Hello, welcome to today's seminar with AlzeCure Pharma. Before I hand over the word to the CEO, Martin Jönsson, I will give some practical information here. If you want to send in a question for the Q&A session, you can use the form to the right to submit your question, we'll then take it during the Q&A. With that said, I hand over to you, Martin. Thank you so much, Ludvig. Welcome everybody to today's seminar. The seminar we will have is on TrkA-NAM, our pain project, which is another non-opioid treatment of severe pain conditions. Today's presenters will be Märta Segerdahl Storck, who is our Chief Medical Officer at AlzeCure Pharma. Märta, she is an M.B.A., Ph.D. She has done research on Karolinska Institutet and has a long background in several global companies such as Lundbeck, AstraZeneca, as well as Grünenthal. Then we have our Head of Discovery & Research, Pontus Forsell, who is a Ph.D., who has done research and also a Ph.D. in medical biochemistry and biophysics from Karolinska Institutet. Then you have me, Martin Jönsson. I'm the CEO of AlzeCure Pharma. The agenda for today is that we will have a brief introduction to AlzeCure as a company, what we are focusing on our business model. After that, we will go in and talk about the unmet medical need and the opportunities for TrkA-NAM in pain treatment. Thereafter, we will go into TrkA-NAM and look at it as a next-generation non-opioid analgesic. This presentation will be done by Pontus Forsell. Then we will go into a Q&A session where you have the opportunity to send in questions, then we will have concluding remarks. Going in and talking about AlzeCure very briefly. We are a company who are focusing on Alzheimer's disease and pain, and we are a spin-out out of AstraZeneca. We were founded in 2012 and became a commercial company in 2016 with funding from the Swedish Alzheimer's Foundation. We are based at Karolinska Institutet, we are developing small molecule candidates, first-in-class properties, best-in-class properties. We have one project called Alzstatin, which we developed to be a preventative and disease-modifying treatment against Alzheimer's. We have NeuroRestore, which is a novel symptomatic treatment of cognitive disorders to improve learning and memory capabilities, where we are focused on Alzheimer's disease, but also see opportunities in several other indications, such as depression. We also have a platform for pain projects. Here we are also working with neurotrophins, which we then are blocking off to treat pain conditions. As a company, we are listed at Nasdaq First North Premier Growth Market here in Stockholm since 2018. Our business model is that we are a research and development company. We research and develop projects into early clinical phase and then to out-license them. With out-licensing, our goal is to use this to drive our other projects forward. Our pipeline of small molecule programs looks like the following. We have NeuroRestore, which is a positive allosteric modulator to treat Alzheimer's and other cognitive disorders. Here we have a positive phase I, and now we are preparing this project for a trial in Alzheimer's patients. Here we have gotten a grant from the European Innovation Council, which we got last year, and we are now preparing to start a trial in early Alzheimer's patients this year. Our project, Alzstatin. Here we last year selected a clinical candidate, which we now are preparing for a clinical phase. This is a treatment to prevent that individuals are developing Alzheimer's, but also to treat individuals who have Alzheimer's. Going into our pain project. We have ACD440, which is a TRPV1 antagonist, where we focus on neuropathic pain and also are working with orphan. Here our orphan indication is erythromelalgia. We have positive data in chronic patients with peripheral neuropathic pain, showing very positive safety tolerability, and pain reduction. We diminished pain with around 50% in patients with chronic peripheral neuropathic pain, which were temperature induced. We also have received an orphan designation from the FDA for the indication erythromelalgia. We, this year earlier, a couple of months ago, also got an orphan designation from the European Medicines Agency. This project, we are now preparing for the next phase. From the FDA, we have also for this indication, pain in erythromelalgia, received positive feedback on a potential pivotal trial from the FDA. Then we come to the project that we will talk more about in detail today, that is ACD137, which is a negative allosteric modulator where we focus on osteoarthritis. Here we have selected a CD, which we have developed in-house, and we also have several other molecules in this series. Lately, we have published data on TrkA-NAM ACD137, which we are welcome to share with you and that you can download with this QR code. When it comes to the market that we are targeting with regard to TrkA-NAM ACD137, this is osteoarthritis. Osteoarthritis is a growing market and a very big market. There are today more than 500,000 who are suffering from osteoarthritis. The market is worth around $10 billion and growing 5%-9% annually and is expected to do so for the coming 10 years. We are building on the TrkA-NAM on science, which are well-validated, both pre-clinically and clinically. This is a project that we now look forward to take into the next phase. To talk about the opportunities for TrkA-NAM with regard to different indications, we will have Märta Segerdahl, who is our Chief Medical Officer, presenting this to you. Märta, please. Thank you, Martin. I'm happy to present this to you. A little bit of information on the indications we are considering. There's probably many more, but what we are considering right now and where we have non-clinical data. Also, I'll tell you quite a bit on the major unmet medical needs in these areas. When it comes to osteoarthritis pain, you've all heard of it, and you know that you can buy ibuprofen or diclofenac or naproxen to treat your pain, but there's still a huge unmet medical need. Pain starts mostly when you start for physical activities or if you've been too physical in your activities. Later in the disease, you may also have pain during rest and during night. Pain at rest is more common in hip OA. It's not only knees that can have osteoarthritis, it's also other joints in your body. Swelling and edema is also a problem for these patients. Osteoarthritis, as