Good morning, everyone, and welcome to the Dogwood Therapeutics Virtual KOL event. At this time, all attendees are in a listen-only mode, and a question- and- answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Dogwood website following the conclusion of the event. I'd now like to turn the call over to Greg Duncan, Chief Executive Officer and Chairman of the Board of Directors at Dogwood Therapeutics. Please go ahead, Greg. Thank you very much, Tara, and welcome to everybody attending this morning's presentation. We're delighted to share why we're so excited about Halneuron as a potential new treatment for patients who are suffering from chemotherapy-induced neuropathic pain. For those of you who are new to the Dogwood story, Dogwood is a clinical-stage biotech company. We are focused on novel new treatments for both pain and neuropathy. We believe our approach is further differentiated given our focus on cancer and chemotherapy-related pain. We have two assets in the pipeline. We'll spend most of the time today on Halneuron, which is a NaV1.7 inhibitor, but we also have SP16, an LRP-1 agonist, which is poised to go into development as adjunctive therapy alongside chemotherapy to prevent immersion to neuropathy during chemotherapy treatment. The trial will likely dose patients the second half of this year, and the trial is fully funded by the National Cancer Institute based on very exciting preclinical data supporting the program. I'm also pleased to tell you I work with a terrific team. We have a team that has extensive experience in developing blockbuster medicines, including two significant additions to the pain armamentarium, CELEBREX and LYRICA, several billion-dollar drugs, or drugs that have either been developed and/or commercialized by our team. We have a group of people who have managed successful pain programs and are bringing that effort to bear on the development of Halneuron. Next slide, please. We will be making forward-looking statements during today's presentation. All of our forward-looking statements are contained in this presentation are relevant as of today, September 1st, 2026. Next slide, please. I'm pleased to tell you we've assembled a first-class faculty for today's presentations. We'll go through several topics. Our first speaker is Dr. Iain Dukes. Iain is a venture partner at OrbiMed who brings more than 20 years of pharmaceutical research and development and business development leadership to today's discussion. Iain has deep experience in the field of ion channel therapeutics, and this is obviously quite relevant to the development of Halneuron, our NaV1.7 sodium channel inhibitor. He was previously a Board member of Kartos Therapeutics, which Ipsen acquired last month. Iain previously led all licensing deals for Merck Research Laboratories as the Senior Vice President for Business Development and Licensing, and has held senior R&D roles at both Amgen and GlaxoSmithKline. Earlier this summer, we were pleased to welcome Iain as the Chairman of our Scientific Advisory Board. Today, Iain will speak to the role of Nav ion channels in pain signaling and how Halneuron differentiated mechanism of action. Next up will be Dr. Mike Gendreau, our Chief Medical Officer, who has led Dogwood's clinical development programs since early 2021 and has been guiding the Halneuron phase II-B study from its design through enrollment, which I'm pleased to tell you exceeds 230 patients as of today in the ongoing trial. Mike's career spans Senior R&D and Chief Medical Officer roles at Cypress Bioscience, where incidentally he helped bring SAVELLA through FDA approval for fibromyalgia, another pain condition, and MicroProbe Corporation, along with two decades of independent consulting on late-stage pain and CNS drug development programs. Mike will walk us through the phase II-B clinical research summary to date and share with you what you can expect when we unblind the ongoing phase II-B study later this fall. Following Mike, we're joined by Dr. Mark Joyce, a board-certified Psychiatrist and Investigator with CNS Healthcare of Jacksonville since 2003. Mark earned his MD from the University of Alabama and completed his psychiatry residency at my alma mater, Emory, and presently serves as a site investigator on our current Halneuron phase II-B study. Mike will share his perspective on the unmet need in chemotherapy-induced neuropathic pain and his blinded observations from the ongoing trial. Finally, we're joined by Dr. Jerry Evarts, a chemistry and manufacturing specialist with over 20 years of industrial experience in small molecule synthesis, including CMC leadership roles at Calistoga, Acerta, and Day One Bio. Jerry has supported programs from early scouting through phase III and NDA submission. At Dogwood, he's overseeing the complex synthetic manufacturing of tetrodotoxin, a process requiring more than 30 complex synthetic steps to the development of Halneuron drug product. Jerry will provide us with an update on advancing the first-ever synthetic formulation of tetrodotoxin to support Halneuron phase III development and ultimately commercialization. At this point, we're going to turn off the camera to maximize view on the slides. We'll bring the speakers back on camera as we get to the Q&A. Next slide, please. I thought it would be helpful to give you a sense of the patient journey, as we progress Halneuron through its development, because this is ultimately what the problem we're trying to solve. As you may be aware, chemotherapy-induced neuropathy results in somewhere between two-thirds and three-quarters of patients experiencing some form of neuropathy, most notably for today's discussion, moderate to severe pain. These patients can also experience numbness, tingling, sensitivity to cold, insensitivity to temperature, muscle weakness, and balance disturbance. Gait disturbance, if you will. As I mentioned, it's roughly two out of three or three out of four patients who experience this as they go through their chemotherapy because of the off-target damage to the neurons in the periphery, generally speaking, the hands and the feet. When oncologists observe this, there's several courses of action they can take. If the pain tends to be mild, the doctors will wait and watch and continue on with the chemotherapy treatment regimen. Unfortunately, as that pain goes to moderate to severe stages, we begin to think about altering the chemotherapy regimen. At moderate levels of pain, oncologists will often either reduce the dose or increase the intervals between doses for patients who are being administered chemotherapy. That is a terrible outcome, but it gets even worse when we get to severe pain, where doctors and the patients have to come to the very difficult choice of on/ off. Do they carry on with the chemotherapy, or do they stop the chemotherapy altogether? This problem is not inconsequential. This is germane to patients maximizing their chemotherapy regimen. At present, oncologists are not treating the pain component of chemotherapy-induced neuropathic pain. Those patients get referred to a pain specialist, often a neurologist, anesthesiologist, or an internist with a specialty or a pain clinic specifically. At present, these pain specialists are left with very little choice. Right now, the most commonly used drugs are used off-label. That includes duloxetine, or Cymbalta, as you may know it, pregabalin or gabapentin, the alpha-2 deltas, and opioids. Unfortunately, none of these drugs really get the job done once you get to that moderate to severe stage for most of these patients. As Mike will come on to tell you in a minute, we have about half of the patients in our current trial who are on these medications, yet still qualify for having moderate to severe pain. That pain specialist represents our initial call point. Based on the profile that is emerging with Halneuron, which appears to be quite safe, have little incidents with other drugs and drug-drug interactions, we think over time, oncologists represent a very significant market development opportunity as we consider lifecycle management plans where we plan to, presuming success in the current trial, move upstream and use Halneuron concurrently with chemotherapy, not just to address the pain, but potentially to maximize the efficacy of the chemotherapy regimen. The less tinkering we do with that regimen, the better the outcomes are likely to be. That is the patient journey. These are ultimately the patients whose lives we hope to help as we move forward with Halneuron's development. Next slide, please. To quantify this, and I will use U.S. data, I will provide a global estimate in a minute, there are about 18.5 million cancer survivors in the U.S. as of today. A little under 58% of those patients are treated with chemotherapy, which is a pretty large number. That is 10.7 million patients. Of those 10.7 million patients, about seven in 10 go on to develop moderate to severe neuropathy of some form. Of that 7.5 million patients, a little over 40% actually go on to develop painful or severely painful neuropathy. That is the group of patients we are looking to treat. Right now, there are 3 million people in the U.S. that qualify for this particular diagnosis. A very large opportunity, I think you will agree. Unfortunately, this big problem gets even bigger. As time goes on, we are increasing cancer diagnoses. Each year, in fact, estimates are that there is 2 million newly diagnosed cancer patients in the U.S.. If we run through those same filters of those treated with chemotherapy, those who develop moderate to severe neuropathy, and those who have painful or severely painful neuropathy as their dominant symptom, we are seeing an increase of over 330,000 patients each year added to the already existing 3 million patients. This is a very large opportunity, which gets larger. Just forecasting to the future based on rough timelines, if we were to launch Halneuron in 