Virios Therapeutics Inc Aktie

Good morning, everyone, and welcome to the Dogwood Therapeutics Virtual KOL event. [Operator Instructions] 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 2 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 LRP1 agonist, which is poised to go into development as adjunctive therapy alongside chemotherapy to prevent emerging to neuropathy during chemotherapy treatment. The trial will likely dose patients in 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 2 significant additions to the pain armamentarium, Celebrex and Lyrica, several billion-dollar drugs are drugs that have either been developed and/or commercialized by our team. So 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 1, 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 a 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 Halneuron's differentiated mechanism of action.

Next up will be Dr. Mike Gendreau, our Chief Medical Officer; who has led Dogwood's clinical development program since early 2021 and has been guiding the Halneuron Phase IIb 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 2 decades of independent consulting on late-stage pain and CNS drug development programs. Mike will walk us through the Phase IIb clinical research summary to date and share with you what you can expect when we unblind the ongoing Phase IIb 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 [indiscernible] Emory and presently serves as a site investigator on our current Halneuron Phase IIb study. Mike will share his perspective on the unmet need in chemotherapy-induced neuropathic pain and his blinded observations from the ongoing trial.

And 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 2/3 and 3/4 of patients experiencing some form of neuropathy, most notably for today's discussion, moderate to severe pain, but 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 2 out of 3 or 3 out of 4 patients who experienced this as they go through their chemotherapy because of the off-target damage to the neurons in the periphery, generally sticking the hands and the feet. When oncologists observe this, there are 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's 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. So 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. And 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's 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 life cycle 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. So 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'll use U.S. data, I'll 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's 10.7 million patients. Of those 10.7 million patients, about 7 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'll agree. Unfortunately, this big problem gets even bigger. As time goes on, we are increasing cancer diagnosis. Each year, in fact, estimates are that there's 2 million newly diagnosed cancer patients in the U.S. If we went 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. So this is a very large opportunity, which gets larger.

Just forecasting to the future based on rough time lines, if we were to launch Halneuron in 2030 or 2031, we're 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's 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're diagnosing cancer earlier. So that rate of cancer is expected to grow pretty significantly over the next 1.5 decades.

Next slide, please. Right now, based on drugs that are used, which are all generic, if we look just at the 7 major markets, which just for clarity is the U.S., EU4, U.K. and Japan, you'll note that sales for CINP drugs based on this particular condition totaled $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's Lyrica and Neurontin or pregabalin or gabapentin, as you may know them, and 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? So 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's 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 puffer fish 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 are warm, 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 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. So you can imagine they have a very difficult lifestyle, if you will.

What we do know is that the bad actor in leading to congenital insensitivity to pain syndrome is the loss of NaV1.7 functionality. So 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 Halneuron's Phase IIb trial this fall. So 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. So in the next series of slides, I'll go over the role of sodium-gated ion channels in pain signaling and the differentiated mechanism of action of Halneuron with respect to its block of NaV1.7 versus 1.8. Could I have the next slide, please?

So what are sodium-gated voltage channels? So 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 the plasma membrane and beta subunits that exert a modulatory function on their activity. The alpha subunits themselves consists of 4 repeated domains labeled 1 through 4, each of which contains 6 membrane spanning segments. The S4 of 1 of these 6 serves as a voltage sensor and controls the opening of the channel in response to a change in the transmembrane voltage potential. In excitable cells, the opening of sodium-gated total channels enables a rising phase of action potentials and their propagation.

Next slide, please. So there's a large super family of which NaV1.7 and 1.8 are members and the family is shown on the right-hand side of this slide. There are 9 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 skeletal muscle and NaV1.7 to 1.9 in dorsal root ganglia. This distribution in the dorsal root ganglia is particularly significant because this has target tissue for the peripheral pain modulation.

Could I have the next slide, please? So in terms of the role of NaV in pain, they are important in the peripheral signaling of pain, both NaV1.7 through 1.9. Nav1.7, as you've heard already, is a particular interest because it's genetic validation for this target in the sense that subjects who have loss of function of NaV1.7 are unable to feel pain. Noncentral components of the pain perception were related to NaV1.7 activation include transduction of pain stimulating at peripheral nerve terminals and axonal transmission of action potentials to the CNS. Chronic pain conditions, including inflammatory pain, also you have an increase in expression levels of NaV1.7, pointing to its critical role in hyperalgesia and allodynia.