Martin mentioned, there's more than 500,000 people worldwide, according to the WHO Global Report on Disease. In the U.S., it's definitely more than 14 million adults that are affected. Symptomatic OA is about in 10% of men and in 13% of women above 60. Not only the knee, as I mentioned, can be affected, but also other joints, hip, spine, hands. There's a number of different sub-indications in this group as well. The older you get, the higher the risk is that you actually develop osteoarthritis. Of course, you can have joint replacements, and quite a few people do, but many want to wait for as long as possible, and in some areas, it's not really an option. You can have to wait for several years before you actually qualify for surgery. There's a number of current therapies. I'll tell you a little bit more about those and also there is a risk for side effects in older individuals. The higher the risk is that you have osteoarthritis, the higher also is your risk of having side effects with current therapies. What's in people's pharma cabinets at home now? Of course, exercise is core treatment, both to reduce stiffness and to reduce pain, and very often it's the last resort for patients to actually exercise. Weight reduction because you have an increased risk of OA if you are heavily overweight. Pharmacological treatment should always be combined with exercise. High -level recommendation is actually only for oral non-steroidal drugs like celecoxib, for instance, or ibuprofen, naproxen. High -level evidence is also available for intra-articular injections of corticosteroids, but everyone doesn't want to do that, and you don't repeat it too many times. Other drugs actually have many have the indication, but it's a weak level of evidence. The effect size is not very large. Topical treatments are not recommended, nor are strong opioids, though quite a few patients actually receive them. What are the side effects? What are the downsides with current treatments? Because if current treatments were perfect, there would be no need for a good treatment, for a new treatment. A lot of people actually have non-steroidals give them gastrointestinal problems like gastric ulcer, gastritis, diarrhea, nausea. It's about one quarter of patients may actually stop taking the drug due to this. Another quarter of patients stop taking them because they don't work at all. In elderly patients, they're extremely much more sensitive to kidney problems. A large proportion of older patients admitted to hospital are so because of drug side effects due to non-steroidals. This is quite unknown, but it's actually a very costly problem for healthcare. paracetamol has very few side effects, but also very low efficacy. Opioids, patients get constipated, they're nauseated, they get dizzy, they fall over, et cetera. They have an impaired cognition and probably forget their doctor's appointments. What happened to the NGF antibody story? 15 years ago, monoclonal anti-NGF antibodies were developed and in phase III of clinical development for OA pain, and for neuropathic pain, and also for cancer-related pain. The effect was absolutely stunning, and it was dose-related. During the development of Pfizer, which was a frontrunner of all these projects, tanezumab, they had some patients developing something called rapidly progressing osteoarthritis. That was quite unexpected, and it was mostly in combination with non-steroidals and non-steroidals were then a rescue treatment, so if the drugs didn't work, they took non-steroidals. This rapidly progressing OA was dose-dependent, so the lower risk, the lower efficacy. Thus, as a result, anti-NGF antibodies never reached the market because agencies considered that the benefit did not outweigh the risks of this drug. However, they're now being applied in pain management for cats and dogs. The anti-NGF antibodies have validated our target as a relevant pain treatment as in ACD137. As we will tell you later on, we can avoid adverse effects seen by the antibodies. How does ACD137 differ from NGF antibodies? Of course, that's key information because the problem today is largely safety. The NGF antibodies, NGF is released at the site of an injury. If it's an injury, whether it's peripheral injury or it's an inflammation in the joint, the TrkA is a receptor for this nerve growth factor, NGF. It's located on the neuron, the sensory fibers that make you feel pain. There's also receptors on the immune cells. You get swelling and you get pain. NGF leads to this inflammation and pain, and the anti-NGF antibodies inhibit this, but they also inhibit some other pathways in the pathway from NGF to the general inflammation, et cetera. What happens is that the anti-NGF antibodies are very unselective. We say that ACD137 is a TrkA receptor negative allosteric modulator. NGF antibodies, they stop the NGF, which are very important also for nerve growth, for reconstitution of injured. They give a pain signal, but they're also important for the restitution of the tissues. They take the pain away through the TrkA mechanism. Our drug doesn't take the NGF, the inhibitory effects. It only treats the pain part, which is the TrkA. We avoid all the side effects that we're seeing with the antibodies that we know now are related to this so-called p75 receptor. ACD137 can treat pain and stiffness. It can treat pain signaling, and that will improve mobility and wellness because quality of life is also a very, very important piece of the puzzle for these very many patients. I will go further into another indication, which we think is very timely, very important, and clearly underserved. It's a type of peripheral neuropathic pain that is induced by chemotherapy, so cancer treatments. This is a growing patient group. In 2023, the five-year survival of cancer was 85% or more in 25 countries in Europe, North America, Oceania. In the U.S., the five-year relative survival rose from 75% in the 1970s to 90% in 2016. Now, the survival rates for the most common and for the most aggressive types of cancer, survival rates are between 99% and 100%, which is quite impressive. That's not what we learned 20 years ago, and I think that's also very much what's in the back of our minds when we think of cancer. A very important reason for this is the screening programs that have been implemented, at least in the Western world, as well as also improved treatment regimens. Considering