2030 or 2031, we are talking about 4 million people here just in the U.S. who are suffering from CINP of moderate to severe variety. The global incidence of CINP is about 10x that of the U.S.. So if you think of 3 million patients here in the U.S. today, that is roughly 30 million people worldwide who are potential candidates for Halneuron therapy based on their own specific journey. The worldwide incidence of cancer is unfortunately expected to grow pretty dramatically. In fact, by 53% by 2040. This is a result of patients living longer, so more time to develop cancer. But importantly, we are diagnosing cancer earlier, so that rate of cancer is expected to grow pretty significantly over the next decade and a half. Next slide, please. Right now, based on drugs that are used, which are all generic, if we look just at the seven major markets, which just for clarity is the U.S., EU4, U.K., and Japan, you will note that sales for CINP drugs based on this particular condition total $1 billion. These are all generic drugs. You can imagine with new entrants into the area, with branded pricing, this number is expected to grow pretty significantly. As I mentioned, the most commonly used drugs are the alpha-2 deltas, that is LYRICA and Neurontin, or pregabalin or gabapentin, as you may know them, and then followed closely by duloxetine or Cymbalta. Opioids, unfortunately, are part of the therapy here, as are a hodgepodge of other therapies. There have been 11 of 12 studies previously in CINP that have proved failures in studies, which I think speaks to the fact that none of these drugs, under rigorous conditions, are really getting the job done for these patients. So large market, expected to get larger, and in fact, we could be the first new therapy, a real game changer for these patients as we progress through phase III and commercialization. Next slide, please. What is our solution? Our solution is Halneuron. Just for those who are not familiar, Halneuron is tetrodotoxin, which is a voltage-gated sodium channel blocker. It is a very potent small molecule that is found in puffer fish and other marine animals. Specifically, it is not a peptide or a protein, it is a potent small molecule. The actual source of tetrodotoxin is not the fish. But bacteria that thrive in the environmental contaminated waters in which the fish reside. Specifically, we have harvested tetrodotoxin from the ovaries of pufferfish located in the South China Sea, which is very polluted waters, which results in extensive bacteria development and a very good harvest, if you will, for tetrodotoxin. Unfortunately, as temperatures have warmed, the fish are now migrating to warmer waters with less bacteria, and that harvest is substantially less. So we are pleased to be moving to a synthetic program, which Jerry Evarts will expand on in a minute. Halneuron works as an analgesic by binding to the NaV1.7 sodium channel. This is a sodium channel responsible for pain signal transmission. We modulate pain transmission in the peripheral nerves, thus we see no CNS side effects. In fact, Halneuron does not cross the blood-brain barrier. Halneuron is administered as a subcutaneous injection, buy- and- bill if you will, for those of you who are familiar with the commercial structure here in the U.S. for reimbursement, and has already demonstrated statistically significant and durable pain reduction with a very acceptable safety profile in both cancer and chemotherapy-related clinical pain studies to date. As an adjunct, but an important validator of this target, loss of NaV1.7 function leads to the very rare genetic disorder, congenital insensitivity to pain syndrome. You can see a former The New York Times magazine article highlighting the difficult role these patients face. We do know that these patients do not feel pain, so they have terrible outcomes in life. They don't feel heat, they don't feel glass, et cetera. You can imagine they have a very difficult lifestyle, if you will. What we do know is that the bad actor in leading to the congenital insensitivity to pain syndrome is the loss of NaV1.7 functionality. We believe it stands to reason, if we can modulate an overactive ion channel, which is signaling pain to patients, that we can deliver clinical benefits for patients, and that's what we've seen to date, and that's what we hope to see when we unblind the Halneuron phase II-B trial this fall. With that background, I'd be delighted to turn the presentation over to Dr. Iain Dukes, who will talk about NaV1.7 and NaV1.8 channels, and specifically Halneuron 's approach is differentiated. Iain, over to you. Good morning. In the next series of slides I'll go over the role of sodium-gated ion channels in pain signaling and the differentiated mechanisms of action of Halneuron, with respect to its block of NaV1.7 versus NaV1.8. Could I have the next slide, please? What are sodium-gated voltage channels? They comprise a family of integrated membrane proteins that conduct sodium ions from the extracellular space through a cell's plasma membrane. Structurally, they consist of alpha subunits that assemble to form a pore through which the sodium ions flow in a plasma membrane, and beta subunits that exert a modulatory function on their activity. The alpha subunits themselves consist of four repeated domains, labeled one through four, each of which contains six membrane-spanning segments. The S4 of one of these six serves as a voltage sensor and controls the opening of a channel in response to a change in the transmembrane voltage potential. In excitable cells, the opening of sodium-gated sodium channels enables the rising phase of action potentials and their propagation. Next slide, please. There's a large super family, of which NaV1.7 and NaV1.8 are members, and the family is shown on the right-hand side of this slide. There are nine NaV family members that differ in their structure, regulation, and importantly, in their tissue distribution. The NaV1.X family are all expressed in the brain, whereas a few isotypes are also expressed in the periphery. In particular, NaV1.5 is expressed in the heart, NaV1.4 in the skeletal muscle, and NaV1.7 to NaV1.9 in dorsal root ganglia. This distribution in the dorsal root ganglia is particularly significant because this is the target tissue for the peripheral pain modulation. Could I have the next slide, please? In terms of the role of NaV in pain, they are important in the peripheral signaling of pain, both NaV1.7 through NaV1.9. NaV1.7, as you've heard already, is of particular interest because of its genetic validation for this target in the sense that subjects who have loss of function of NaV1.7 are unable to feel pain. Non-central components of a pain perception that are related to NaV1.7 activation include transduction of pain stimuli at peripheral nerve terminals, and axonal transmission of action potentials to the CNS. Chronic pain conditions, including inflammatory pain, are associated with an increase in expression levels of NaV1.7, pointing to its critical role in hyperalgesia and allodynia. Next slide, please. In terms of how sodium channel signaling differs between NaV1.7 and NaV1.8, we have a couple of cartoons here showing what happens during nerve damage from chemotherapy triggers and how Halneuron inhibition of NaV1.7 provides selective modulation of pain. First of all, the role of NaV sodium channels. NaV1.7 is critical to setting the depolarization threshold, and therefore the probability of signaling an electrical signal requiring transmit pain. Essentially an on/off switch. NaV1.8 on the other hand acts as a dimmer or amplifier to increase pain signaling duration or intensity. NaV1.9 separately is thought to be involved in cold pain sensing and small fiber neuropathy. What makes Halneuron different is by selectively inhibiting NaV1.7 rather than NaV1.8, the drug specifically inhibits the transmission of pain stimuli from the receptors that sensitize the pain through the transmission to the CNS. We have preclinical data that demonstrates the pain reduction is greater with Halneuron than you see with a NaV1.8 inhibitor in preclinical rat models. Importantly, no additional pain reduction effect is seen when combining a NaV1.8 inhibitor on top of Halneuron, highlighting the importance of a NaV1.7 target. Next slide, please. TTX, otherwise now known as Halneuron, is a selective NaV inhibitor for pain management. As you've already heard, it's a natural chemical originally isolated from a puffer fish and is a highly potent inhibitor of NaV function. Unlike traditional local anesthetic blockers of NaVs, like lidocaine, TTX binds to a unique site on the extracellular domain of the S4 segment voltage sensor and inhibits its activity that way. TTX's highest potency is against NaV1.7, followed by NaV1.4. Because it does not readily cross the blood-brain barrier, this provides functional selectivity to Halneuron. Next slide, please. Let's just review for a moment the validation of TTX, other than Halneuron, as a potential best-in-class analgesic. Preclinical studies involving local as well as subchronic administration have demonstrated analgesic effects in a variety of animal models. Multiple clinical studies have been formed with TTX in cancer patients, as well as in patients with chemotherapy-induced neuropathic pain. All these studies reported durable efficacy in subjects who demonstrated an initial response. TTX was generally well-tolerated, with oral hypoesthesia and paresthesia, numbness or tingling in the oral region as the principal reported AEs that were generally transient. Next slide, please. At this point, I'll hand it over to Dr. Gendreau. Michael? Thank you, Iain. Next slide. I am going to give a summary of where we stand with the clinical development to date. I wanted to take a two-slide detour first and talk a little bit about chronic pain versus acute pain. When you start trying to target chronic neuropathic pain as your