Hello, and a warm welcome to today's webinar with AlzeCure Pharma. With us today, we have the CEO, Martin Jönsson, Rolf Karlsten, MD, and PhD, and CMO, Märta Segerdahl. If you have any questions, please use the form that is located to the right, and we'll take that up during a Q&A after the presentation. And with that said, please go ahead with your webinar here, Martin. Thank you so much. Thank you, Martin. Welcome everybody to today's webinar, and today's presenters on the topic of pain and neuropathic pain and one of AlzeCure's assets. The presenters are Associate Professor Rolf Karlsten, who is a leading pain specialist. He's working at Akademiska, Uppsala, as well as Uppsala University, and he has also a long history in drug development and has been working at AstraZeneca. Then I have the pleasure to have my colleague, Märta Segerdahl, with me, and Märta is MD, PhD, Associate Professor, has a specialty as well in pain and anesthesiology, and has a history within academia, and then has also worked for very many years in industry. Has worked for companies like AstraZeneca, Lundbeck, and Grünenthal, et cetera. Then you have me, Martin Jönsson. I am the CEO of AlzeCure. I have a history in pharma with more than 20 years experience, worked at Roche and Ferring Pharmaceuticals. If we are looking at today's agenda, we are going to look at pain and the etiology and medical need, which will be presented by Professor Rolf Karlsten. Then we will go over and talk about our asset, our TRPV1 antagonist, and Märta Segerdahl will talk about that assets and the clinical results we are having and where we are heading. After that, we will have a Q&A session, and you are very welcome to send in questions, and we will answer them, and then we will have a very short concluding remarks and take-home messages, so that's the agenda for today, and just short on AlzeCure. AlzeCure, we are working and focusing on Alzheimer's and pain, areas of great unmet medical need. We are a spin-out of AstraZeneca, who were active in this field, and when Astra left CNS, AlzeCure was created by researchers from AstraZeneca. We have been sponsored by the Swedish Alzheimer's Fund, who is still an owner in the company, and we are based at Karolinska Institute, and we are working with so-called small molecules and developing first-in-class properties. We have three platforms. We have Alzstatin, which is an innovative, preventive, disease-modifying treatment against Alzheimer's, with the goal that individuals should not develop Alzheimer's. Then we have NeuroRestore, which is a treatment that we are developing to improve cognition, learning and memory capabilities. And then we have our platform of pain assets, where we have two, which I will come back and talk about. We are listed in Sweden at Nasdaq First North since 2018. As a company, our business model is to be a research and development company, and our aim is to out-license our project. Currently, we have four projects, and we aim to out-license one to two of those projects to then focus on fewer projects and finance the other projects with the out-licensing we are doing. Our pipeline looks as following. So we have NeuroRestore, our Alzheimer's asset, where we are focusing on improving learning and memory capabilities. Here, we have had a positive readout in phase one on safety, tolerability, and also target engagement, showing that we activate centers in the brain, which are key for learning and memory capabilities, as well as for the treatment of depression. Then in Alzstatin, we have two assets, and here we last year came with a new asset that we have been developing in-house. Now we have two assets that we are examining to decide on one, which we then plan to take into phase one. Then in our pain platform, we have ACD440, which we will focus on today, a TRPV1 antagonist, focusing on neuropathic pain. We on this asset have positive phase two data showing good safety, tolerability, and also pain reduction. Then our second pain project is ACD137, which is a negative allosteric modulator focusing on osteoarthritis. Here, we this year selected a new candidate that we are working on towards phase one. What is great for this year is that we have a new member in the team, the previous Global Head of Research and Development at Eli Lilly and who also was at AstraZeneca. He has joined our company, sitting in the board, and has also invested in Alzecure. Jan has a long history for working in the US, have worked on very many assets who have been approved in the US and have a vast experience. We are very, very happy to have Jan as a member of the Alzecure team. And in our platforms of pain that we will be focusing on today, we of course have TrkA NAM that I mentioned, where we are focusing on osteoarthritis. There we have more than 300 million patients and huge unmet medical need, and then we have ACD440 that we will focus on today, and more than 600 million individuals are suffering from neuropathic pain. Here we have an asset in phase 2, and this mechanism, the TRPV1, was awarded the Nobel Prize in 2001. With this, I would like to hand over to Professor Karlsten to present on pain. Please, Rolf. Oh, thank you very much, and thank you for your introduction. Well, we can actually take the next slide, as you already presented me. My presentation today is focused around different kinds of pain and also some epidemiology and the burden of pain. And we will go through some current pharmacological treatments, the ones we usually use, and also aspects of unmet medical needs. Take the next slide. When it comes to different types of pain, we usually talk about acute or chronic pain, and these are quite simplistic. They're just based on how long duration the patient has had his pain, how long time it has been. Acute pain, typical acute pains are postoperative pain or post-traumatic pain, which usually subsides when the lesion heals. Chronic pain, on the other hand, is pain that has persisted for more than three months, and that's the only definition, which is a bit, could be discussed a lot because it doesn't say that you have to have pain all the time. It can be some days a week, and it doesn't say anything about the etiology, so we also discuss pain from a mechanistic point of view, and then we divide it into nociceptive pain, which is caused by lesion or disease, which is due to a lesion that activates nociceptors. Neuropathic pain, on the other hand, is a lesion or disease in the somatosensory system. That