Next slide, please. So in terms of how sodium channel signaling differs between NaV1.7 and 1.8, 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. So first of all, the role of NaV sodium channels. So 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 for to increase pain signaling duration or intensity. NaV1.9 separately is thought to involved in cold pain sensing and small fiber neuropathy. So 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. And importantly, no additional pain reduction effect is seen when combining a NaV1.8 inhibitor on top of Halneuron, highlighting the importance of the NaV1.7 target.

Next slide, please. So 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 the 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 activity that way. TTX's highest potency is against NaV1.7 followed by NaV1.4. But because it does not readily cross the blood-brain barrier, this provides functional selectivity to Halneuron.

Next slide, please. So let's just review for a moment the validation of TTX other than Halneuron as potential best-in-class analgesic. So preclinical studies involving local as well as subchronic administration have demonstrated analgesic effects in a variety of animal models. Multiple clinical studies have been performed 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. And 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. So I'm going to give a summary of where we stand with the clinical development to date, but I wanted to take a 2-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's a much more difficult clinical target than acute pain states, and I'd like to talk a little bit about why that is.

So the first comment is that chronic pain does not tend -- 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. And that's always been a problem. We see patients who are telling us they're in terrible pain and you don't see a good reason for it. Or in the case of neuropathy or neuropathic pain, you know that they have had nerve damage and it's very difficult to really quiet those nerves down so that they -- the patient doesn't 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. And so what's happened over the last 20 or 30 years, we've recognized there's 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's nociceptive pain. The body knows what to do with that. You get an acute pain signal 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'm hurt, I'm hurt, I'm hurt, there's something wrong here. And 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. And so your therapeutic approach to dealing with a chronic neuropathic condition where the brain has changed its interpretation needs to be different.

And then in the middle, we have something called nocioplastic pain. That's a newer term. That's been developed over the last 20 or 30 years as we understand central pain conditions such as fibromyalgia, where we can't find damage in the periphery. We can't find nerve damage yet these patients consistently report much higher levels of pain than we would expect. And what we have found, and I'll 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. So this is some work that was done by a lab in Michigan about 20 years ago. But I think it's very interesting, and I want to just 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. So this was a controlled pain signal. And 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.

And on this graph on the left here, this blue dot is normal patients. When you apply about 2 kilograms 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. And 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 4 to 4.5 kilograms of pressure, pain says now that the patient tells you that starts to hurt. That's what the green dot on this line is. And 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. So we can correlate activation locations in the brain with patient telling us they're experiencing pain.

Then we go to fibromyalgia patients, which have the centralized pain or nocioplastic pain. And when we look at them and apply 2 kilograms per square centimeter pressure, they report pain comparable to the 4.5 kilogram pressure at that lower pressure, which a control patient does not report pain. So they're reporting pain at the low stimulus. And 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. So what came out of this work and it's been expanded on since is that the statement that 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.

So 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. So we get some of the nocioplastic effects and then we have the chronic nerve damage, which changes how the -- both how the spinal cord transmits pain and it also changes the number of the sodium channel pores on the nerve. So we get increases of these NaV1.7 to 1.8 ion channels as well in these chronic pain states. So a 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. So Halneuron is -- we've already told you it comes from the puffer fish, at least the original material is a biological material. It's a very, very potent inhibitor of the sodium channels. We're using 30 micrograms of drug per day in terms of the treatment dose. That is 100-fold to 1,000-fold less drug than you typically use for most analgesics is when you think about drugs you might have experience with acetaminophen or NSAIDs, you typically take 10 or hundreds of milligrams per day of those drugs. This is microgram doses.

And I stress that because when you use such a small amount of drug, there's less opportunity for off-target effects. It's very specific for its target, and we're 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, so we get drug levels within an hour when we give it subcutaneously. And it has a half-life of 4 to 8 hours. So 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. So treating chronic pain really is different than treating acute pain. We administer this as a 1 milliliter subcutaneous injection once a day over a number of days, depending on the dose being delivered to the patient. And as I said, it's 30 micrograms that's 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 was done a number of years ago. This is a patient population with cancer-related pain. So they're 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 who was randomized 1:1 between tetrodotoxin or Halneuron and placebo. This was a responder analysis where they were treated for 4 days. So they got injections twice a day for 4 days and then all treatment was stopped.