endpoint or as your indication, it is a much more difficult clinical target than acute pain states, and I would like to talk a little bit about why that is. The first comment is that the experience the patient has with chronic pain does not tend to correlate well with the degree of tissue damage or inflammation that you can measure as a clinician. We see patients who telling us they are in terrible pain, and you do not see a good reason for it. In the case of neuropathy or neuropathic pain, you know that they have had nerve damage, and it is very difficult to really quiet those nerves down so that the patient does not experience much pain. Yet in clinical medicine, we tend to treat chronic pain as if it were acute pain, and that has not been very successful. What has happened over the last 20 or 30 years, we have recognized there is different forms of pain, and we have to treat them differently. The traditional acute pain, you hit yourself with a hammer, you cut yourself with a knife. That is nociceptive pain. The body knows what to do with that. You get an acute pain signal. It goes up the spinal cord to the brain. The brain knows what that is. Pain is always an interpretation, but these very acute traumatic pain signals are easy to interpret. The brain knows what that is, and you get an appropriate response in terms of pain and pain healing. On the other extreme, you have neuropathic pain, where the nerves are damaged, and the brain can get confused by that constant signaling, saying, I am hurt, I am hurt, I am hurt, I am hurt. There is something wrong here. Over time, you get changes in both the way that peripheral signal is transmitted to the brain and also in the way the brain processes that information, what it interprets as pain. Your therapeutic approach to dealing with a chronic neuropathic condition where the brain has changed its interpretation needs to be different. In the middle, we have something called nociplastic pain. That is a newer term. That has been developed over the last 20 or 30 years as we understand central pain conditions such as fibromyalgia, where we cannot find damage in the periphery. We cannot find nerve damage, yet these patients consistently report much higher levels of pain than we would expect. What we have found, and I will show you on the next slide, is that they have experienced changes in the way the brain interprets that electrical signal, that pain signal. Next slide, please. This is some work that was done by a lab in Michigan about 20 years ago, but I think it is very interesting, and I wanted to share it to show how chronic pain and acute pain are different. This was an experiment trying to correlate brain activity with patients' reported pain signaling. This was a controlled pain signal. In other words, we're putting pressure on a patient's thumb, and you can dial up the pressure and make it painful, or you can give a low degree of pressure so they can feel pressure, but it's not reported as painful. On this A graph on the left here, this blue dot is normal patients. When you apply about 2 kg per centimeter squared pressure to the fingernail, they tell you, I feel that. Maybe it's a little bit uncomfortable, but they don't rate it as very intense pain. When we look at brain signaling, which is this is functional fMRI brain signals, we don't see any signal in the brain. We don't see the pain centers in the brain lighting up telling us, yes, we're processing pain. If we dial up the pressure to around 4kg to 4.5 kg per centimeter squared of pressure, pain says no. The patient tells you that starts to hurt. That's what the green dot on this line is. If you look at these brain scans, you'll see all these green activation portions in the brain. That's telling us the brain is now processing that signal coming up the spinal cord as a painful signal. We can correlate location, activation locations in the brain with patient telling us they're experiencing pain. Then we go to fibromyalgia patients, which have this centralized pain or nociplastic pain. When we look at them and apply 2 kg per square centimeter pressure, they report pain comparable to the 4.5 kg per square centimeter pressure at that lower pressure, which a control patient does not report pain. So they're reporting pain at the low stimulus. When we look in their brain, which is the red highlights in these brain scans, you can see they're lighting up those same pain areas in the brain as the control patients did at much higher degrees of stimulus. What came out of this work, and it's been expanded on since, is that this statement you can say when the patients tell you with fibromyalgia that they're experiencing pain, it's all in their head. That's true. They're still experiencing pain as interpreted by the brain comparable to what a control patient does with much higher degrees of stimulus. We have to be aware of what's going on with chronic pain because when we get chronic neuropathic pain, we have changes in both pain processing at the brain. We get some of the nociplastic effects, then we have the chronic nerve damage, which changes both how the spinal cord transmits pain, and it also changes the number of these sodium channel pores on the nerve. We get increases of these Nav1.7 and NaV1.8 ion channels as well in these chronic pain states. Number of reasons why treating these patients is challenging, and it's one of the reasons that we're pretty excited about our Halneuron data, as I'll show you now. Next slide. Halneuron is, we've already told you it comes from the pufferfish, at least the original material. Is a biological material. It's a very, very potent inhibitor of these sodium channels. We're using 30 mcg of drug per day in terms of a treatment dose. That is a 100-fold to a 1,000-fold less drug than you typically use for most analgesics. If when you think about drugs you might have experience with, the acetaminophen or NSAIDs, you typically take 10 or 100s of milligrams per day of those drugs. This is microgram doses. I stress that because when you use such a small amount of drug, there is less opportunity for off-target effects. It is very specific for its target, and we are not giving a lot of drug to run around in the periphery and cause other problems. It also is a drug that has a fairly fast onset. So it has a Tmax of around an hour. We get drug levels within an hour when we give it subcutaneously, and it has a half-life of four to eight hours. Interestingly enough, if this were an acute pain drug, you would see a pretty quick effect, and you would see it wearing off. That is not what we actually see, as I will talk in a minute. Treating chronic pain really is different than treating acute pain. We administer this as a 1-ml subcutaneous injection once a day over a number of days, depending on the dose being delivered to the patient. As I said, it is 30 mcg that is dissolved in a milliliter of water for injection. Next slide. The first clinical study that showed possibilities of applying this treatment to chronic cancer pain was this study. It was done a number of years ago. This is a patient population with cancer-related pain. So they are not all neuropathic. Some of these patients can have pain directly related to their tumor. It can be related to neuropathy, or it can be related to peripheral pain secondary to the surgery or the radiation that they received. In this case, we treated 165 patients. It was randomized one-to-one between tetrodotoxin, or Halneuron, and placebo. This was a responder analysis where they were treated for four days. So they got injections twice a day for four days, and then all treatment was stopped. Then the patients were followed for two weeks with no additional treatment and assessed to see if they had had a meaningful reduction in their pain or a meaningful reduction in opioid use, in this case, at that endpoint two weeks later. What was seen was that the Halneuron-treated patients had 51% of those patients manifested a response, either pain reduction, in most cases it is pain reduction. A few patients, they stopped using their opioids. Compared to a 35% response rate in placebo. Even though the placebo response rate was a little higher than we like, we still had statistically significant results with this relatively small cancer trial. This was the first indication we had that tetrodotoxin administered as this injectable Halneuron formulation could make a meaningful difference in treating a patient's cancer-related pain. What was even more interesting to this was the durability of response. The next slide I mentioned to you we treated these patients for four days, and then no treatment was delivered. For those patients who said or manifested a response, had this 30% reduction in pain, they were continued to be monitored to see how long that pain reduction lasted without any further treatment. In this top graph here, the light blue, these lines represent each individual patient who was a responder in the first part of the trial, and the length of the line is how long that treatment response lasted, how long their pain reduction lasted. You can see of the Halneuron responders, the average response was 57 days for a treatment that, again, was four days long and for a drug that had a four- to eight-hour half-life. We definitely have something going on here biologically in terms of how pain is being processed. We do not see any evidence that the Halneuron is still bound to the receptors. We think we have had a change in processing of how pain happens in or is interpreted in these patients. The lower graph are those placebo responders. 