the increase in yearly incidence, not but not the least breast cancer, prostate cancer, colon cancer, and lung cancers, which are the foremost common kinds, the number of individuals is still increasing because there's more patients who have cancer. Many are caught in screening programs, and many more survive more than five years. That means that there's a growing group of people who suffer or can suffer from chemotherapy-induced neuropathic pain. Actually, this group is growing so fast, there's no really good epidemiological data of how many they are. We just know how many are diagnosed and how many are treated. Per patient group. Those are longitudinal studies and data is actually developing over time. Pain after irradiation treatment for cancer is high. In ENT cancers, so ear, nose, and throat, is about 38%. In general, it's between 30% and 40% of colon and breast cancer are the only other two indications where radiation is a common treatment. When it comes to chemotherapy-induced neuropathic pain overall, it does differ between the different chemotherapeutic agents and the type of malignancy. The intensity of this pain of the chemotherapy-induced neuropathic pain often sets the dose limit for chemotherapy. If patients have too much pain, they have to stop dosing and wait until it wanes a bit. If we can reduce this pain in the acute situation, we could actually optimize the chemotherapy and thereby increase effects further. Chemotherapy-induced pain is very intense in the acute phase. It often attenuates over time, but remaining provoked symptoms can last for very many years in combination with a loss of sensation. Patients can say that it's like they're walking on pins and needles or walking on Lego pieces, if you have them at home, or on coal, depending on how they are. This is the typical mix. They require steady shoes because they have a loss of sensitivity and in combination with pins and needles, and provoked by cold, even at normal ambient temperature. A typical patient looks like this because patients come, and they show you, they draw a pain drawing, and what they demonstrate is something that we call a sock. This is where the pain is, sock and glove distribution. That's very typical. When the doctor examines the patients, they can say that, "Okay, you have a loss of sensation here," and that's where they'll have all these crosses back and forth with the lines that are perpendicular and the cross. Most of them also have so-called hyperphenomena. That means that you can elicit pain with cold or with pinpricks, but especially cold in these patients. In the summer, they can sleep with their warm socks on just to be able to sleep and not be in pain. What is the current standard of treatment? Same treatments as for other peripheral neuropathic pains is actually used. It's serotonin, norepinephrine, reuptake inhibitors, duloxetine, gabapentinoids, tricyclic antidepressants, and they have a very poor efficacy, less than in other neuropathic pains. It's not good in the other types, but it's even worse here. It's like 12 - 15 that you have to treat. Treating 12 - 15 patients to have one with sufficient analgesia is not a very good treatment result. Many patients just need to have better coping strategies, which is tough. There's two studies actually dedicated in chemotherapy-induced neuropathic pain on clinicaltrials.gov. One study funded by the NIH demonstrated a significant reduction of pain versus placebo. Two ongoing studies are one NaV1.7 channel and one calcium channel blocker. We don't know what happens with those. They still have another year to go. There's one completely negative study with pregabalin. One reason that we don't know more is probably because the grading systems that is used in oncology questionnaires, they don't even ask about pain. They ask about function. Can you handle yourself at home? Can you cook? Can you hold a mug? Can you do your toiletry as you should? Et cetera. This is not really measuring the problem. One study actually looked more into this, and they looked at patients who had been treated for colorectal cancer. It turned out that this was after several years, 9% of the survivors had painful neuropathic pain, and 9% of all those patients who have been treated for cancer, that's quite a few. Non-painful chemotherapy-induced neuropathic pain was reported by 22%, and those 22% also include those with evoked pain, so with stimulation-induced pain. Time since diagnosis was related to chemotherapy-induced pain. It can actually start a couple of years after end of treatment. Higher disease stage, so higher total dose of chemotherapy is, of course, important and related. Survivors with painful chemotherapy-induced neuropathic pain, they report a much worse global quality of life. Painful chemotherapy-induced neuropathic pain must be distinguished from non-painful patients, as they say only painful patients were related to worse quality of life. I think it's probably a little bit of modification here because I think they missed a few in the 22% that were actually suffered from stimulation-evoked pain. I will not tell you more about this, just a list just saying that there's quite a few, almost all of our most common chemotherapeutic agents, they actually cause neuropathy is just very well known, and it's how the symptoms of neuropathy is what drives your maximum dose. The same as with osteoarthritis, and that my colleague Pontus Forsell will tell you quite soon as well, is that NGF antibodies have shown promise in alleviating pain also in chemotherapy-induced neuropathic pain. They were halted because of the side effects that were found in the Pfizer program. It's not because of the Pfizer, because it was a general, there's a target-related problem with the NGF antibodies being unselective and not being only effective on the TrkA, which is the part of the NGF downstream activity that is related directly to pain. This one I already showed you, just for remembering. In summary, OA pain affects more than 500 million people worldwide, and it increases because the aging population increases. Current therapies are not very efficacious. They have limited tolerability. Chemotherapy-induced neuropathic pain is growing. Very few have an effective treatment. 