means the nervous system, and a new term that has been accepted quite recently is the term nociplastic pain. The typical patient is Fibromyalgia or IBS. Here we talk about patients who have pain due to an altered nociception, despite no clear evidence of nociceptive and neuropathic pain. In the clinic, we see signs, evidence of sensitization of the somatosensory system. As I said, the main patients we see are the ones we call fibromyalgia. The fourth category is idiopathic pain, which is just a nice word to say that we actually do not know what the cause is, and that is not an unusual mechanistic diagnosis in at least a pain center. You can take the next slide. How common is it to have chronic pain? One of the biggest and most cited articles is from Harald Breivik in Oslo and his colleagues, who published in 2006, where they had telephone interviews with more than 46,000 people in European countries. They, in this study, classified chronic pain in adults that had a duration of more than six months, including at least the last month and several days a week. They also rated their pain at least 5 out of 10 on a numeric rating scale. As you see, six months here. It is usual that we use six months as a cutoff in the clinical trials because some conditions like postherpetic neuralgia, we see spontaneous recovery, and to avoid including patients who have spontaneous recovery during the studies, it's quite common to use this criteria. Of course, 20% of the adult population don't seek medical care. Many of these patients, they think it's enough to take some paracetamol or some NSAID, not even seeking medical care. There's a subset of patients that have been defined as having a high-impact chronic pain. In a survey that was published in 2019 from the U.S., where they looked at more than 15,000 individuals, and a pain duration of at least three months and almost every day, and they classified patients who had at least one limitation in daily activity and classify those as high impact chronic pain, we can see that 4.8% of the patients have that kind of pain. In this group of patients, we see the ones who seek medical care. You can take the next slide. But that's not the only thing. Chronic pain is costly for society. In a publication, in Swedish publication 2003, it was estimated that the cost from moderate to severe chronic pain in Sweden is around SEK 87.5 billion. And out of that, an overwhelming minority is indirect costs and SEK 7.5 billion direct costs in the healthcare. It is also a frequent reason for seeking medical care. It's estimated that 20%-40% of the visits to primary care, and around these, like 50% due to chronic pain. And it's also associated. Chronic pain is often associated with other diseases. Obviously, pain is a symptom of a disease many times, and they have a background disease. There are lots of comorbidities, psychiatric comorbidities, mainly anxiety and depression, and we have many elderly patients with cardiovascular and neurological and endocrine diseases, and this has a high impact on the way we can treat these patients, what kind of medications we can use. You can take the next slide. Didier Bouhassira in Paris, France, he had a publication, 2019, where he estimated the prevalence of pain in different neuropathic pain conditions. Obviously, these conditions are associated with pain, but not all patients actually have chronic pain, but here you can see that quite a substantial amount of the patients with postherpetic neuralgia, painful diabetic polyneuropathy, neuropathy related to surgery, MS, spinal cord injury, and stroke, have a chronic pain condition. And it's been estimated in France that the prevalence of neuropathic pain is around 7%, and of that, moderate to severe pain with a neuropathic characteristic is around 5%. You can take the next slide. Another aspect is that looking at the global burden of disease, and this was published in Lancet two thousand and twelve and has been repeated and with the same kind of results, but I show you here the original. And you can see the highlighted white ones with red arrows that are conditions that are usually associated with pain or in the top of these diseases that cause years lost in disability. Low back pain is the world leader. You can take the next slide. And also, other aspects of having neuropathic pain. There is a slide that shows the results from a study that was conducted at our center in collaboration with the Karolinska. The majority of the patients we had in that study were actually my patients, but it was our PhD student, Ann Forsström, who was involved from our side. And you can see here that I took the slide with SF-36, that there are many aspects of having a chronic neuropathic pain. If you look at physical function, physical role, obviously bodily pain, but also general health, vitality, social function, role, emotional role, and mental health, they are severely affected. And these patients have a physical role or physical function that is comparable to patients who have a chronic heart disease, and a psychiatric pattern that mimics patients who are treated for depression, and that's in the same patient. So this adds difficulty in treatment of patients with neuropathic pain. Now, we have to be aware that these patients are from specialty clinics, so this does not represent all patients with neuropathic pain, but these are the ones we see at special clinics. You can take the next slide. Looking at different types of pharmacological treatments that are used in clinical medicine, obviously, there are other stuff that we use at specialty clinics, but highly specialized clinics, but I haven't included those because they are just some few patients. When it comes to nociceptive pain, we use old, simple analgesics, paracetamol, NSAIDs, usually available from any store, and weak opioids like paracetamol combined with codeine, or in some cases, strong opioids. Neuropathic pain has to be treated in a very different way. Here, even though NSAIDs are the most prescribed medication for neuropathic pain, which is quite alarming, it has no effect at all. If it's a localized pain condition, we can use local treatments like lidocaine patches or capsaicin patches, but the mostly used drugs are antidepressants and antiepileptics. Some I call them mixed opioids, and the example is tramadol, having an effect on both the mu receptor and also decreasing the reuptake of serotonin and norepinephrine. In some selected cases, at least short-term