35% of the placebo patients in this trial reported a pain improvement, but you can see here the durational response in the placebo responders was around 10.5 days. Biologically very different. The placebo responders did what we are accustomed to seeing in pain trials, that you always get placebo response, but it tends to go away pretty quickly after you stop treatment. In comparison to the Halneuron patients, we had a much longer response, which really gave us an idea we are doing something really beneficial in these difficult to treat patients, and that encouraged us to move on to the neuropathic study I will talk about next. Next slide. The next target the company went after was chemotherapy-induced neuropathic pain, which is our current indication we are pursuing. This study was a dose-ranging study. It was a phase II-A study designed to pick the optimal dose and dosing frequency for the phase II-B studies that we are currently running. This was a predecessor study. What came out of this study without spending a lot of time on it, is we found that 30 mcg dose was the most effective dose of between 7.5 mcg, 15 mcg, and 30 mcg. But we found that dosing at once a day instead of twice a day worked just as well with a better side effect profile, better adverse event profile. We selected once a day dosing at that 30 mcg dose to carry forward into our current large phase II-B study to really try and establish this as an effective treatment for CINP. Next slide. The study that is currently running, and that will be reporting out in a few months, the design is shown here. We have a screening and randomization phase where the patients carry an electronic diary for at least a week and sometimes longer, where we establish that they have chronic neuropathic pain, that their pain level is adequate to be a member of our study, that they are consistent in how they report their pain, that they are reliable pain reporters, and so on. We have a number of criteria we look at during this run-in period, as well as lab work, and exams by the clinician to make sure they are appropriate patients for the study. If they meet those criteria, they are then randomized 1:1 between Halneuron treatment or a placebo. This protocol calls for eight injections delivered over 14 days. It is up to the treating clinic about exactly how they deliver those eight injections. Most clinics give four one week and four the next week, although they can give five and three or two and six, whatever works best for that patient and that clinic in terms of providing these injections. The goal is to provide eight treatments over a two-week period. Then, as we saw previously with the cancer-related pain study, all treatment is stopped after two weeks. We then follow the patient for another two weeks with no further treatment, and then look at the primary endpoint, which is the week four end of treatment visit, to see how much their pain has changed from that initial baseline value. Here, again, we're looking for a responder analysis where we're looking for a reduction in pain from baseline. But in this case, we're using a 50% reduction threshold as a definition of a response. So it's a fairly high hurdle. You have to have a very significant reduction in pain to meet this criteria. But if you do, you'll be classed as a responder, and we'll compare the response rate on drug to the response rate on placebo. We look at a number of other endpoints, of course, as well, as this is an exploratory phase II-B. We're trying to set ourselves up for a phase III registration program where we need to understand the adverse event profile, the response profile in terms of not only their pain, but how well they sleep. Does it help their fatigue? Does it help their quality of life? All of those endpoints are being assessed in this study. Our enrollment goal here is to recruit between 210 and 240 patients. As Greg mentioned at the beginning, we've currently recruited 232 patients, so we're very near the endpoint here. Our last patient to be randomized will be this week. So we're wrapping up the study starting this week. Next slide. We had an interim analysis last December, so we can tell you a little bit about where we think the trial stands. We're still blinded, of course. These interim analyses are done by an independent statistical group. They have a charter which tells them exactly what they can and can't tell you to maintain the blind among the clinical study team. But they were able to tell us that based on the first 97 patients who participated in this study, that we were seeing a durable treatment pattern. What that meant in this context was that we were trending towards separation from placebo statistically. With 97 patients, we did not expect to be statistically separate. But they did tell us that with the current trends, a study size in the range of 210 to 240 would have an 80% power to be statistically significant. So that's what we designed the study to achieve. As you can tell, with 232 patients enrolled, we're just about there. Some of the observations with that interim analysis population, we only had a 4.4% dropout rate, at that point in time of our 97 patients. That's a much lower dropout rate than we're accustomed to seeing in chronic pain clinical trials. Duloxetine had a 20+% dropout rate in their registration clinical trials. Pregabalin was 30% - 40%. SAVELLA, the one I developed, was also in the 30% range. We are very excited about how well-tolerated Halneuron is. It is very well-tolerated, and this is a very motivated population. These patients have survived cancer. They have gone through cancer chemotherapy, and then they have this sequelae of their treatment where they are dealing with chronic pain that can be, in some ways, as bad as their cancer was. The fact that this is a potential treatment opportunity for them, they are very motivated, and that is reflected partly in this low dropout rate. When we looked at the population who participated in the interim analysis, we were really surprised to see the five-year duration of moderate to severe neuropathic pain. What that means is these patients, for five years on average since their cancer chemotherapy stopped, and they had developed neuropathic pain. They are cancer survivors, and they have now been dealing with this neuropathic pain that was a result of the cancer chemotherapy on average for five years. We suspect that if you have had severe neuropathic pain for five years after chemotherapy, you have probably tried every treatment under the sun. When we looked at the medical history on the patients we enrolled, indeed at least two-thirds of them reported having tried treating their neuropathic pain with other chronic pain medications, such as duloxetine, pregabalin. You name it, they have tried it. At least two-thirds have gone through that. Our protocol allows them to come into the trial still using drugs such as duloxetine or pregabalin. As long as they meet our moderate to severe neuropathic pain criteria at baseline, they are allowed to take these other medications as long as they take them chronically. We are providing a treatment on top of these other background therapies and still seeing a treatment effect. That was very rewarding to see that, yes, in fact, we can treat these patients no matter what else they are taking. In conclusion then, if this study is successful, it will be the first randomized controlled clinical trial to get a meaningful pain reduction effect in CINP patients done under what FDA would view as chronic pain design. This trial is really designed to set us up for a phase III program. Next slide. One other thing I will quickly tell you, we have an open label study. In fact, Dr. Joyce is going to talk about a bit. This open label study is the patient successfully completed the double-blind study. They were eligible to enroll in this open label study where they would be given access to Halneuron on an open label basis. It allows us to look at durability pain improvement. It allows us to look if we can maintain pain improvement over longer periods of time, as you would want to do in commercial use. It lets us look at the feasibility of reducing the number of injections needed over time if a patient has an initially beneficial response to the treatment. Next slide. The design of the open label study is shown on this diagram. It is a 12-week study. Now the patients were treated for two weeks in the double blind. No treatment for two weeks. At week four, they are now eligible to go into open label. Depending on how much pain they report as they enter open label, they're going to be assigned to either receive two injections or four injections. If the pain is below four on a zero to 10 scale, they get two injections. If it's four or greater, they're going to get four injections. That's for the first month. They come back the next month. We again assess their pain level, decide if they need two or four injections. Again, they get those injections. They come back for the third month, do the same thing again, and at the end of the 12 weeks, they're assessed to see how they did during the open label part of the program. They continue to carry this diary. They continue to give us daily pain scores. We now will have a profile of each patient from the beginning during the double blind, all the way through 16 weeks later, after having received a variety of treatments depending on how well they responded to the initial round. Again, we'll look at changes in a number of outcome measures, but pain being the primary one here as that's what FDA expects to see in a registration trial. Next slide. As of a few weeks ago, we had randomized 217 patients, now up to 222. We'd only had nine patients early termed in the entire study. This supports what we saw during the interim analysis, where we saw less than 5% dropout rate. We continue to have this very low dropout rate, with a much larger patient population now. 189 patients have successfully completed the double-blind part of the study. As of, again, August 10th, we had 65 patients who had entered the open label phase. That's actually now up into the 80s, as we've had a lot of patients enter recently. Again, very good completion for this 12-week study. We still have only had two patients decide to stop treatment early. It's 