9%-10% of the patients develop chronic neuropathic pain, and it's specifically sensitive to thermal stimulation. Current treatments don't work well. Based on the data with NGF antibodies, there's a huge amount of data in patients with NGF antibodies. It's a validated target because the efficacy was very, very good. NGF is a validated target for OA pain and also for chemotherapy-induced neuropathic pain. We believe that ACD137, not having the side effect profile of the NGF antibody, is a very promising candidate for the treatment, both of acute and chronic neuropathic pain. Pontus, I leave the word to you. Hello, everyone. My name is Pontus Forsell. I'm Head of Discovery & Research here at AlzeCure Pharma. I'm also one of the co-founders and the preclinical project lead of the TrkA -NAM program. Today I will present a presentation titled "Next Generation Non-Opioid Analgesics." I'll just give you a short background to the target pathway. Upon a release in the body, it could be as depicted here in the skin or in a deeper lying tissue like the knee joint. NGF is released from surrounding cells at the trauma site. This released NGF travels to different kinds of cells where the receptor for NGF is expressed, and the receptor is called TrkA. Those cells could be immune cells like lymphocytes, macrophages, or resident mast cells in the skin. There is a non-neuronal effect of NGF TrkA leading to increased inflammation at the site of the injury. NGF also binds to TrkA receptors on neuronal cells, as depicted here in this nerve ending in this figure here. Upon binding of NGF to TrkA, the nerve fibers will be sensitized. They will upregulate certain ion channels like TRPV1, NaV1.7, and NaV1.8, leading to allodynia at the site of injury and also pain sensation. This NGF TrkA pathway is very well validated. In man, it is actually validated by either deletion or mutations of the NGF or TrkA gene. These mutations or deletions lead to a painless phenotype. These individuals do not sense pain. That is, of course, not good because pain is the human body's defense, so you will not use the part of the body that has been injured. Secondly, the pathway has also been validated by the anti-NGF antibodies, which actually demonstrated a step change in clinical efficacy in treating several types of pain. To summarize this pathway, NGF TrkA pathway is very well validated both within nociceptive and neuropathic pain. I will talk a little bit more about the pathway and especially the neurotrophins, which is a family of protein hormones which NGF belongs to. NGF stands for nerve growth factor. It's one of the neurotrophins, as you can see here. There are other neurotrophins named BDNF for neurotrophin 4 and 5 and NT3, and they also come in pro forms. We have a pro form of proNGF or proBDNF. These different neurotrophins bind to different receptors. I can see in this figure here, NGF binds to TrkA, and the other neurotrophins bind to specific other receptors on the cell membrane. The receptor to the right is called p75NTR. It's a common receptor for all the neurotrophins and all their pro forms. It doesn't only bind NGF, but it also binds NT4 and NT3. The different receptors have a different functionality, of course, but they, the TrkA, TrkB, and TrkC receptors signal in similar pathways, that's probably spatial or temporal dependent. The p75 receptor has a totally different signaling pathway, more regulating cellular survival or apoptosis. Several attempts have been made to target this pathway for the treatment of pain, and the first attempt involved general inhibitors of both TrkA, TrkB, and TrkC, these are called Trk inhibitors. They target the catalytic site of the receptor, which is a kinase domain. They are non-selective. They inhibit all three different forms of the Trk receptor, but not the p75 receptor. These molecules were discontinued for the treatment of pain due to severe adverse events like CNS-related side effects. They are now two different compounds in clinical use for the treatment of different malignancies. The second generation was the anti-NGF antibodies. They are delivered by infusion, not by a tablet or pill, and they neutralize NGF or proNGF, thereby inhibiting the binding of the ligand to the receptor. The anti-NGF antibodies will inhibit both the p75 signaling as well as the TrkA signaling. They are more selective than the Trk inhibitors, still the anti-NGF antibodies do inhibit two different pathways, the p75 receptor-mediated pathway and the TrkA-mediated pathway. The third attempt to target this pathway involves the negative allosteric modulators, which ACD137 belongs to. This is a more, and actually the most selective mechanism of targeting this NGF TrkA pathway. These molecules only bind to TrkA, so they are highly selective towards TrkB and TrkC, and does not at all affect p75 signaling. Currently, we are only aware of two different negative allosteric modulators of TrkA that is under development, and that is ACD137 and a compound that is in phase II right now for the treatment of oral pain by Asahi Kasei. To summarize this, TrkA is a validated pathway for the treatment of pain. Allosteric modulators might be opportunity also for biased signaling because they are more modulating the activity rather than inhibiting it. This slide is just a summary showing different indications that the anti-NGF antibodies were being developed for. These are three different antibodies, tanezumab, fulranumab, and fasinumab from Pfizer, Lilly, J&J, and Regeneron. They are either in phase III or in phase II. Many of these studies showed a positive effect on the pain perception. It gives a flavor of the potential indications that molecules targeting the NGF TrkA pathway can be used in. Here we can see also different forms of peripheral or neuropathic pain like diabetic peripheral neuropathy or cancer pain or post-herpetic neuralgia. However, these anti-NGF antibodies suffered some severe adverse events like RPOA, rapidly progressing OA, found in a small portion of patients, but still enough to be dose-limiting for the anti-NGF antibodies. Why is that? Why did we see this effect of the anti-NGF antibodies? Well, our hypothesis is that it's due to the fact that the anti-NGF antibodies are not only inhibiting the NGF TrkA pathway, but also the proNGF or NGF pathway mediated by the p75 receptor. There are now quite many reports describing the involvement of p75 in bone mineralization or in bone homeostasis, suggesting that there is a link between p75 and potentially rapidly progressing OA also. There was also a nice paper