Then the patients were followed for 2 weeks with no additional treatment and assessed to see if they had a meaningful reduction in their pain or a meaningful reduction in opioid use in this case, at that endpoint 2 weeks later. And what was seen was that the Halneuron-treated patients had 51% of those patients manifested a response, either pain reduction, in most cases, it pain reduction in a few patients, they stopped using their opioids compared to a 35% response rate in placebo.

So even though the placebo response rate was a little higher than we like, we still have statistically significant results with this relatively small cancer trial. So 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. But what was even more interesting to this was the durability of response.

So the next slide. I mentioned to you, we treated these patients for 4 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.

And you can see of the Halneuron responders, the average response was 57 days for a treatment that, again, was 4 days long and for a drug that had a 4- to 8-hour half-life. So we definitely have something going on here biologically in terms of how pain is being processed. We don't see any evidence that the Halneuron is still bound to the receptors. We think we've had a change in processing of how pain happens or is interpreted in these patients. The lower graph are those placebo responders, 35% the placebo patients in this trial reported a pain improvement. But you can see here the duration of response in the placebo responders was around 10.5 days.

So biologically very different. The placebo responders did what we are accustomed to seeing in pain trials that you do -- 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're doing something really beneficial in these difficult-to-treat patients, and that encouraged us to move on to the neuropathic study I'll talk about next.

Next slide. So the next target that the company went after was chemotherapy-induced neuropathic pain, which is our current indication we're pursuing. And this study was a dose-ranging study. It was a Phase IIa study designed to pick the optimal dose and dosing frequency for the Phase IIb studies that we're currently running. So this was a predecessor study. And what came out of the study without spending a lot of time on it is we found that 30-microgram dose was the most effective dose between 7.5, 15 and 30. But we found that dosing it once a day instead of twice a day worked just as well with a better side effect profile, better adverse event profile. So we selected once-a-day dosing at that 30-microgram dose to carry forward into our current large Phase IIb study to really try and establish this as an effective treatment for CINP.

Next slide. So the study that's currently running and that will be reporting out in a few months is shown -- the design is shown here. We have a screening and randomization phase where the patients train 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're consistent in how they report their pain, that they're reliable pain reporters and so on.

So 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 that -- those criteria, they are then randomized 1:1 between Halneuron treatment or placebo. This protocol calls for 8 injections delivered over 14 days. So it's up to the treating clinic by exactly how they deliver those 8 injections, most clinics give 4, 1 week and 4 the next week, although they can give 5 and 3 or 2 and 6, whatever works best for that patient and that clinic in terms of providing these injections. The goal is to provide 8 treatments over a 2-week period.

And then as we saw previously with the cancer-related pain study, all treatment has stopped after 2 weeks. We then follow the patient for another 2 weeks with no further treatment and then look at the primary endpoint, which is at the week 4 end of treatment visit to see how much their pain has changed from that initial baseline value. And 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 IIb. 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. And as Greg mentioned at the beginning, we've currently recruited 232 patients. So we're very near the endpoint here. And 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. This 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 the 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. And 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-plus percent dropout rate in their registration clinical trials. Pregabalin was 30% to 40%. Savella, the one I developed was also in the 30% range.

So we're very excited about how well tolerated Halneuron is. It's very well tolerated, and this is a very motivated population. These patients have survived cancer. They've gone through cancer chemotherapy. And then they have the sequelae of their treatment where they're dealing with chronic pain that can be in some ways as bad as the cancer was. And the fact that this is a potential treatment opportunity for them, they're very motivated. And that's 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 that the 5-year duration of moderate to severe neuropathic pain. What that means is these patients were 5 years on average since their cancer chemotherapy stopped and they developed neuropathic pain.