treatment with strong opioids. The big group with patients with nociplastic pain are treated in essentially the same way as patients with neuropathic pain, and that reflects the possible mechanisms of action, meaning sensitization of the somatosensory system, which we can sometimes treat with antidepressants and antiepileptics, sometimes mixed opioids, but strong opioids are not a treatment that should be given to these kind of patients. The problem. One of the problems here is that only 30%-40% of patients respond to active drug treatment in trials and have at least 50% pain relief. If you look at placebo, it's usually around 20%, leaving the numbers needed to treat in a range of around 5-7. That's a figure that often is around, that we need to treat five to seven patients to get one patient with real pain relief, which can be debated if. But that's the way NNT is calculated. It's important to understand also that non-pharmacological treatment is the first option for neuropathic pain and sometimes even cases of nociceptive pain. The next slide. What do we need? Well, the first one is actually that we need education and training. The knowledge about pain, pain analysis and pain treatment is not at the level that we would like in the medical community. It's a small part of the education of doctors and nurses. But we also need better treatments. We need higher efficacy. But even more, we need more predictable efficacy. Now, it's more like trial and error. We take one of these potential compounds, antidepressants, antiepileptics or anything, and just try and see if it works. And if it doesn't, we try something else. But we need to be able to select patients based on the mechanism of action of the drug and compare that with the pain-generating mechanism, and to try to understand which patient to give what kind of treatment. And for that, we need to find positive predictors for effect. Another important aspect is that many of these drugs that we are using have CNS-related side effects, and it's a common reason for discontinuation. Feeling dizzy, feeling drowsy, feeling drunk, sedated, and you just stop using the medication. We also need drugs with less risk for addiction. Obviously, any kind of opioid is connected to risk for addiction, but also pregabalin and gabapentin, for instance. What could be done then to come to this point? Other mechanisms of action, obviously, but also, it would be really important to have a possibility to administer some simple local treatments in the affected pain area, which could be just a hand or a foot or something, and not treat the whole patient. In that sense, we could have higher local exposure, low systemic exposure, and increase the chance for analgesic effects without the bothersome effects of sedation, drunk, feeling drunk, et cetera. That concludes my presentation, and the next slide, I guess, is the end slide. Yes. Thank you. Thank you, Rolf. And then Martin? Mm-hmm. Yeah. Mm-hmm. Yeah. So thank you so much for listening in to this webinar. I'd like to tell you a little bit about our asset, ACD440, which is a novel TRPV1 antagonist, so that's capsaicin antagonist in neuropathic and nociceptive pain. As you may be aware, that there is an opioid crisis in the US, and there was recently, in September this year, an editorial written by Professor Clifford Woolf, Harvard Medical School, also stressing this, "And what do we need instead?" Well, there is no one-size-fits-all because there's a number of different pain diseases. They're all different. They have different characteristics, and the same drug, of course, cannot be used to treat all of them. And we need not only phenotyping tools, so we know who to treat, but we also need specific treatments to address the specific ailments in the different pain indications. Neuropathic pain is a long-lasting pain that is due to a disease or injury to nerve tissue. For instance, postherpetic neuralgia, painful diabetic polyneuropathy, or pain after chemotherapy, or even after an injury or surgery. Neuropathic pain affects 7%-8% of the general population, which is a fairly large number, and people are rarely aware of this. And what's also troublesome is that 80% of patients are not satisfied with treatment. In general, neuropathic pain is more severe than non-neuropathic pain, so for instance, nociceptive pain, and is also associated with worse health compared to non-neuropathic pain. And this, of course, has a major impact on quality of life, including then rating as for depression, rating as bad as coronary artery disease or poorly controlled diabetes. Patients often describe their symptoms as walking on pins or walking on coals on fire, which tells you a little bit about the intensity and constant, sense of pain. I would just like to give you a short example. So the back here is of a gentleman who is, very... was a very prominent person in the finance business, and he had postherpetic neuralgia, and he was so badly off that he asked his physician actually to cut this painful skin out. So on the cartoon to the left, you can see what normal skin would look like, with a skin biopsy from a healthy area. But comparing then to his pain area, which this other right-hand cartoon is from, you can see that there's fibers going up close to the skin, and these contain TRPV1 fibers, so TRPV1 receptors. They are sensitive to different types of pain conditions, for instance, heat and other temperature sensations. In peripheral neuropathic pain, we know that TRPV1 receptors are upregulated, and they do become more superficially located in the skin. ACD440, we have developed that as a topical gel formulation because it gives a low systemic exposure. It's very suitable for a topical administration to any body area except for the eye, which you need to be very sensitive for. It has good properties for use, so it's fast-drying, it doesn't stick, it doesn't stain, and it's easy to administer by patients. It has a good shelf life. That means that you can actually use it for quite some time, couple of years, without changing the package. It's a good treatment option for neuropathic pain from a practical perspective, also in primary care, which is not always the case for other types of local treatments. And we do have a patent application submitted for the ACD440 gel formulation. If you want to target peripheral neuropathic pain, you need also to look at subgroups of patients, and I mentioned phenotypes in my very beginning of this talk. So only