in Nature a couple of years ago, where they demonstrated that p75 actually limits the inflammation in the knee joint in an arthritis model in animals. Removing this break by inhibiting the interaction between NGF and p75, which the anti-NGF antibodies do, will unleash that break and you get an escalation of the inflammation. Also, the Trk inhibitors that are on the market for oncology, like I mentioned, it has been given to a couple of thousand patients right now. It is larotrectinib and another molecule called entrectinib. These molecules have so far not been reported to have anything resembling RPOA as adverse events. TrkA -NAMs have been demonstrated to have improved CNS safety profile. In the bottom of the picture here, you can see an article or a figure from an article demonstrating what happens to the femur, which is lower being in [Non-English content]. This is the cortical bone, so the dense outer layer of the bone. If you knock out p75 from these animals, you can see that the density of the bone is much less than in wild type animals. It also is similar for the trabecular bone, the more soft bone within the inside of the actual bone. That sort of wraps up the background of this program. Now I will go a little bit into the actual TrkA -NAM program that we have here at AlzeCure. It's actually a program that goes back more than 10 years in the company. It was based on positive allosteric modulators of Trk receptors that we identified early in 2013. Within this chemical series, we then, after a couple of years, identified selective negative allosteric modulators. They were inhibiting the TrkA activity rather than increasing it as with the PAMs. Myself and our Director of Medicinal Chemistry, Gunnar Nordvall, we have worked on this target at previous positions in other companies, and we knew that identifying molecules with this kind of profile was not easy. We decided to embark on a journey where we optimized this initial hit, and you can see in the figure to the right here that this initial hit is actually the black line to the right. After lead optimization of this molecule, we were able to increase the potency of the molecules very much, and at the same time retaining a good selectivity towards other Trk receptors. ACD137 was selected as a clinical candidate in 2024. This is a slide showing just a summary of the TrkA -NAM program. Like I mentioned, we had a quite extensive lead optimization effort. We synthesized more than 860 molecules. We were able to identify or synthesize molecules with very good potency, below 10 pM, which is extremely potent molecules. In general, they have very good selectivity towards TrkB and TrkC, usually higher than 10,000-fold, and also solve the X-ray structure of the molecule. Importantly, they have, in general, low blood-brain barrier permeability. Meaning that the molecule will not be exposed to such high levels in the brain, which is good from a CNS-related side effects. We have finally demonstrated that several TrkA -NAM molecules have analgesic and anti-inflammatory effects in various in vivo models of pain. Why do we think that selectivity for TrkA over TrkB and TrkC is important? All the Trk receptors are involved in neuronal function, both during development but also in adult individuals. It's important from a CNS side effects, but also from side effects related to peripheral nervous system that you are not targeting TrkB and TrkC. This is a summary of different molecules, different TrkA -NAM molecules, also two Trk inhibitors, as well as an anti-NGF antibody here, tanezumab, is included in the table. I just want to highlight ACD137 in the top row, where you can see we have an IC50 on TrkA receptor, approximately 1 nM, and it's 20,000 nM more or less on TrkB and TrkC. Given it's roughly 20,000-fold selective for the other Trk receptors. If you calculate the ratio for the other TrkA -NAM molecules, you will see that it's much less. Obviously for the Trk inhibitor, there's no selectivity whatsoever between the different Trk receptors. Interestingly, if you look at tanezumab, which is extremely potent, it's 1 pM, the affinity at least for this antibody towards NGF. It's not that selective actually. It's 1,000-fold selective towards TrkC, and there's been no reports on the selectivity towards TrkB. Actually, the ACD137 molecule is the most selective molecule of all these different molecules targeting the TrkA -NAM or NGF TrkA pathway. I've been talking a little bit about BBB permeability and the importance of not targeting TrkB. TrkB is intimately involved in memory performance or cognitive function. Here we have compared the Trk inhibitor larotrectinib, which is actually on the market now, in a model of memory in animals. The higher the bar, the better the memory. When we administer this Trk inhibitor to these animals and then perform a memory test, we can see that there is a trend to decrease memory already at 3 mg/kg, and that's become significant at 30 mg/kg. On the other hand, when we administer the TrkA -NAM molecule, there is no effect of memory function, suggesting that we have, compared to Trk inhibitors at least, a better side effect profile with respect to cognitive function. Summarizing this a little bit, selective and peripheral targeting of TrkA, we think that's a promising way forward for new analgesics. We have identified highly potent negative allosteric modulators. We have synthesized, as far as we know, the most selective compound for TrkA over TrkB. We think that this selectivity is really the key to obtain a safe compound with low side effects. How about efficacy in animals? We have tested it, like I mentioned, in several different models. This is an NGF induced pain and inflammation model where we inject NGF. It's a little bit artificial, but it's been used as our screening models. We inject NGF in the hind paw of the animal, and quite fast you will have an inflammation established within 10 - 15 minutes, and the animals will also have a heat allodynia. This is what we have tested to the left here, the analgesic effect of ACD137. You can see animals treated with only vehicle. They have a certain level of heat tolerance. This tolerance is decreased, so they withdraw their paw much faster when we have injected NGF. You can see we can reverse this paw withdrawal latency in a nice dose-dependent manner with ACD137. To the right, we also have the inflammatory effect of NGF. You can