So they are cancer survivors and have now been dealing with this neuropathic pain that was a result of the cancer chemotherapy on average for 5 years. We suspect that if you've had severe neuropathic pain for 5 years after chemotherapy, you probably tried every treatment under the sun. When we looked at the medical history on the patients we enrolled, they indeed at least 2/3 of them reported having tried treating their neuropathic pain with other chronic pain medications such as duloxetine, pregabalin you name it, they've tried it. At least 2/3 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're allowed to take these other medications as long as they take them chronically. So we are providing a treatment on top of these other background therapies and still seeing a treatment effect. So that was very rewarding to see that, yes, in fact, we can treat these patients no matter what else they're taking.

So 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. So this trial is really designed to set us up for a Phase III program.

Next slide. One other thing I'll quickly tell you, we have an open-label study. In fact, that 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'd be giving 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'd want to do with -- in commercial use. And 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's a 12-week study. So now the patients were treated for 2 weeks in the double blind, no treatment for 2 weeks. So at week 4, they're 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 2 injections or 4 injections. So if the pain is below 4 on a 0 to 10 scale, they get 2 injections. If it's 4 or greater, they're going to get 4 injections, and that's for the first month. They come back the next month. We again assess their pain level, decide if they need 2 or 4 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. So 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. And again, we'll look at changes in a number of outcome measures, but pain being the primary one here is 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 9 patients early-termed in the entire study. So this supports what we saw during 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 10, 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 2 patients decide to stop treatment early, 3% dropout rate at the current time. And we now have around 20 patients who have completed the open-label study and again, many more coming in at this point. Our last patient be enrolled in the double-blind study will be this Thursday. So 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 the study. Dr. Joyce and I have worked together for probably over 20 years on various studies. And 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 I'll be talking about. Our site has enrolled -- well, we screened 9 participants enrolled 7, and we have completed 2 participants in the open-label phase. And at this point, nearly -- all but 2 of the subjects are in the open-label phase.

But 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've worked with over 100 companies over the last 20 years. My background is in psychiatry, but I've 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're discussing, we were able, as I said, to screen -- well, the data of the slides was 7. We've screened 9 at this point and enrolled 7 and as I said, all but 2 are in the open-label part of the study. And we have had no drops from the study for any reason, including adverse events. So next slide, please. All right. So this is just a little bit -- we've had a bit of an update instead of the 6, we've now got 7, and we're waiting to see the outcome of that screen. But generally, our patients have tolerated the injections very well.

As Mike alluded to, this population of cancer survivors are now -- well, they're used to dealing with pretty severe consequences of their chemotherapy and cancer in general. And they have been generally willing to return to the clinic for multiple injections, very few complaints. And this is, as an aside, been a really pleasant population to work with.

Next slide. So compared to the numbers Mike was mentioning, we only saw a small number of cancer-induced neuropathic pain patients at our site. And of course, we're still all blinded. But we were encouraged over what we saw firsthand. First of all, these patients with this condition are looking for answers, Halneuron has -- may have some benefit for some of these very difficult to manage patients. And 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 distal 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. So that's it in a nutshell. And I would just add two sort of unofficial parenthetical comments. One is the therapeutic effect was substantially noticeable in the side effects, 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. So some useful effects and a very well-tolerated compound. And without a doubt, without exception, I can tell you everyone who has finished the double-blind -- I mean, the open-label phase of the study has expressed interest in continuing the compound. That was their level of benefit.

So I'll turn it over to the next speaker.

Good morning. Next slide, please. The active ingredient in Halneuron neuron, as we've said, is tetrodotoxin abbreviated TTX. It is found in many species, both terrestrial and aquatic, although historically and most notoriously in Fuubutsushi, 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 in the river and during which months. The toxin was isolated near the turn of the 20th century, which -- 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 preeminent 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 Mt. 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 puffer fish, specifically the ovaries of females and could obtain approximately 1 gram per 20 kilos 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 are 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 4x more potent than cone shell poison, which as a reference for you movie buzz is the toxin they plan to instantly incapacitate T-rex in Jurassic Park 2. 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 Turkey. 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 has 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 in purifications, we chose Indena in Milan, Italy, a CRO steeped in handling high-potency chemicals, especially natural products. Over the next 2 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 glycosylate. It's absent in synthetic material. We made approximately 4 grams, which is so little. However, at 30-microgram 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-gram commercial batches. A 20-gram 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 a kilo. 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, bacteria 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 glycosylate exception. That's 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 micrograms of TTX and 100 milligrams of lactose. The material shown here are all dissolved in water, vialed into 5-milliliter vials, freeze-dried and finally capped and printed. A purpose of the lactose is distinguished between completely empty vials and those containing the TTX as 30 micrograms is not visible in a 5-mL vial. Below is a typical production line for such high potency processes. And in fact, today, we are visiting our drug product manufacturer to take a look at how things will go in the future. Thanks.