one in five has sufficient pain relief with existing products. And the target indication for us is the patients who have increased sensitivity to actually to sensory stimulation, so for instance, cold or heat. These problems may sound minor, but these are major problems in everyday life for these patients. Wind, draft of the wind can be very painful, for instance, or taking a shower because it's hot. Here you can see a cartoon where neuropathic pain can actually be subdivided into different groups, so one has only hypoesthesia, that it means they don't really feel, but they feel pain. They can't feel that you touch, but that means that there's basically no sensory fibers telling you that there is something there. And the rest, which is two-thirds of the patient or a little less than little more than half, they have increased sensitivity to heat or cold, so that's thermal hyperalgesia, or they have a so-called mechanical hyperalgesia, which is much more common in painful diabetic polyneuropathy, so about 4%, doing the math from the numbers, 4% of the general population actually suffer from chronic peripheral neuropathic pain with any type of sensory hypersensitivity. The upregulated TRPV1 receptors can actually be present in all etiologies, but you have to have the nerve fibers at the end in the skin for this to be of practical importance. 2.3% of the general population then suffer chronic peripheral neuropathic pain with thermal hypersensitivity. One example of these patients with having a very high representation of TRPV1 receptors in the skin are patients with postherpetic neuralgia, like the gentleman I just showed you. In with ACD440, we have demonstrated efficacy in a phase Ib study, that means in healthy volunteers. We exposed them to the gel, and we had a very strong efficacy profile. We had a highly significant analgesic effect on so-called laser-evoked pain. It's like a very short, stinging pain, where the pain intensity was about 50% of in the treatment subjects, versus the placebo-treated ones. The mechanical sensitivity was also decreased, so pain on mechanical sensitivity. We had a very long duration of action. We only applied the gel for an hour, then we had to take it off to do our assessments, and it still had a long duration of action of nine to 11 hours. The models we used are very well validated and have been used with many, many marketed compounds, so we are very well on par with these, or actually better than competitive compounds. We have a very good safety profile. In the beginning of this century, many companies tried to develop TRPV1 antagonists for treatment, but companies treated the whole body. So you take it systemically, and you will, of course, treat all TRPV1 receptors in the body. But if you give it locally, then you will have no systemic effects. You will only... But we also didn't have any local adverse effects. We had a very, very low systemic exposure to the gel. We have a 500-fold margin to systemic exposure, giving any type of TRPV1 antagonistic effect, which is quite amazing. This indicates a potential in nociceptive pain, also, not only neuropathic pain, but this specific study actually indicates the potential in local nociceptive pain, such as burn injury or shingles pain, for instance. We then continued to a phase II trial in patients with peripheral neuropathic pain with hypersensitivity. As I mentioned, they have increased sensitivity to skin stimulation. We had positive feedback from the FDA based on our pre-IND submission supporting us conducting this trial, and we conducted a randomized crossover placebo-double-blind phase II clinical trial in 14 patients. So seven of them first had ACD440 and then switched over to placebo for one week, and the seven patients did it the other way around. In the patients who actually demonstrated thermal hyperalgesia, that is 40 degrees Celsius of heat, that means normally you would feel that's a lukewarm. It's like a normal hot shower. That evoked pain in these patients, and if this pain was reduced by about 50% in patients who received when they received ACD440, but not when receiving placebo. So as you can see on this cartoon to the right, you can see that the placebo patients remained pretty much with their initial pain intensity, while patients receiving ACD440 actually had a reduction in pain about steps of from reduction of three steps on the 0 to 10 scale, which is clearly clinically significant. Now, which were these patients? Who were they? Well, they were actually patients who did have a representation of the receptor in the skin. This is a specific phenotype, where we can say that we can tailor the treatment because we can identify already before the trial that these are the patients who are likely to respond, and this actually turned out to be true, by the results of this trial. So what are the advantages with a topical pain treatment? Of course, peripheral neuropathic pain becomes more common with higher age, and also increases with a sedentary lifestyle and obesity, because they're also linked to lifestyle diseases. With increasing age, people also commonly have many comorbid diseases, cardiovascular, diabetes, and they take several different medications. Most prescribed treatments have side effects involving the CNS. They get dizzy, they have balance problems, they have cognitive problems. They can be drowsy, sedated. It affects their ability to drive cars, to run heavy machinery. For instance, if you work in a factory, you need to run heavy machinery, you have a work injury, it's really a conflict whether you should continue working or you should work with pain or stop working because you cannot work with your treatment. There's also a high risk for drug interactions increasing these problems. So due to its topical formulation, ACD-440 gel has no drug interactions because this basically doesn't give you enough drug exposure in the blood to give interactions, and it can also be used together with other drugs due to the same reason, and can thus be a complementary treatment to other pain treatments. The topical and the idea of TRPV1 receptor antagonist is actually clinically validated. Novartis had a TRPV1 receptor, SAF312, sorry, three one two, which was reformulated from an oral formulation into a topical formulation as eye drops, and it is under development for ocular pain. It's been used in postoperative pain after laser corrective surgery or cataract surgery. You can see the data down here to the right, where