see there is an increase on the inflammation. That's actually the volume of the whole paw that we are measuring, and this we can reduce with ACD137. Sorry, this is the inflammatory markers. We have measured a couple of inflammatory markers through skin biopsies in these animals, and one marker that is really increased by NGF is CGRP, causing vasodilation and thereby the resulting edema. This is increased a lot with NGF, and you can see we can block this increment with ACD137. There is also a trend to an effect on IL-18 with NGF and ACD137. We are not only reducing pain in this model, but we're also reducing biochemical markers of inflammation. What about other disease-like models where pain is one component? This figure here shows the effects of ACD137 in a model of neuropathic pain, namely the chemotherapy-induced peripheral neuropathy, where pain is one component. Here we have used docetaxel for inducing, which is a chemotherapy, and for inducing the neuropathy. Then we have administered ACD137 at three different doses and compared that to the effect of a known analgesic called gabapentin. The higher the curve goes, the less pain the animals have. Here on the top we have naive animals. On the bottom we have in the black animals with peripheral neuropathy or painful peripheral neuropathy. We can see at increasing doses that ACD137 can reduce this pain as much as 100 mg / kg of gabapentin, which is a quite high dose actually. Another model, this is a model of the postoperative pain model, which is mostly a nociceptive pain model. The animals have an incision, and it is called the Brennan model, and then the pain is measured 24 hours after surgery. The same here. The higher the curve goes, the less pain the animals have. You can see here that also there is a nice dose-dependent decrease of pain with ACD137 reaching at least at three hours time point, reaching up to the same analgesic effect as tramadol, which is an opioid-based analgesic. In these two models, both in a neuropathic pain model and in a nociceptive pain model, ACD137 gives a good analgesic effect. We have also tested this analgesic effect in a model of OA, namely the MIA-induced model of arthritis in rats. MIA or monoiodoacetate is injected into the knee joint of the animals, and after a couple of days, there is an inflammation formed, and that will eventually lead to degeneration of the knee joint and a painful knee. Here we have administered ACD137 twice daily orally from day three to day 21, when we terminated the study. Here in this figure, we have assessed pain by two different methods, non-evoked pain, and that's measured on how much weight the animals put on each leg. You can see here on the upper left of this figure, this is naive animals, and then they are given this monoiodoacetate, and that will change how much the weight they put on that particular knee or leg. It's less weight. Here we can see that ACD137 is reducing that, so they distribute the weight more evenly. Interestingly, we have here compared the effects of ACD137 to tanezumab. It's a quite high dose given to these animals. You can see that ACD137 is equally effective as the anti-NGF antibody tanezumab on non-evoked pain. To the right we have evoked pain. You can see there's also a nice dose-dependent effect of ACD137 reaching up to the same analgesic effects as tanezumab. It's a little bit hard to see, tanezumab is the open circle on the top here. Essentially, both ACD137 and tanezumab more or less completely reduce the pain of these animals. Just wanted to say that this effect of ACD137 are as efficacious as the tanezumab anti-NGF antibody. Looking into a little bit more on the inflammation and also the joint pathology of these animals. To the left, we have the inflammation of the knee joint. It's measured actually by just measuring the diameter of the knee joint. There's a quite pronounced swelling of the knee joint after administering this monoiodoacetate, as you can see here in the left part of the figure. That is decreased in a dose-dependent manner with ACD137. Here tanezumab actually shows a little bit better anti-inflammatory effect with respect to the knee joint. We have also looked into the knee joint histology and tried to score the pathological events occurring in these knee joints. You can see that the control animals here, of course, they have a perfectly healthy knee joint. Inducing arthritis in these animals will increase pathological condition in the knee joint, and that can be reduced significantly by ACD137. This reduction was not statistically significant with tanezumab, maybe suggesting that targeting the NGF TrkA pathway with a negative allosteric modulator could be more protective for the knee joint than targeting NGF. We looked a little bit more into that, and I will just show you this slide as a background to how the knee joint cellular morphology or anatomy of the knee joint. This is a healthy knee joint to the left. The articular cartilage is built up of different layers. We have collagen fibers, both vertical and horizontal, and then different cells in different layers before the actual bone here. To the right, we have a figure depicting what it looks like in an arthritic knee joint. You have swelling of the knee joint, less synovial fluid, and the cartilage will be affected. You will not have this smooth surface, but more a ruffled surface. The collagen fibers will be disoriented, and also the cellular layers are not so well defined. There are several abnormalities here in this knee joint. Then we looked with hematoxylin and eosin staining of the knee joint of these animals that we had in the study. This is just one figure from several, but wanted to at least give you a flavor of how it can look on a cellular level in the knee joint. To the left, we have a healthy knee joint from naive animals. You can see the cartilage surface is really smooth. You have a well-defined cellular layer before the bone. Giving or administering MIA or monoiodoacetate to these animals will give a ruffled surface, because you will not have this well-defined cellular layer like we have in the healthy joint. Administering ACD137 seems to be protective. You have a smooth surface, only very small ruffled stuff here, well-defined cellular layers here, and that is not seen with tanezumab. This almost looks like non-treated MIA animals. You have ruffled surface, cellular abnormalities. We think here