So just to wrap up here to 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 4. Our goal is to run a PK Phase I study comparing the synthetic with the naturally harvested tetrodotoxin and we will commence the 2 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's a possibility, but it's most prudent to plan on 2 studies moving forward with an interim assessment in the first Phase III study in the quarter -- 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. But I don't 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. So to summarize, we believe, and I hopefully you'll 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're hoping to see that same result in the fall. The NaV1.7 target is further validated by this genetic defect known as congenital insensitivity to pain syndrome and 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.

So 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. [Operator Instructions] Our first question comes from Jason McCarthy at Maxim.

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 NaV1.8 and you're going to bring up Journavx and there's been some issues with its onset and Latigo is out there now with the flashy IPO, and there seems to be this focus on the 1.8. Can you just compare and contrast those 2 approaches? Because to us, it seems like there seems to be a little bit of a disconnect.

Yes. Maybe I'll have Mike address the first question on onset and then I'll ask Dr. Dukes to speak to how our program differentiates from other 17s and 18s. Mike?

Well, first, both the Latigo program and the Vertex program, those are acute pain models. So that's quite different than our real-world neuropathic pain studies. So they're looking at bunionectomy, where you are surgically insulting the patient, if you will, and then you're treating immediately to see if you can reduce pain over 24, 48 hours. So that's really a very different model. And so that's really acute pain. So that's why I talked about the difference between chronic pain and acute pain. We're going after a chronic pain conditions. So it really is quite different than treating acute pain. So they're not directly comparable. It doesn't mean Nav 1.8 wouldn't work in chronic pain. It doesn't mean that Nav 1.7 wouldn't work in acute, but you're comparing a bit of apples and oranges there.

Yes. And I would just say, but just to echo that, 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 1.7 and because of the lack of selectivity and the fact that 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's 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. So none of these issues apply to Halneuron because of the functional selectivity that drug has against other ion channels of concern and the fact that our tolerability data to date certainly proves that point.

Yes, 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, Journavx will be pursuing a DNP program or 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.

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?

Yes. And then I'd also like to let Dr. Dukes address that as well. But I will tell you that we don't know. I don't have hard data that can answer that question. But I -- 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's something called descending inhibition. Pain gets gated at the dorsal root ganglia. So there's a lot of mechanisms that have evolved with evolution to control how pain is experienced, how it's interpreted. There's 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're changing that pain signaling network. I don't know exactly how it's changing, but that's consistent with what we see clinically. And I 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, it's -- that's a reset that's changing a network I suspect you're doing something similar, but I can't prove that.

Like neuroplasticity or something?

Yes. This is one way to say it. Dr. Dukes, you?

Yes. Yes. It's hard to say at this point. I think 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. Just last question. What could the size and scope of a Phase III look like? And assuming that the Phase IIb is successful, there is the potential that it could serve as 1 of the 2 likely required pivotal trials?

Mike, why don't you handle that one, given your regulatory expertise.

Yes. Let me answer the second question first. We do not anticipate this can serve as a pivotal registration trial. 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 2 registration studies. In terms of size and scope, they need to be 12 weeks with 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 IIb study is going to really tell us how big these studies need to be in terms of numbers of patients.

Our next question comes from Sean Lee at H.C. Wainwright.

Very informative presentation. I just have a couple of questions mostly on Halneuron could be used in the clinic. So my first question is for the CINP patients today, as you mentioned, you get treated with a lot of different therapies, including duloxetine, topicals, opioids. So what's the typical sequence of treatment these patients get. And if Halneuron does get approved, how would it slot into this treatment regimen?