3% dropout rate at the current time. We now have around 20 patients who have completed the open label study, and again, many more are coming in at this point. Our last patient to be enrolled in a double-blind study will be this Thursday. We're wrapping up the study, and top-line results will be later this fall. Next slide. Now I'm going to hand it off to Dr. Joyce. He is an investigator at CNS Healthcare Jacksonville. He's one of our very experienced investigators in this study. Dr. Joyce and I have worked together for probably over 20 years on various studies. He's one of the investigators I really trust in terms of his observations and the way he conducts clinical trials. Dr. Joyce. Great. Thank you. Next slide, please. Just to let you know a little bit about the numbers that I will be talking about, our site has enrolled. We screened nine participants, enrolled seven, and we have completed two participants in the open-label phase. At this point, nearly all but two of the subjects are in the open-label phase. In general, as an investigator, I participated in more than 200 clinical trials over various indications involving pain, depression, vaccine development, anxiety, weight loss, and others. We have worked with over 100 companies over the last 20 years. My background is in psychiatry, but I have specialized in clinical trial evaluation over the last 20-plus years in various indications, both psychiatric and medical. I was asked to evaluate Dogwood's Halneuron product because of our experience at the site with CNS compounds. In the cancer-induced neuropathic pain study we are discussing, we were able, as I said, to screen. The date of the slides was seven. We have screened nine at this point and enrolled seven. As I said, all but two are in the open-label part of the study. We have had no drops from the study for any reason, including adverse events. Next slide, please. All right. This is just a little bit, we have had a bit of an update. Instead of the six, we have now got seven, and we are waiting to see the outcome of that screen. Generally, our patients have tolerated the injections very well. As Mike alluded to, this population of cancer survivors are now. They are used to dealing with pretty severe consequences of their chemotherapy and cancer in general. They have been generally willing to return to the clinic for multiple injections. Very few complaints. This is, as an aside, been a really pleasant population to work with. Next slide. Compared to the numbers Mike was mentioning, we only saw a small number of cancer-induced neuropathic pain patients at our site. Of course, we are still all blinded. We were encouraged over what we saw firsthand. First of all, these patients with this condition are looking for answers. Halneuron may have some benefit for some of these very difficult to manage patients. Clearly, some of our patients have experienced improvement in symptoms. The treatment itself is very well tolerated. Nothing really scary was seen at the site. There are some very predictable, very mild adverse events associated with the compound, and we did see that on a regular basis. Typically, that involved perioral numbness or lingual numbness, which was very mild, very brief, and usually resolved within hours rather than days. We saw patients report meaningful improvement in their neuropathic pain after several weeks of treatment. That sort of went along with the data that Mike just reviewed. Next slide, please. That is it in a nutshell. I would just add two unofficial parenthetical comments. One is the therapeutic effect was substantially noticeable, and the side effect, very mild side effect profile was sufficiently frequent for us at this site to make maintaining the blind required more discipline than it ordinarily would, I would say. Some useful effects and a very well-tolerated compound. Without a doubt, without exception, I can tell you everyone who has finished the double blind. The open-label phase of the study has expressed interest in continuing the compound. That was their level of benefit. I'll turn it over to the next speaker. Good morning. Next slide, please. The active ingredient in Halneuron, as we've said, is tetrodotoxin, abbreviated TTX. It is found in many species, both terrestrial and aquatic, although historically and most notoriously in fugu sushi, which is puffer fish. It is the tingle in your mouth that can border on problems with poorly prepared fish. Over 5,000 years ago, Chinese medicinal practitioners described using puffer fish to treat convulsive diseases. At the time, they already understood where in the fish the highest concentrations were, they understood where to catch the best fish, the sea or the river, and during which months. The toxin was isolated near the turn of the 20th century, but it wasn't until 1964, when R.B. Woodward at Harvard University figured out, or in other words, elucidated the structure. Prior to the structural proof, the same toxin from various sources were misidentified as unique entities, further confusing the true source of the powerful neurotoxin. Woodward was the pre-eminent chemical mountain climber of natural products during the 20th century, as pursuing the total synthesis of natural products has often been compared to mountain climbing. Why did you make it? Because it was there. After his publication and up until now, the never-ending race to have the definitive total synthesis has been running, and while TTX may not be the Mount Everest of targets due to its small size, it is a very notable peak that many climbers climb or have attempted to climb. WEX, the original sponsor of the program, harvested pufferfish, specifically the ovaries of females, and could obtain approximately 1 g per 20 kg of ovaries caught in the South China Sea. That is a lot of fish. As mentioned, Chinese medicine instructed to harvest the eggs from the sea rather than the river. That is because the dirtier or more polluted the waters, the higher the content of TTX. Over time, the availability of fish and the content in them has dropped, making harvesting TTX unsustainable. This creates an interesting contrast. The more polluted the water, the higher the TTX content, but the greater the risk of an unknown contaminant in the extracted material. Naturally occurring TTX needs to be tested for the presence of many bacterial impurities and all the heavy metals you can think of. When you see the structure of tetrodotoxin, it is not what you think. It's tiny, and it looks just like a sugar. It is not a multi-domain peptide-based poison like a snake venom, or an enormous marine toxin like palytoxin or maitotoxin. However, it is one of the most potent substances known. Indeed, it is not BOTOX or botulinum toxin, but it is approximately four times more potent than cone shell poison, which, as a reference for you movie buffs, is the toxin they plan to instantly incapacitate T-Rex in The Lost World: Jurassic Park. That is all to say TTX itself has some punch. The molecule is so small, you might immediately think, why not just make it? How hard could it be? Well, it's difficult enough that we first tried to fish somewhere else. Next slide, please. The last batch of TTX was sourced from China in 2019. Two things then occurred, COVID, and apparently cleaner waters. The recovery from locally sourced fish dropped, and shipping highly toxic TTX from China became a serious roadblock. Prior to Dogwood making synthetic TTX, we did try changing our fishing hole. We changed to fishing in the Mediterranean near Türkiye. Indeed, we could find the fish, but the toxin levels were economically unworkable. We would need to make it. As of 2023, the most practical published, free-from-patent protection, total synthesis from everyday laboratory chemicals required more than 30 chemical transformations. The route had just been published in 2022 Nature paper by Dirk Trauner, originally at Berkeley and now at Penn. A key feature of this route is that the toxicity is not introduced until the final synthetic step, which allows us to use any vendor in the world for the early portions. For the final steps and purifications, we chose Indena in Milan, Italy, a CRO steeped in handling high-potency chemicals, especially natural products. Over the next two years, Indena verified and improved the Trauner route, and in July of this year, we completed our first synthetic GMP batch, ready for conversion to drug product and use in the clinic. The synthetic material is chemically identical to naturally sourced material in every way, except, of course, the largest impurity in fish-derived material is a glycosylated. It's absent in synthetic material. We made approximately 4 g, which is so little. However, at 30 mcg doses, this represents 130,000 doses. We are now working to optimize the synthesis to really large scale, which we envision to eventually be approximately 20 g commercial batches. A 20 g batch will go a long way, approximately 1.6 million doses. Next slide, please. The advantages of synthesis are numerous. Despite the 30 steps, the source of the starting material is a common sugar, as inexpensive as $500 /kg. The synthesis takes time, but with appropriate planning and staging materials, a steady stream of TTX will be available. We now have complete control over what exactly goes into our synthetic stream. We no longer need to worry about what other toxic impurities, metals, bacterias may be in our drug substance, meaning purity is not related to the environment. As we further develop the manufacturing process, we gain additional valuable IP positions. This is both for the synthesis and the purification methods that continue to build ring after ring of proprietary knowledge around our manufacturing process. An example would include purity and impurities and our isolation technique. The purity and impurities of all batches of TTX, whether sourced naturally or synthetically, are the same, with the glycosylated