that ACD137 or other molecules targeting TrkA in this same mechanism will have, at least in these models, have a protect the knee joint. Clearly an advantage over anti-NGF antibodies, I would say. Just to summarize this, we have identified ACD137 through an internal medicinal chemistry program, highly potent and selective negative allosteric modulators, similar analgesic efficacy as the anti-NGF antibodies, and ACD137 is currently in preclinical development. With that, I thank you very much for your attention. Thank you so much, Pontus. We are now going over to a Q&A session. Ludvig, please. Yes, thank you so much for your presentation here. As Martin mentioned, now we will now carry on with the Q&A. If you have any questions, you can send them in via the form to the right. The first question here is for Pontus. You have two pain products in your portfolio. What is the difference between TrkA-NAM ACD137 and ACD440 TRPV1? Well, the most obvious is that they are targeting different proteins or targets within the body. TrkA-NAM is targeting TrkA, while ACD440 is targeting TRPV1 or VR1. They are both proteins involved in pain sensation, but they are different mechanisms behind these two molecules. That's the most important thing that distinguish them. Then, of course, we have different ways of administering the molecule. The ACD440 is administered as a topical gel, while TrkA-NAM will be administered as a tablet or pill. It's an oral administration. They are suitable for different kinds of pain, I would say. That's essentially what distinguish them. Thank you so much for that answer. The next question here is for Märta here. You observed both an analgesic and anti-inflammatory effects with ACD137 in the preclinical model. What is the clinical relevance of the combination of these effects? It's actually quite important because when patients have less inflammation, they have less swelling around the joints, that means that you can actually mobilize your joint better. That adds to your pain relief. Having the pain relief on top of that increases function and quality of life. You can actually do more things actively, and you will have less pain. Thank you. The next question here is maybe both for Pontus and Martin here. I'll let you sort that out. In the MIA model, ACD137 had protective effects on the knee joint. What does this mean for the project from a scientific and commercial standpoint? Let's begin with the scientific point. From a scientific point of view, we think that the effects that we have seen, so this knee joint protective effect, which is not seen with other kind of molecules like the anti-NGF antibodies, which actually have this, if anything, the opposite effects. Well, they induce rapidly progressing OA, although in a very small set of patients. I think that's really a key feature. Also the anti-inflammatory effects of the molecule in this model is of importance. If we go over on the commercial side or perspective of this, I would say if we would only have a symptomatic effect and pain relief, let's say that, and I think this is a fair prognosis regarding sales. Sales would potentially be in peak sales around $1 billion to $2.5 billion to $3 billion. Looking at forecasts from experts within this field, when you have a so-called disease-modifying and protective effect, these forecasts say that sales could be expected to be doubled, so up towards $5 billion in peak sales. Of course, this makes this program even more interesting and attractive from a commercial perspective. Thank you so much. The next question here. How would you expect to position ACD137 to all OA patients or a subcategory? Märta please. I would actually say that it would be applicable to the whole group of OA patients because of its both anti-inflammatory and pain-relieving effects. I would not see necessarily that there is a need for a subgroup that would be responders. You could always say that, okay, if you do not tolerate, you could think of it as a second line. The features we have and the safety that we seem to have so far, we are looking at safety studies, of course, as the next step. It actually should outperform everything that is on the market now for the whole group. I think to Märta's point, it's all about efficacy. If you have a better efficacy, you would be chosen as a first line. With the alternatives that are on the market today, they are not sufficient, which would position TrkA -NAM in a very positive position. Yeah. Just adding on to the safety, because what actually makes people stop taking these treatments and make the doctors stop prescribing is actually a lot of safety rather than lack of efficacy. Thank you. What endpoints do you expect in proof of concept and pivotal clinical trials? Are there any good biomarkers one can use? The biomarkers for the OA pain, I would say that the market or the arena for OA treatment, there's very many drugs that are approved for the indication. That means that the outcome measures are very standardized. There's something called a WOMAC scale. You actually measure morning stiffness, how painful it is to walk the stairs, if you have pain at night, and things like that. Of course, you can always measure swelling. In order to have an efficacy that's good enough, I don't think the biomarkers are that important actually. It's something that we, of course, need to look into. Thank you. There are anti-inflammatory biomarkers, of course, and there's potential competitors that are looking purely on the anti-inflammatory side, and they could have some effect on the anti-inflammatory part. I believe that the pain relief and also the lack of safety problems when it comes to joint destruction are the key features. Thank you. Do you expect ACD137 to have a disease-modifying effect in OA? Given the findings in the animal study in the arthritis model, it's not unlikely. We, of course, don't know until we have done the clinical studies. The combination of an anti-inflammatory effect, of course, with a good analgesic effect. The combination of anti-inflammatory effect with this protective effect, which we saw in the knee joint, could suggest that there is a disease-modifying effect also in OA in man. Future will tell that definitely in clinical trials, I would say. Thank you so much. Märta, maybe you could tell us a little bit, how does the competitive landscape look like? Well, apart from all the drugs that are on the market