Sure. Maybe I'll kick off based on what we know, and I'd ask Mike to jump in here. So 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're 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's recommended by ASCO as the only potential viable treatment. But as Mike mentioned, the data we're collecting from this study, it was originally about 2/3. I think, Mike, it's still blinded, but we're down to about half of the patients on some form of concomitant med. So we'll be able to assess Halneuron's efficacy used as a stand-alone therapy as well as on top of other therapies. And I think that's 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're almost building your evidence to run over a step edit right away. Now 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're hoping, as we unblind the data, that we do show an effect, both as a stand-alone and on top of those other therapies. So 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're seeing in the clinical trial. Mike, anything to add to that?

Only that when we say 2/3 of the patients were using other chronic pain drugs, that's concurrently with our trial enrollment. And these are 5 years later, I suspect this population has tried everything available by the time they get to our clinical trials. So 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. So 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.

That's very helpful. My next question is on the effect size. So 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. And does this change for patients based on what kind of chemotherapy do they receive, whether it's platinum-based or taxing based?

Mike, why don't you start and then I'll chip in afterwards.

Yes. Effect size when you're doing responder analysis is a bit tricky. Typically, when we talk about effect size, we're talking about continuous analysis 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. So we are now using a 50% responder analysis. It's 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. And so 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 clinically important difference MCID. So anytime you have a 30% reduction in pain, that is something the patient notices. It's considered to be a meaningful change. And if you have a statistically significant reduction on a 30% responder analysis, by definition, that's clinically meaningful. We're looking at a 50% threshold. You can look at different thresholds, you can look at 30, 50, 70. We're using a 50% threshold but I don't expect there's going to be any debate with FDA whether or not a statistically significant study using a 50% threshold isn't clinically meaningful to those patients. Greg?

Yes. Maybe, Sean, just to build on what Mike said, obviously, p value of less than 0.05 in this trial will be critical in classic sense to meet FDA definition. But just to provide a little context, as I think we're all aware, there's nothing approved to treat these patients. So this would be the first potential drug to benefit patients. And 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's about 30% of patients who demonstrated a 50% or greater reduction compared to 15% in 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's a little less than 2:1 on, 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.

That's very helpful. My last question is on the dosing of Halneuron. So with 8 subcutaneous doses over 14 days, where would the patients -- where would this be administered for the patients? And how does it compare to what they typically received. Would this be sort of a barrier for them to receive these injections?

Mike, maybe you can speak to the 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 8 doses over 2 weeks. I mean, 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, but 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. And so I think at this point, the benefits are worth the cost. And 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. And that's not going to be my area of expertise, but perhaps Mike or others could talk about that. But we have to reconstitute the drug and administer it within a short period of time. And that is something that would be an issue for ongoing use of the drug.

Yes, Sean, we are collecting safety data as we speak, as I'm sure you're well aware. And so over time, we could certainly see potentially home administration, you start the patient 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. And 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. But as Dr. Joyce has mentioned, we've had a handful of patients stop short of their 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 5 years.

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. It's -- no one's got that indication. We're not aware of anyone 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. So 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. We -- 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.

Yes. I think, Danny, just to add to Mike's comments, we think this is a great life cycle management opportunity for us. But if you think about it, we could be further optimizing chemotherapy, which will be massive outcome in and of itself. So not just treating the pain component, but maximizing chemo could be a secondary benefit of the program moving forward. So we will certainly endeavor to explore that moving forward.

Great. And Greg, if I can sneak in a few more. I have a couple for Dr. Evarts. 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. So 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.

And then that would be the follow-up question is your synthetic TTX intellectual property covers both process and COM 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. And we also have some ideas on some very, very minor impurities, their origin and how to prevent them. And then once we come across the line with that, that means that Dogwood TTX is more pure than naturally occurring or your general synthetically produced TTX. So you would then need to find out what you don't know and then avoid it again. So overall, in total, the barrier to entry is very, very high in this space.

Greg, it 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 1 or 2 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 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, and that's certainly an option as well. So we'll explore all 3 versus a stand-alone option as well.

Okay. Great. And back to the trial design, what does 80-plus percent statistical power mean on a practical level?

Mike, that's probably best for you or Dr. Dukes.

Let Dr. Dukes answer that.

Can you ask the question again, please, sorry?

Yes. No problem. What does 80-plus percent statistical power mean on a practical level?

Power calculation.

I'm not a statistical expert. I think it's not best asked of me.