exception. That is because the preparative chromatography method, for which we hold patent coverage, uses mildly acidic conditions, and the impurities are part of an equilibrium process that is unavoidable. Also, how purified aqueous chromatography fractions are handled forward greatly affects the quantity of these impurities, and we have developed concentration techniques that minimize this, again, creating new IP. Dogwood TTX will be superior to natural material and well-protected by a portfolio of IP, creating a prohibitively high barrier to entry. Next slide please. Halneuron drug product is a very straightforward manufacturing process, and this is a representation of the formulation. Each vial for reconstitution and single injection contains 30 mcg of TTX and 100 ml of lactose. The materials shown here are all dissolved in water, viled into 5-ml vials, freeze-dried, and finally capped and crimped. A purpose of the lactose is to distinguish between completely empty vials and those containing the TTX, as 30 mcg is not visible in a 5 ml vial. Below is a typical production line for such high-potency processes. In fact, today we are visiting our drug product manufacturer to take a look at how things will go in the future. Thanks. Just to wrap up here, give you a sense of what we can expect in the future. We will harvest the data this fall. We will commence our FDA interactions, coming up in quarter four. Our goal is to run a PK phase I study comparing the synthetic with the naturally harvested tetrodotoxin. We will commence the two phase III studies that we are projecting, starting in the second half of next year. We often get a question, would one study get it done? We think it is a possibility, but it is most prudent to plan on two studies moving forward with an interim assessment in the first phase III study in the second quarter of 2028. NDA prep following the completion of the studies, and filing the NDA second half of 2029. Next slide please. There are many other places we think this particular mechanism could play. Mild CINP is certainly one option. Diabetic peripheral neuropathy is another option of the moderate to severe variety. Chemo pain prevention and acute pain associated with ambulatory surgery are all areas we think this particular mechanism may have relevance. I do not want to lose sight of the fact that the initial target for Halneuron, which is moderate to severe CINP, represents 4 million unique patients here in the U.S. and roughly 40 million patients worldwide. Last slide please. To summarize, we believe, and I hopefully you will agree at this point, that cancer and chemotherapy related pain represent a major unmet medical need. Our lead asset, Halneuron, has demonstrated both statistical and clinically meaningful reductions in pain to date. We are hoping to see that same result in the fall. The Nav1.7 targeted further validated by this genetic defect known as congenital insensitivity to pain syndrome. The Dogwood Therapeutics team has developed a significant number of drugs that have actually gone all the way through to commercialization. We hope to bring that experience to bear on reaching Halneuron's full potential, and we expect to harvest the data in the fall of this year. That completes our prepared remarks. We would now like to progress to the Q&A section. Tara, if you could bring up the speakers on camera, we will proceed accordingly. Great. Thank you, Greg. At this time we will be conducting a question- and- answer session with all of our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Jason McCarthy at Maxim. Please go ahead, Jason. Hi guys. Great presentation. Thanks for taking the questions. My first question is just about the speed of onset. You had mentioned, the Tmax is within an hour. How does that compare to some of the NaV1.8s, and we're going to bring up JOURNAVX, and there's been some issues with its onset. Latigo goes out there now with the splashy IPO, and there seems to be this focus on the NaV1.8s. Can you just compare and contrast those two approaches? Because to us it seems like there seems to be a little bit of a disconnect. Thank you, Jason. Yeah, maybe I'll have Mike address the first question. Yeah on onset, and then I will ask Dr. Dukes to speak to how our program differentiates from other NaV1.7s and NaV1.8s. Mike? Well, first, both the Latigo program and the Vertex program, those are acute pain models, so that is quite different than our real-world neuropathic pain studies. So they are looking at bunionectomy, where you are surgically insulting the patient, if you will, and then you are treating him immediately to see if you can reduce pain over 24- 48 hours. So that is really a very different model, and so that is really acute pain. So that is why I talked about the difference between chronic pain and acute pain. We are going after a chronic pain condition, so It really is quite different than treating acute pain. So they are not directly comparable. It does not mean NaV 1.8 wouldn't work in chronic pain. It does not mean that NaV1.7 wouldn't work in acute. But you are comparing a bit of apples and oranges there. Yeah, and I would just say that, just to echo that the validation for NaV 1.8 is mostly in acute pain, and Vertex's suzetrigine is clearly indicated in that for that category. With respect to NaV 1.7 past failures, SiteOne obviously comes to mind. That program required very high doses to inhibit NaV1.7, and because of the lack of cell activity, and the fact that the SiteOne also hit NaV 1.5, they ran into cardiovascular AE issues, which we have not seen to date with Halneuron. This was also a problem that plagued the Genentech program. You could also look at Pfizer's NaV 1.7 inhibitor program, and that had an issue. It is more of a chemistry issue, but their molecules bind very heavily to plasma proteins, and so the free fraction wasn't high enough to actually have a therapeutic effect. None of these issues apply to Halneuron because of the functional cell activity the drug has against other ion channels of concern, and the fact that our tolerability data to date certainly proves that point. Thank you. Yeah, Jason, I would just add that we believe the potency and selectivity of Halneuron is a differentiator, as is our focus in cancer-related pain. As you're probably aware, Vertex will be pursuing a DPN program that is in process that will read out next year. We do believe our specific focus in cancer-related pain and CINP is a further differentiator of our approach. Thank you. Do you guys have any thoughts on potential molecular mechanism drivers of the durability and the duration of effect that you could be seeing? Is there any NaV 1.7 alteration or acquired mutation or what do you think is driving that or could be driving that? Mike, do you want to speak to that? Yeah. I would also like to let Dr. Dukes address that as well. I will tell you that we do not know. I do not have hard data that can answer that question. My personal suspicion is this is chronic pain. I talked about how the brain is involved in interpreting pain. Pain goes up and down the spinal cord. There is something called descending inhibition. Pain gets gated at the dorsal root ganglion. There is a lot of mechanisms that have evolved with evolution to control how pain is experienced, how it is interpreted. There are ways the body has to turn it down, to turn it up. For whatever reason, when I think about why this would have a durable effect, I think we are changing that pain signaling network. I do not know exactly how it is changing, but that is consistent with what we see clinically. When you think about other disease states like depression, I was involved with one of the studies where we give psychedelics to depressed patients, and you see with a single treatment how you can change the way they experience their mood over months and months. Again, that is a reset. That is changing a network. I suspect we are doing something similar, but I cannot prove that. Like neuroplasticity or something. Yeah. That is one way to say it. Dr. Dukes, you- Yeah. It's hard to say at this point. I think, though, the fact that Halneuron has a very unique binding site compared to all the other sodium channel blockers could indicate why we see a durable effect that others do not see, just because of a unique binding site, and that might change how the channel is regulated long term. But again, this is hard for us to prove at this point. Got it. Last question. What could the size and scope of a phase III look like? Assuming that the phase II-B is successful, is there the potential that it could serve as one of the two likely required pivotal trials? Mike, why don't you handle that one, given your regulatory expertise? Yeah, let me answer the second question first. We do not anticipate this can serve as a pivotal registration trial, if for no other reason than we're using biologically sourced TTX in this study. Our phase III program is going to be with the synthetic that Dr. Evarts talked about. So, I think FDA would look at that and say, that's not really the same drug, even though it's chemically identical. So this is very supportive. It's going to teach us about dosing and duration of response and adverse event profiles and so on. But at this point, I'm assuming we're going to have to do two registration studies. In terms of size and scope, they need to be 12 weeks. The FDA guidance for chronic pain indication is 12 weeks primary endpoint, so minimum 12-week study. There'll be some negotiation with FDA based on sample size in terms of how much exposure data we need. But in terms of getting an efficacy signal, the current phase II-B study is going to really tell us how big these studies need to be in terms of numbers of patients. Got it. Thank you for taking the questions. Thank you, Jason. Yes. Thanks for the questions, Jason. Our next question comes from Sean Lee at HC Wainwright. Please go ahead, Sean. Hey, good