really, so nonsteroidals of different types. There's a number of products that are in the pipeline, so to say, so are in clinical development. I know there's some TrkA inhibitors, NAMs on the market or in early development. Nothing really established yet. When you look at phase II, phase III programs, these are basically anti-inflammatory antibodies or proteins, injectables. There's not really that much that is just specifically toward pain. There's nothing that's directly versus the pain mechanisms per se. I would say there's three products that are right now in clinical development, but they're all also injectables. Of course, it's easier with a pill a day. That's where we land. Thank you so much. Martin, this is still an early asset. What is the interest from the market here? We see active interest in TrkA -NAM, and we have seen it increasing, so it's very positive. Thank you so much for that. Maybe one for you here, Pontus. Why would a TrkA -NAM molecule be safe when both anti-NGF antibodies and Trk inhibitors have failed due to safety? I would say that the more selective mechanism of ACD137 not targeting TrkB or TrkC or p75NTR is really key here. This is also supported, that it's a safe mechanism. It's supported by findings with the protective effect in the knee joint. I would say that those two things are really beneficial for the ACD137 molecule and TrkA -NAMs in general. Thank you so much. Another question which has been sent in to us here. Paxman develops a product for CIPN that cools the hands, thereby limiting chemotherapy's exposure to the nerves. What is your view on this? Well, I think that would be fantastic. We haven't really seen the results yet. We know that the trial is there, and we know it has completed the clinical phase. So far, we're not aware of any results that have been published. Thank you. Another question for you, Märta, here as well. Is TrkA -NAM a molecule more or less effective than a NaV1.7 or NaV1.8 inhibitor? Well, if you look at NaV1.7 or NaV1.8 as oral or injectables, that's one thing. If you look at NaV1.7 as a topical, that's basically lidocaine that you use for insect bites, et cetera. It's not taken up. What these two NaV channels do is that they affect how the pain signal is transmitted through the nerve fiber and up to the brain so that we can perceive pain. The TrkA -NAM molecule actually reduces the irritation or the start of the signal in the nerve fiber. I would say that if there's nothing starting the signal, it's much more likely to have a broader effect than a NaV1.7, NaV1.8 because the input to the nerve fiber is actually what drives the signal at the very end. There is NaV1.8 inhibitor that's been approved now for post-operative pain. It's about as efficacious as a TYLENOL or very weak opioids. I think that for chronic pain, I think the TrkA -NAM is a much more likely probability of success going forward. Right now, they're looking at NaV1.8 as an oral product for chronic pain. So far we haven't seen the results that we're going to see results from that target. It would be great to have options. Especially if you could combine them, but we're not there yet. Thank you so much for that. What is the timeline for ACD137 to come to a clinical trial? What pre-clinical work is left? We are preparing for safety tox. That's where we are, and that is what we are preparing for. Specific timelines we don't want to give. Thank you for that, Martin. Pontus, why is a small molecule preferable to anti-NGF antibodies? Well, I would like to come back to the selective mechanism, of course, not targeting the other neurotrophin receptors, TrkB or TrkC or p75. Also in general, of course, the ease of use, a pill versus intravenous infusion, it's much easier for the patients. We also have the cost of goods, where a small molecule often is cheaper to develop and synthesize than large molecules. I think those two really give a small molecule the upper hand. Thank you so much for that. Moving on to the last question here. It's one for you, Martin. Do you plan to take TrkA-NAM project into clinical studies or out-license the program? We have begun to develop the plans for clinical studies. We are having dialogues with regard to out-licensing. If we will out-license or not depends on who we are talking about, the offers we are proposed as well as our alternatives with regard to our cash position and out-licensing of other projects. We know that TrkA-NAM is a very attractive program. The longer we can drive it, the higher value we can develop. Of course, that would be ideal for current shareholders. We are optimistic and are keeping all options open. Thank you so much for that. As I mentioned earlier, that was all the questions we had for today. Now hand over to you, Martin, for some concluding remarks. Thank you so much. Let's go to take-home messages based on today's presentations. What we can say is that there is a very large unmet medical need, both in osteoarthritis as well as in chemotherapy-induced neuropathic pain. These patient groups are growing with the aging population as well as overweight problems. Today, more than a billion individuals are, for instance, suffering from OA. Sales last year forecasted to have hit $10 billion and expected to grow 5%-8% per year in the coming 10 years. A huge market and opportunity. As we have heard today, we have a strong validation for TrkA -NAM that NGF TrkA pain signaling is attractive route to go. We have data here, which is both genetic, preclinical as well as clinical. ACD137 or TrkA -NAM is a negative allosteric modulator blocking on NGF signaling. We have several attractive molecules where ACD137 is our lead candidate. With a more selective mechanism, as we have heard today, we hope to be able to offer a safer treatment than the anti-NGF antibodies, which showed a very attractive efficacy. As we heard here today, TrkA -NAM under AlzeCure is on development as an oral medication, which we think is key when you want to go in and treat large patient populations. We are preparing it for clinical trials. With that, I would like to thank everybody for listening in today. I recommend you to download our recent article showing new results comparing with anti-NGF antibodies. Ludvig, I'm handing over to you. Thank you so much for that, Martin. Yes, we thank all of you for tuning in and sending questions, and I wish you a pleasant day. Thank you so much. Thank you. Thank you.