All right. So when we look at effect sizes and trial results, we do something called the power calculation. That is, you look at the trends you see at that point in time. And then you can do -- you model that data, if things don't change over time, how many patients do you need to enroll? 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. So that's called the 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 calculation. So in this case, our interim analysis statistical committee did an 80% power calculation for us. And that's where the 210 to 240 number came from.

Excellent. I have a couple more here, Greg, if there's time.

Sure, why don't we get to those, and then we'll wrap up.

Okay. 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. And then a follow-up here, specifically, could its Nav 1.7 mechanism, potentially allow it to manage treatment-related neuropathic pain without interfering with anticancer efficacy of radiotherapy or chemo. And is this something you'd consider investigating clinically?

Yes. I think Mike just addressed that. There's 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. And so using it alongside would certainly be one of the top life cycle management program ideas we would consider moving forward. Again, because we not just addressed the pain, but we could maximize the chemotherapy regimen. But there are -- if you think about it, this mechanism is relevant whatever the form of damage. So if you think about diabetic peripheral neuropathy. It's a different etiology. It's high blood sugar, reduced circulation, creating the damage of the neuropathy, the painful neuropathy and diabetic patients, but it's the same Nav 1.7 signaling process that leads to that overread on pain. And so that would be another area we could explore as well irrespective of the cause of damage. So using it alongside of chemotherapy or other forms of neuropathic pain.

Great. Okay. And our last question comes from Kambiz Yazdi at U.S. Bancorp. BTIG. Thanks Kambiz for weighing in here. Can the panel comment on what's specifically about Halneuron's natural product derived structure and peripheral pharmacokinetic profile allows it to avoid liabilities of prior Nav 1.7 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?

Yes. Maybe I'll 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 Nav 1.5, which got in trouble relative to cardiovascular effects. Iain also mentioned the high protein binding from one of the Pfizer programs. So we see this a lot in innovation. The first compounds may or may not be the right solution, but it doesn't necessarily invalidate the target. We think the target is still quite relevant and that the uniqueness of Halneuron as a chemical, its structure, its long duration. This 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. And look no further than congenital insensitivity to pain syndrome, where these patients don't have Nav 1.7 functionality and don't 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...

Yes. 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.

Excellent. So Tara and Greg, this concludes the questions from the audience portion of the question-and-answer.

Thank you, Danny. And maybe just to summarize here, and thank everybody. Obviously, we've gone a little over the -- a lot of 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-plus percent probability of success at the Phase IIb readout this fall. We think there's ample room for Nav 1.7, 1.8 for a whole variety of patients. I mean I think it's 1/5 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.

Welcome to the 2026 Annual Stockholders Meeting for Dogwood Therapeutics, Inc. Our host for today's call is Greg Duncan, CEO and Chairman of the Board. [Operator Instructions] I'll now turn the call over to our host, Mr. Duncan, you may begin, sir.

Good morning. I am Greg Duncan, and I have been appointed Chairman of today's meeting. I would like to express a sincere thank you on behalf of the entire Dogwood Therapeutics Board and our executive management team for your attendance at this year's meeting.

I now call the meeting to order. Angela Walsh, Chief Financial Officer and Treasurer of Dogwood will serve as the Secretary for today's meeting. I would also like to introduce Emily White of Equiniti Trust Company, who has been appointed as the Inspector of Elections for today's meeting. Ms. White has previously taken her oath as Inspector of Elections.

To start, I would like to introduce the current directors of the company. In addition to myself, the directors are Dr. Abel De La Rosa, Abel has served as an Independent Director since December 2020. David a.k.a. Rick Keefer. Rick has served as an Independent Director since 2018; John C. Thomas Jr., John has served as an Independent Director since December 2020. Dr. Melvin Toh, Melvin has served as a Director since October 2024. Dr. Richard Whitley, Rich has served as an Independent Director since December 2020.

And last but not least, Alan Yu. Alan has served as a Director since October 2024. Also in attendance today are representatives of FORVIS Mazars LLP, the company's independent registered public accounting firm.

Now let me turn the proceedings over to Angela Walsh, who will provide instructions for today's meeting.

Thank you, Greg. We will proceed with the formal business of the meeting in the order set forth in the notice of our Annual Meeting of Stockholders and the proxy statement. We will first present the 5 proposals submitted for approval by our Board. We will take questions related to the proposals. We will then open the polls for voting.