there's a significant reduction in pain. And then they conducted a phase 2b study in chronic eye pain, completed almost a year ago, so ten months ago. And after that, they closed the deal with Bausch + Lomb, worth $155 million in upfront payment and a total deal value of $2.5 billion. And that deal was to a great extent including the SAF312. Summarizing, the ACD-440 gel has demonstrated proof of mechanism by reducing temperature-evoked pain in healthy volunteers and in patients at a clinically relevant magnitude, which means that it could be used for treating acute nociceptive pain, as in the phase one B study, in peripheral neuropathic pain with hypersensitivity, as in the phase two A study. It's also safe, has a minimal risk for CNS or other systemic side effects, and it can be used safely together with other analgesics and drugs commonly used to treat other comorbidities. It's easy to predict treatment responders, so you don't have to use a trial-and-error paradigm. You can actually base your treatment selection on the bedside phenotype testing by just provoking patients with something that is lukewarm in the doctor's sense. You can expect a short time to onset and have a twice-daily dosing without pain breakthrough, and it's easy for patients to self-administer. So TRPV1 receptor antagonism is a clinically validated target mechanism, as also demonstrated by Novartis in their phase two studies. And currently, we are at AlzeCure planning for the next clinical trial in phase two with our compound, ACD440. So thank you so much for listening. Thank you so much, Märta, and now it's time for a Q&A session on, following up the presentation. So please, Martin. Yes, thank you very much for that presentation. And like you said, now we'll jump into the Q&A section here. And we'll start with the first question here from Philip at Redeye. "How can the placebo effect in studies be minimized? That's a very good question. I think I can start, and Rolf could probably continue. There's of course a number of ways that have been tried through the years, and one is to train patients actually on what they should rate. And that's the paradigm that's been used all the way, even as a company has developed this as their trademark and patented it. The other ways are having less interactions with patient during the trial as it's ongoing, having less study visits. You can also have a very strict scheme on how to interact, because a lot of the interaction is about how does the patient interact with the trialist or the study nurses? And another thing is how you actually formulate your informed consent form. So there's a lot of different aspects to this. Maybe you have something to add on to this, Rolf. It's a very, very good question and a very difficult, difficult one to answer because as Märta said, many, many things have been tested, and the results are not that encouraging in trying to reduce the placebo effect. But many of these things can reduce the variability in the study, which has an impact on the possibility to show effect. To be able to show effect, we also need to include patients with quite a high level of pain and exclude patients with low levels of pain because they don't actually have much to improve. So there are ways of trying to make a study more effective, but to eliminate the placebo effect, that's not possible. Because it's not a... It's a patient who once is a placebo responder, is not obviously a placebo responder in another trial or in another, even in another. If you have multiple crossovers, for instance, they can be a placebo responder in one occasion, but not in another. So it's not easy to eliminate. ... thank you for that answer. We'll move on with the next question here. Which are the largest companies within pain? Is that for you, Martin? Yes, I would say that there are several who are active within the pain area. I would say that the largest for the moment is Eli Lilly, both with regard to what they have and also with regard to the pipeline that they are having. And then, of course, Grünenthal is also a big player within this field. In the US, Endo has also been a major player with lidocaine patches. You have companies doing pain research and have done pain research like Pfizer, Merck, MSD. So, there are many. And I mean, if we look at the amount of patients and the number of all visits to hospital, pain is the biggest of all indication areas, so many are active there. Thank you for that. Marta- Sorry. Märta, would you like to point out any other companies as well? No, I think that was a good, good selection, but there's also... when one gets the prescription, it may have another name on it because there's so many generics. There haven't been any new treatments for a very, very long time, so patents have ran out, and there's so many generics, so many people sell the substances on, you know, with perhaps a different name on the box. Yeah. We could have mentioned Purdue, who had OxyContin, who are now getting off the market. So yeah. Yeah. Okay, thank you for that answer, and adding to that previous question, how has the interest within the field developed, and do you believe a Lecanemab moment is needed for interest to increase substantially? Märta, do you want to take that? I could do so. Yeah, and there has been a need and a search for a very long time. And I think the statement that I had earlier on with this editorial by Clifford Woolf says a little bit about this, because there's been so much research now on biomarkers, different targets, different mechanisms, people going away from opioids, and the U.S. paving the way and giving a lot of subsidies to companies developing other types of treatment, rather than getting something on the market, has actually boosted this. So I think we need just to have the one drug that actually is successful coming out of there, and the interest will increase substantially. And we should say here as well, I mean, there are a few areas, like in pain, where also the society is extremely engaged. So if you take the U.S., with NIH and the HEAL initiative, et cetera, which is enormous around the huge problem that there is when it comes to, effective, pain treatments. Because so many of the patients, especially on neuropathic pain, are ending up on opioids. More than 60% of all the U.S., neuropathic pain patients are ending up on opioids, and, we know what opioids leads to. And in the U.S., in 2020, they said that the cost for society for opioids, both direct