morning, guys. Very informative presentation. I just have a couple of questions, mostly on how Halneuron could be used in the clinic. My first question is for the CINP patients today, as you mentioned, they get treated with a lot of different therapies, including duloxetine, topicals, opioids. What is the typical sequence of treatment these patients get? If Halneuron does get approved, how would it slot into this treatment regimen? Sure. Maybe I will kick off based on what we know, and I would ask Mike to jump in here. There really is no hard and fast as to whether pregabalin or gabapentin or opioids are used first or second or third. We do know that, and I think you are probably aware of this, all of those drugs have attempted to study CINP, and unfortunately, I think 11 of the 12 have failed. There is one positive crossover study with duloxetine, which is why it is recommended by ASCO as the only potential viable treatment. But as Mike mentioned, the data we are collecting from this study, it was originally about two-thirds, I think, Mike, it is still blinded, but we are down to about a half of the patients on some form of concomitant med. We will be able to assess Halneuron's efficacy used as a standalone therapy, as well as on top of other therapies. I think that is important because if I was to draw an analogy from a reimbursement perspective, if we have data that shows Halneuron is effective on top of these other therapies, by definition, you are almost building your evidence to run over a step at it right away. This is a drug that will be used as an in-office drug. It will be buy- and- bill, in the doctor's office. So reimbursement tends to be more favorable there. But we are hoping, as we unblind the data, that we do show an effect both as a standalone and on top of those other therapies. We do believe the full 3 million patients, be they on other therapies or not, would be candidates for the drug if they qualify for having moderate to severe neuropathic pain, which is in fact what we are seeing in the clinical trial. Mike, anything to add to that? Only that when we say two-thirds of the patients were using other chronic pain drugs, that's concurrently with our trial enrollment, and these are five years later. I suspect this population has tried everything available by the time they get to our clinical trial. They probably have tried most drugs available prior to coming to our trial as well. But I don't think that's going to change a lot. Doctors are very comfortable prescribing Neurontin or gabapentin or pregabalin, and that's likely to continue. But they don't have an indication for it. They don't really work very well, as evidenced by the fact that by the time they get to our trial, they meet moderate to severe neuropathic pain criteria. If we succeed, we'll be the first one that has really demonstrated being effective in this condition as opposed to just something you can hand out and hope. I see. That's very helpful. My next question is on the effect size. What, I guess, change in the daily pain scale, or what responder threshold would you really see as a clinically meaningful threshold rather than just statistically detectable? Does this change for patients based on what kind of chemotherapy they receive, whether it's platinum-based or taxane-based? Mike, why don't you start and then I'll chip in afterwards? Yeah. Effect size when you're doing responder analysis is a bit tricky. Typically, when we talk about effect size, we're talking about continuous analyses, such as mean change in pain from baseline on an NRS scale. That's traditionally what we do. We originally were heading that direction. We thought we'd have an effect size in the 0.4 range. But we've learned from our interim analysis that we're better using a responder analysis to get the most efficient study design. We're now using a 50% responder analysis as the best way to differentiate placebo from drug responses. That's what we think we're seeing in terms of the study. We'll know when we unblind, of course. The clinically meaningful is an interesting idea. FDA many years ago, based on evidence, based on a lot of literature, decided that 30% reduction in pain from baseline, whether you measure that continuously or as a responder, was a clinically meaningful improvement or a minimal clinical important difference, MCID. So anytime you have a 30% reduction in pain, that is something the patient notices. It is considered to be a meaningful change. If you have a statistically significant reduction on a 30% responder analysis, by definition, that is clinically meaningful. We are looking at a 50% threshold. You can look at different thresholds. You can look at 30%, 50%, 70%. We are using a 50% threshold, but I do not expect there is going to be any debate with FDA whether or not a statistically significant study using a 50% threshold is not clinically meaningful to those patients. Greg? Yeah. Maybe, Sean, just to build on what Mike said. Obviously, a p- value of less than 0.05 in this trial will be critical, in classic sense, to meet FDA definition. Just to provide a little context, as I think we are all aware, there is nothing approved to treat these patients. So this would be the first potential drug to benefit patients. Just to give it some additional context, if you look at other chronic pain meds, not approved for CINP. But if you look at LYRICA, for example, for chronic pain, you see a ratio of roughly 2:1 of drug to placebo. In LYRICA's case, which I know from my Pfizer days, you see a range depending on dose. But if you took the middle of that range, it is about 30% of patients who demonstrated a 50% or greater reduction compared to 15%, hence a 2:1 ratio. Again, this is not CINP, this is another form of chronic pain, but that 2:1 ratio, I think, would represent a success. If you look at Cymbalta's OA studies, you see a response rate of about 50%. It is a little less than 2 to 1. But both LYRICA and Cymbalta are several billion-dollar drugs. So I think to summarize here, if we hit the 0.05 value or less on a 50% pain reduction, which by the way, commercially is a very nice thing to be able to communicate to patients, and we hold up on that roughly 2:1 ratio of drug to placebo, I think we have something that could be a real game changer for patients in the CINP community. Thank you for that. That's very helpful. My last question is on the dosing of Halneuron. With eight subcutaneous doses over 14 days, where would this be administered for the patients, and how does it compare to what they've typically received? Would this be a barrier for them to receive these injections? Mike, maybe you can speak to what we're seeing in the clinical trial, which is the best evidence we have, and then I can speak to how we would see this being used over time. I was going to say, I'm going to send it to Dr. Joyce. What do you think about eight doses over two weeks? These patients all did it, but I'll let Dr. Joyce share his experience. They did all do it, and we didn't have any complaints. I will tell you the number of doses in that period of time required some scheduling hoops to jump through and to get all of the medicine in the designated time period. Didn't have a single person who was not pleased with the outcome though, if they entered the open label phase. I think at this point, the benefits are worth the cost. I would imagine that further development might include how to tweak the compound to make it a little more stable in solution to move forward. That's not going to be my area of expertise, but perhaps Mike or others could talk about that. We have to reconstitute the drug and administer it within a short period of time. That is something that would be an issue for ongoing use of the drug. Yeah, Sean, we are collecting safety data as we speak, as I'm sure you're well aware. Over time, we could certainly see potentially home administration. You start the patients in office. I can give you an analogy. That's what happens with a lot of patients treated with CIMZIA. For rheumatoid arthritis, the doctor prescribes it in office, gets control of the patient, and then they're sent home on a maintenance regimen for at home administration. That's subject to discussion with FDA, but certainly that is a path we could pursue, presuming success with the current trial. As Mike outlined, I think very nicely, we're looking at different maintenance doses in the open label extension, which could influence the design of the phase III to make it less of a patient burden of coming back to the office. As Dr. Joyce has mentioned, we've had a handful of patients stop short of their eight injections over the trial, which I think reflects the need for a new therapy, and the fact that these patients are, on average, suffering from CINP for five years. I see. Thank you for that, and thanks again for taking my questions. Thank you, Sean. Appreciate you participating. Yes, thanks for the question, Sean. I'll turn it over to Dan Ferry at LifeSci Advisors to read a few of the questions we got over the webcast. Thanks, Tara. I know we're over time here, Greg, so I do have a bunch that we probably won't get to. The first one is, what competition do you have in cancer chemotherapy-related pain space? Mike, do you want to take that one? Sure. Not much. No one's got that indication. We're not aware of any advanced programs really targeting CINP. It's a tough indication. I think to the extent that we're successful in this area, we're going to own that indication for a while. Okay, great. Mike, as a follow-up, can Halneuron be used during chemotherapy? We think yes. That has to be proven, of course, but one of the advantages of this tiny dose we're using, the drug is not metabolized. It doesn't protein bind. It doesn't tend to interact off target. I mentioned it has a lack of off-target effects. It has no metabolic interactions. When you give something in conjunction with chemotherapy, you worry about, is