synuclein. And that is spreading, affecting, in this case, glial cells more than nerve cells, which is a little different from other aggregation prion-like diseases.
We are basically hindering that spread with the antibody. We're stopping that spread, and then, of course, by protecting the oligodendrocyte from exposure to that toxic agent, we may have an effect. That's the theory, and that's what we've shown in recent, reasonably good preclinical studies. It's always a degree of translational challenge here from animal models, in vitro models to humans. We do measure alpha-synuclein in CSF and the effects on target engagement. I will not go through any detail here, but we have previously talked about that we have target engagement, so we have as much, as much as possible, shown that we actually engage the target in humans, which is important. Of course, we cannot get into the brain and look at what the microglia is doing with alpha-synuclein, but the assumption is that that preclinical data translates.
The neurofilament biomarker reader is a great one, but unfortunately for MSA, we have very, very little prior data. You know, for other diseases, we have a lot of prior data. So quite frankly, we don't know what neurofilament may sort of give us in terms of biomarker read in a population like this. We don't even have natural progression data on neurofilament. So we are breaking new ground here in many ways. We did have a natural progression study run in parallel, but we did not collect neurofilament in that study.
So this is something we have to model on the study we have today, and we basically have the only data set in the world to look at this in a decent way for deciding whether that is going to be an important readout or other readouts like MRI are equally important. I hope that tried to explain. You asked a technical question that is a little hard to answer, but more than based on sort of preclinical data that we have so far. I hope that answered the question reasonably well.
As a reminder, anyone who wishes to ask a question may press star followed by one at this time. And the next question comes from Lucy Codrington from Jefferies. Please go ahead.
... Hi there. Thank you for taking my question. So just on the split between the two forms, is there any difference in the rate of progression between the two forms of MSA? And could therefore that have influenced what you saw in the study, and might it be possible that you prioritize one over the other? Thank you.
That's a really good question that we're looking into really right now. And I don't want to go into details because first of all, we go into very, very small numbers. We already had a small study. But obviously the two different diseases are, sorry, I should rephrase that. Within the disease, the two different types are quite different, which makes that analysis extremely interesting. So we're definitely going to look more in detail into the different subtypes. How that will influence our decisions, who to include in in coming studies, it's really hard to say at this stage. But it's safe to assume that basic differences in the pathology, distribution, as you see in the two different diseases, may also translate to different treatment effects.
And, and then we're looking into that, and we're happy to come back with that because it's a really, really important question.
Thanks.
And we do have a follow-up question from Xian Deng from UBS. Please go ahead.
Hey, thank you so much. I just want to try to push my luck a little bit, so in terms of primary endpoint, I understand that you probably won't tell us the exact numbers, but would you be able to describe how does the response curve actually look like? Can you actually see them clearly separated, even though it doesn't hit statistical significance? Thank you.
Yeah, thanks a lot. You're pushing your luck a little bit, but I am willing to endeavor a little bit into explanation here. I mean, obviously, the endpoint is looking at progression, so in order to see some difference, you need separation between the two, and you may ask, when does it occur? How long does it stay? Is it sustainable, et cetera? There are many, many questions there that we didn't primarily address, but the whole design is, of course, to look at separation of the two curves. We had different statistical approaches here, which also is important. This was a Bayesian statistical primary approach, which we like to explain more in scientific meetings.
So it's not the usual approach that you're used to, but we, of course, also look with frequentist approaches in this statistical analysis. So we were innovative not only in the trial design, we also had an innovative way of approaching the readout, which obviously were discussed with regulators beforehand.
Thank you very much.
Ladies and gentlemen, that was the last question. I would now like to turn the conference call back to... over to Johan Luthman, EVP Research for any closing remarks.
Now, thank you for joining this call. We are, of course, as I said at the beginning, encouraged by this data. It's a, it's a field that is full of very challenging scientific questions and, of course, extremely challenging medical questions. As a company, we really need to be at the forefront of those, diseases and try out new mechanisms and try out new indications, and to me, who's been in this field for many years, it's a rare event to see something that, is encouraging, so obviously, this is something that is important for the company, and it's important primarily for, patients that we will progress with this and try to explore what this can bring in terms of value to them in the future. Thank you very much.