and indirect, was $1.5 trillion. That is how large the cost for society is. So it's enormous. Enormous! Thank you for that, and we'll move on with the next question here from Frederick at Redeye. Do you think that it's possible to, in the future, use biomarkers instead of traditional pain scales in pivotal trials? I could take that one on. I think there will be a need for biomarkers to be used for selecting patients, predicting the efficacy of a certain treatment, and also for to select patients, not only for trials, but also in the clinical life and healthcare. And I think there will be an openness with regulators. There is an openness and clear guidance that in phase two, so if you want to demonstrate that the drug actually has an effect, is actually okay, and it would be accepted to be to have a positive readout on a biomarker, but the biomarker needs to be reflected in a change of a change in pain as well. So I don't think we'll get around the end use of a pain intensity score at the end of the pivotal program. Maybe, maybe I could add something there, because in clinical practice, we don't actually focus so much on pain intensity. And it's not a given primary endpoint in treating patients with chronic pain. We have to look at different kinds of functions and the way they can act in their lives more, and the quality of life. And there needs to be. If you can, if you want a label text that you're an analgesic, you have to show difference in pain intensity, obviously. But if you could accept another kind of label text, you should include other aspects of chronic pain as well, because that's you end up many times in patients when you give them treatment, that they have essentially the same level of pain, but they use that to do more things. They can do things they couldn't do before, and they kind of increase their activity because they get some kind of pain relief. They use that to be more active, and they pay it with a little more, that they pain, but they now have the same kind of pain level, but they have another activity in their life, physical activity, et cetera, social activity. So it's a complex picture. I can actually add something, and that is that there are there's a movement now with regulators and with academic scientists and pain clinicians to develop a functional endpoint tool, because those are very scarce today, and they're very, what should I say, not realistic, not down to earth. So it's highly supporting what Rolf is saying, that we need something that tells us that this person is actually better, even though they can accept the same intensity of pain. Mm-hmm. I can also say that the people who are interested in this subject should look at the recent article in Nature, which is actually on the subject of using biomarkers for identifying and assessing pain and pain treatment. Mm. Came out, I think it was in September. There are several pain conditions where you see inflammatory biomarkers increasing when they have their pain, and they actually go down in biomarkers when they get better. We can see that even after non-pharmacological treatment, like, for instance, after rehabilitation programs, we can see that the level of inflammation, if you call it that, inflammatory biomarkers at least, decrease after a successful rehabilitation. So there are many potential coming biomarkers that could be used in some, but not all, pain conditions. We have to realize that pain is not a simple disease. It's a symptom of many, many diseases or conditions. Okay, and we take the next question here directed to you, Rolf: Why is it difficult to develop novel analgesics? I think it's multifactorial. I used to work in the pharmaceutical industry, and when I started there, like twenty years ago, there was a big focus on one pill a day, and it has to be in big indications like osteoarthritis, lung, and back pain, et cetera. It was much more focus on the business case than the scientific rationale. That has shifted, and I think that is a good thing to let science guide what kind of patients we should address with what the kind of mechanism we have, instead of making up business cases that don't really are founded in reality. It's also the fact that if you try to treat... We can treat all pain when it comes to cancer-related pain, essentially, because especially at the end of life, because we can use drugs and methods that completely abolish pain. But those are not possible to use in chronic pain because you can't take away the pain sensation completely. Then you can't function in real life. You will get burned, you will get fractures, et cetera. It doesn't. You really need to have the normal pain sensation available to guide yourself in real life. So we have to address pathological pain, which is more complicated. Mm-hmm. But I think we have many, many future potentials, but that's, that's an obvious one. The other is that benign chronic pain in itself is not directly life-threatening, which means that you don't accept side effects. We have had drugs in companies that actually have had analgesic effects but are stopped due to side effects that are less than many of the drugs we actually use in the clinic today. But they are not accepted today. Side effects are not accepted, and that we have to live with. So I think there are many reasons why it has been difficult. Okay, thank you for that answer, Rolf. The next question is directed to you, Märta. Why is it likely that ACD440 should be successful in the treatment of neuropathic pain? The reason is that, well, that we can actually select which of the patients, who will, would actually respond, just as other treatments of pain, any type of pain, we can't give it to everyone. It won't help everyone. It will help those who have a specific problem where the pain is actually triggered or increased by the patient being exposed to thermal stimuli, so heat or cold. And in those cases, we can actually say that this, this compound will actually reduce that type of pain, and it will not add on, and it will not trigger other types of, of pain as well. And as we have a biomarker, a so-called phenotype biomarker, we can see and understand and examine who's, who will actually respond by just testing if they are sensitive, and grade that sensitivity. I think we could actually treat those patients where that is a key factor. Then also not limiting to, you know, that may not be the only treatment. They may, in most cases, patients would actually need a combination of