it somehow going to decrease the efficacy of the chemotherapy? We don't think that would be an issue with Halneuron. Again, we would have to prove it, but our low dose, our lack of metabolic interactions, the lack of off-target effects, we think you could successfully use this in parallel with chemotherapy to hopefully maybe prevent or modify the development of neuropathic pain that, as Greg mentioned, sometimes limits the use of the chemotherapy itself. Yeah, I think, Danny, just to add to Mike's comments, we think this is a great lifecycle management opportunity for us, but if you think about it, we could be further optimizing chemotherapy— For sure. —which would be a massive outcome in and of itself. Not just treating the pain component, but maximizing chemo could be a secondary benefit of the program moving forward. We will certainly endeavor to explore that moving forward. Right. Greg, if I can sneak in a few more, I have a couple for Dr. Evarts. Sure. First would be, what prevents competitors from manufacturing their own synthetic TTX if your program proves successful? I think that's a very good question. As we continue to gain experience with larger and larger batches of TTX, we learn what others would have to invest a lot to learn, and we're first to the knowledge, and we'll be the first to the IP. That's great. Everyone would be chasing us with tetrodotoxin. There will forever be a race to make a better synthesis. But the end game that we have a lot of IP on is unavoidable. Yeah, and that would be the follow-up question is, your synthetic TTX intellectual property covers both process, and CMC protection. Can you walk us through what that IP protection looks like? Well, right now we have intellectual property on the HPLC method that is used to purify the material, and that is ubiquitous on all publications that you find, reporting presence of TTX in a new organism, which is always interesting. We have just recently submitted new IP around the handling of those fractions to minimize side products or the equilibrium of known impurities. We also have some ideas on some very minor impurities, their origin, and how to prevent them. Then once we come across the line with that means that Dogwood TTX is more pure than naturally occurring or your general synthetically produced TTX. You would then need to find out what you don't know and then avoid it again. Overall, in total, the barrier to entry is very high in this space. Understood. Thank you. Greg, looks like I have one for you here. Have other established pharmaceutical companies inquired about Halneuron partnership opportunities? Good question. Obviously, our job as a management team is to develop Halneuron to its full potential and then create value for shareholders as a consequence. We certainly have had companies inquire, including one or two who have an interest in exploring the data when we unblind it this fall. The bottom line here is we feel very comfortable advancing Halneuron through phase III development as a standalone, but if somebody can come to the table with a deal that creates value, either through reduced costs, accelerated program, reduced need to create a commercial infrastructure, we would consider that, and we will choose the path that makes the most sense for shareholders moving forward. We think, by the way, I should mention we've had interest from pain-specific companies, from general pharma companies, and interestingly enough, oncology companies. If you think about an oncology company, which wouldn't necessarily be an intuitive partner here, many of those companies are considering looking at palliative care. They're already in the doctor's office, and so there's a reason to be able to improve the chemotherapy regimen, engage further with a customer with more value. That's certainly an option as well. We'll explore all three versus the standalone option as well. Okay, great. Back to the trial design. What does 80+% statistical power mean on a practical level? Mike, that is probably best for you or Dr. Dukes. Let us let Dr. Dukes answer that. Can you ask the question again, please? Sorry. No problem. What does 80+% statistical power mean on a practical level? Power calculation. I'm not a statistical expert. Okay. I think that's not best asked of me. All right. When we look at effect sizes in trial results, we do something called a power calculation. That is, you look at the trends you see at that point in time, and then you model that data. If things do not change over time, how many patients do you need to roll? How big does that study need to be to have a minimum 80% chance of having a statistically significant result at the end of the study? That is called a power calculation, and when we do an 80% power calculation, that says what sample size you need to have 80% chance of succeeding at the end. You can do 80% and 90% power calculations. In this case, our interim analysis statistical committee did an 80% power calculation for us, and that is where the 210 to 240 number came from. Okay. Excellent. I have a couple more here, Greg, if we still have time. Sure. Why do not we get to those and then we will wrap up. Okay. That is fine. This is a long one, so bear with me here. Given that cancer patients can experience significant neuropathic pain and nerve damage during and after treatment, has Dogwood considered the potential role of Halneuron as a complementary treatment alongside radiotherapy or other cancer therapies? A follow-up here is specifically, could its NaV1.7 mechanism potentially allow it to manage treatment-related neuropathic pain without interfering with anti-cancer efficacy of radiotherapy or chemo, and is this something you would consider investigating clinically? Yeah. I think Mike just addressed that. There is a very short half-life, and the adverse events are quite tolerable, so we would certainly consider concurrent use with chemotherapy. We think it makes sense, presuming the safety profile holds up. Using it alongside would certainly be one of the top lifecycle management programs, ideas we would consider moving forward. Again, because we not just address the pain, but we could maximize the chemotherapy regimen. If you think about it, this mechanism is relevant whatever the form of damage. If you think about diabetic peripheral neuropathy, it is a different etiology. It is high blood sugar, reduced circulation, creating the damage of the neuropathy, the painful neuropathy in diabetic patients. But it is the same NaV1.7 signaling process that leads to that over read on pain. That would be another area we could explore as well, irrespective of the cause of damage. Using alongside of chemotherapy or in other forms of neuropathic pain. Great. Thanks, Greg. Our last question comes from Kambiz Yazdi over at U.S. Bancorp BTIG. Thanks, Kambiz, for weighing in here. Can the panel comment on what specifically about Halneuron's natural product-derived structure and peripheral pharmacokinetic profile allows it to avoid liabilities prior Nav1.7 inhibitors? With the synthetic tetrodotoxin manufacturing process now underway, what are the key CMC milestones, regulatory gating items needed to be completed prior to entering phase III studies? Yeah. Maybe I will ask Jerry to answer the second part of the question, but I think as Iain had answered before, Kambiz, there is a very high level of potency and selectivity for tetrodotoxin, which we think distinguishes it from prior programs like SiteOne, which had cross-reactivity to Nav1.5, which got in trouble relative to cardiovascular effects. Iain also mentioned the high protein binding from one of the Pfizer programs. We see this a lot in innovation. The first compounds may or may not be the right solution, but it does not necessarily invalidate the target. We think the target is still quite relevant in that the uniqueness of Halneuron as a chemical, its structure, its long duration that has been developed over millions of years, the ultimate natural product, if you will, make it very unique in and of itself, and that the target is quite relevant. Look no further than congenital insensitivity to pain syndrome, where these patients do not have Nav1.7 functionality and do not feel pain. So we think the target is quite valid, and the uniqueness of Halneuron makes it particularly suitable for this patient population. Jerry, would you like to add on to the CMC milestones and regulatory gating items on the way to phase III at a high level, please? Yeah. We are on the eve of our first synthetic drug product manufacturing run, and that will take us into a crossover study to demonstrate to the FDA that synthetic is equivalent to naturally sourced TTX. That will also take us into the start of phase III. On the CMC side, we are looking to have registration batches of drug substance, followed by the same for drug product in the latter half of next year, in the end of next year, and that will carry us through all of our phase III studies while we are frantically working to commercialize the process. Thank you, Jerry. Excellent. Tara and Greg, this concludes the written questions from the audience portion of question- and- answer. Thank you, Danny, and maybe just to summarize here, and thank everybody. Obviously, we've gone a little over the allotted time, but hopefully, that reflects the interest in the program. Hopefully, you'll agree this is a major unmet medical need. This is a very novel approach supported by data previously, and we hope the interim portends a good success, with an 80+% probability of success at the phase II-B readout this fall. We think there's ample room for NaV1.7s, NaV1.8s for a whole variety of patients. I think it's one-fifth of the world's population suffers from chronic pain. There's ample opportunity to do good, and we hope Halneuron is a key step in that evolution for new pain drugs. Thank you again for your time and attention, and we look forward to the data readout in the fall.