treatments. So, for instance, if there's multiple components in the neuropathic pain, which I think we have also discussed, being multifactorial also from a sensory perspective, this could actually give the extra boost of, for patients being able to be outside or, or to have less heat sensitivity, to be able to be out when it's warm out, et cetera. Yeah. I can add on that because it's quite common that we see in the same patient signs of central sensitization based on upregulations in the CNS, as well as peripheral sensitization. So we often need to combine treatments. Okay, and Martin- Maybe we should comment there as well. The trial that we did and had positive results in- Thank you ... was actually, there we allowed combination with other oral medications, and we could see that. So if they were on these medications, we had an effect on pain sensation with 50%. So we showed that it could be combined, and that we have a potential medication that also can be an add-on, and then also that it's local, not having the systemic effects, et cetera. That is actually really, really attractive, and also, which is quite remarkable, is that we had a significant effect already after one week, and most other pain medications need three to four weeks, actually, to show significant effects, compared with placebo. Okay, Martin, how big would you say that the market is for neuropathic pain? The market is around 13, currently, it's around $13 billion. It's the individual biggest pain market. At the same time, as Martha pointed out, only one out of five are happy with the current treatments. The market is growing double digits. GlobalData states that it's growing with, and is expected to grow with around 13%. And the reason for this is that we have an aging population, and with age, we can also expect more people to have pain problem, and also that we have a increasing overweight problem. So a huge market, and many people really need better treatments. Rolf, what would you say are the advantages of local treatment versus oral or systemic? We have a lot of conditions like postoperative neuralgia, posttraumatic neuralgia, which is quite a big indication, actually, and has come up the past 20 years, where we see neuropathic pain conditions following surgery, for instance. We know that 20% of the patients who have been submitted to surgery, one year after surgery, they have a pain condition in the scar area, and around 5% have a severe pain, and 1% are actually quite severely affected by the pain in the operating area, without it being some complication to surgery, but possibly neuropathic components. In these instances, you have smaller areas that are affected, and obviously, you want to. The best thing would be to treat that area and not the whole patient with a drug. So, and then you obviously have all the positive effects that we've discussed, essentially, that you avoid CNS-related, cardiovascular-related side effects, and you can combine it easily with other medications due to the low systemic exposure. So we have quite a lot of patients where the pain problem is localized, and our only option today is lidocaine patches, which are quite complicated to use. Capsaicin patches with 7% capsaicin, you need to do that at the clinic, and it's not easy to do. So the options are very limited today. Okay, thank you for that answer, Rolf. Next question is directed to you, Märta. Can ACD-four forty be used together with other analgesics? Of course, it can. I think we've mentioned that, yes. It can be used with any drug treatment that could be, the patient could be using. There's no risk for interaction, there's no risk for abuse, et cetera. Of course, it could be used together with a lidocaine patch or capsaicin patch. That's for technical reasons, and also the effect may be overlapping with the lidocaine. But otherwise, if you talk about oral treatments and other systemic treatments, of course, it can be- ... Thank you for that, Märta. And, Martin, when would you say it is possible that ACD-four forty could enter the market for the treatment of neuropathic pain? That depends on the indication that we will choose and then prioritize. Because, if we go with, the general, peripheral neuropathic pain, then we have a longer or a traditional development, cycle, where we need to do a phase IIb and then a phase 3, and, then potentially, we could have an approval. So that will take a couple of years. But we also have the option to actually go into an orphan indication, and an orphan indication where there is a huge unmet medical need, and based on that, we could come to the market much quicker. And, going for an orphan indication could also have other advantages since, we could have exclusivity of, seven years. And then based on that approval, we can then take on additional orphan indications or a so-called common indication, which is the bigger. So we are assessing different options and having the discussions on this with different parties. Thank you, Martin, for that answer. And, Rolf, what would you say are the biggest issues with opioid treatments, and what is being done to promote the development of novel non-opioids? The first one would take an hour to answer, actually. There are lots of things around opioids. The first thing is that they are actually not recommended for use in chronic pain, but for short periods. So there are very few studies with long... Looking at the long-term efficacy of strong opioids. So the current recommendation is to use it in very selected patients, highly selected patients in nociceptive pain and neuropathic pain, but for just a limited time, and that is obviously due to the many side effects. Actually, the most common side effect to discontinue medication is bowel obstruction, and the second one is around sedation and also lack of efficacy. Because, for instance, in low back pain, there is no evidence that strong opioids are better than NSAIDs. Still, they are used a lot. So, the lack of efficacy and the side effects, and obviously also the risk for addiction. And the last part of the question was non-opioids, and obviously, many have tried to develop new non-opioids, and I guess this is one of the pathways. I don't think there is a big market for a new opioid today. It has shifted quite dramatically, at least in the pain expert field. We are not looking for a new opioid or a new formulation with an opioid. We need novel mechanisms of action, and as Märta said, we have had none such drug, no novel mechanism of action for decades. We have to remember that gabapentin was not developed for pain, it was developed for epilepsy, and pregabalin is a follow-up. Duloxetine is just an antidepressant. So there's really not a new mechanism of action out there on the market and hasn't been for many, many years. So a new mechanism of action would definitely be tried in many cases. I don't know if we are allowed to say that, but it's probably it would be likely that it would be used off-label a lot just to try and test, because there's such a big need for new drugs. Thank you for that answer, Rolf. And the next question here, a general business question, probably for you, Martin. You have a diverse and promising pipeline, but will you still focus on R&D? I mean, we need to focus more on development of our current assets and generating data that takes products to the market. So as we see it, we will not widen our pipeline. Our aim is to out-license one to two assets to focus on the others. Thank you for that, and are there any other interesting candidates or modalities beyond L-SECURE, for example, Vertex? What should we say? There was just a press release from Vertex, actually, saying that they, their product had gone through phase III, and it was generally safe and tolerable, and it had efficacy versus placebo, but it was not more efficacious than current combinations of non-opioid, weak opioid that's already on the market. Thank you, Märta. I can only say it was published. That's what I know. Mm-hmm. But Märta, maybe we can mention Asahi Kasei's TrkA NAM- Yeah that is now in phase two B, because Yeah, that's true. that mechanism, and the mechanism is validated by the NGF antibodies. So maybe- Yeah, that's true. Because the NGF antibodies were done. I mean, they were stopped in phase three or before that, depending on which company, and they were efficacious, but they had side effects like a rapidly progressing osteoarthritis that made other joints, not that the initially treated one, but the other ones, they had a very rapid progression of their OA, and joints had to be replaced. So that was, of course, a severe side effect, and companies have continued to work on the concept of addressing the NGF-related pain without having the side effect of osteoarthritis, rapidly progressing osteoarthritis. And that has, by Asahi Kasei, they had actually. They are now in phase two and succeeding, and we hope they can continue succeeding and be a front runner for us. Yeah, and of course, we also have a TrkA NAM- Yeah ... that we are benchmarking towards Asahi Kasei, and also actually comparing with the antibodies, and we feel very comfortable. Thank you- So they would. -for that answer. And, Märta, are there any other indications possible for ACD440? Outside of neuropathy, peripheral polyneuropathy, or polyneuropathies or peripheral neuropathic pain, yes, of course. I mean, any pain condition that is reliant on the existence of TRPV1 receptors, increase in sensitivity or abundance in the skin would be likely. So there's acute pains like burns, for instance, or pain during shingles, not necessarily postherpetic neuralgia, but also pain during shingles. Those are two very, very sort of low-hanging fruits from an indication success perspective, I would say. But there's a number of other indications as well that would be considered painful skin indications. And Martin, are there any smaller indications, for example, orphan indications, that could be used to spearhead ACD440 into the market? And if so, why orphan? And the answer on the first question is yes, but I don't want to say exactly which, but we see several. And why orphan? Because with a huge unmet medical need, we can get a fast track, and we also can set up studies which will, how should I say, we can run quicker. And then the exclusivity on when you come in an orphan indication is 50% longer than what you get when you come with a common indication and non-orphan. So there is a lot that is interesting with an orphan. And for a smaller company like us as well, it is that the development costs are not as big. They maybe are only 20% or something like that, compared to a bigger indication. So we see it absolutely as attractive. Thank you. And, that's a wrap of the Q&A section here. And I'll hand over the word back to you, Martin, for some final comments and take-home messages. Yeah. Before I do the take-home messages, I would like to thank Rolf and Märta for their presentations. It's been great, and especially also for this Q&A, where we have discussed this topic. Of course, we are in an area where we see a huge unmet medical need, and we will talk about the take-home messages around this. As we stated, there is a huge unmet medical need. There is no indication area that is generating as many visits to hospital and primary care like pain disorders. The cost for society is astronomical, depending on how you calculate. As I stated before, there is a publication looking both at direct and indirect cost in the U.S. for the opioids, which is stating $1.5 trillion. Also, it is that we have an opioid crisis in the U.S., which is actually reversing mean age in the U.S. So it's not increasing, it's decreasing in the U.S. due to the use of opioids. We also see that neuropathic pain is the area within the pain area that has the largest patient population. As Rolf and Märta alluded to, around 7%-8% of the general population are having neuropathic pain. And also, that's only one out of five patients with neuropathic pain are satisfied with their current treatment. And maybe this is also why we have also so many patients coming back to the hospitals because they are not able to find efficient and safe treatments. And with the ACD440, we have shown efficacy in chronic patients with neuropathic pain, temperature, and also that we have been able to identify the responders with a bedside kit, which is great for the next trial, and also that it can be combined with oral medication, exactly as we did in the trial with the chronic patients. And exactly, this is also what I just said. So it can be used in combination with oral pain medications, which is great and in line with what also Märta and Rolf asked for. And now, as we are speaking, we are preparing for the next phase two, and then we will get back to what that will be in the future. So these were the ending words of today's seminar. Thanks again to Rolf and Märta, and thank you for listening in, and thank you, Martin, for moderating this session.