Please note, if you have already submitted your vote by proxy and do not wish to change your vote, you do not need to vote now and your shares will be voted as previously instructed. You should also have a copy of the rules of conduct for the meeting. These are posted on the registration page and viewing page once you enter the meeting. In order to conduct an orderly meeting, we ask that you follow these rules. Stockholders who are attending this meeting may submit questions through the Ask a Question box located at the bottom of your screen.

Stockholder questions are welcome, but we do not intend to address any questions that are not relevant for the meeting, such as questions specific to an individual shareholder or questions not related to the previously submitted proposals for this meeting. Please submit your questions now to make sure they are received in a timely fashion for our review and response.

At this time, I'll turn the meeting back over to Greg.

Thank you very much, Angela. The following documents will be incorporated in the company's records as part of the minutes of today's meeting. First, a copy of the notice of Annual Meeting of Stockholders stating the date, time, place and purposes of this meeting.

Second, a copy of the proxy statement for today's meeting; and third, the affidavit of Broadridge showing that each stockholder of record on the record date was mailed and deposited with the United States Post Office, packages containing the notice of annual meeting, the proxy statement, form of proxy card and the annual report on Form 10-K.

Will the Secretary please report at this time with respect to the existence of a quorum?

The Board of Directors set April 21, 2026, as the record date for stockholders entitled to notice of and to vote at this meeting. A certified list of the stockholders of the company as of the close of business on the record date has been provided to the company by the company's transfer agent, Broadridge. That list is available for inspection during this meeting and shows that on the record date, there were 33,401,553 shares of common stock of the company issued and outstanding.

On each proposal brought before this meeting, stockholders are entitled to 1 vote for each share of common stock registered in their name. I have been advised that more than 1/3 of the outstanding shares entitled to vote are present. Therefore, I declare that a quorum is present, and this meeting may now proceed.

Let me turn it over to Greg to review the proposals for the meeting.

We will now proceed with the formal business of today's meeting. After all the proposals have been described, we will answer any questions submitted online that are related to these proposals. Please submit any questions as soon as possible for our review. There are 5 proposals to be considered by the stockholders at today's meeting.

The first proposal requiring the vote of stockholders is the election of 7 director nominees to serve until the 2027 Annual Meeting of Stockholders and until their successors are duly elected as well as qualified. The 7 nominees receiving the highest number of votes of shares present virtually or by proxy at this meeting will be elected as directors. The candidates who are nominated for election are Dr. Abel De La Rosa, Greg Duncan, David Keefer, John C. Thomas, Jr., Dr. Melvin Toh, Dr. Richard Whitley and Alan Yu. Each of these nominees currently serves as a director of the company. No other persons have been properly nominated under the procedures required by the bylaws, and I declare the nominations now closed. The Board of Directors recommends that stockholders vote for each of the director nominees.

The second proposal is the ratification of the selection of FORVIS Mazars LLP to serve as our company's independent registered public accounting firm for the fiscal year ending December 31, 2026. The Board of Directors recommends that stockholders vote for ratification of the appointment of FORVIS Mazars LLP as the company's independent registered public accounting firm for the fiscal year ending December 31, 2026.

The third proposal is to approve the amendment to the company's certificate of incorporation to increase the number of shares of common stock and preferred stock authorized for issuance from 43 million and 2 million, respectively, to 195 million and 5 million, respectively. The Board of Directors recommends that stockholders vote for the approval of the amendment to the company's certificate of incorporation.

The fourth proposal is the advisory vote on the frequency of future advisory votes on named executive officer compensation. As required by the Exchange Act, we are asking our stockholders to vote on an advisory or nonbinding basis on how frequently we should hold future nonbinding advisory stockholder votes on the compensation of our named executive officers, otherwise known as a say-on-pay vote. This is the first say-on-pay vote as 2026 is the first year in which we are required to hold a say-on-pay vote pursuant to the rules of the SEC. We currently do not have an established frequency for such votes.

Stockholders may vote to indicate they would prefer that we hold the say-on-pay vote at future annual meetings every year, every 2 years or every 3 years, or they may abstain from the vote. The vote is commonly known as a say-on-frequency vote. The Board of Directors recommends that stockholders vote for 1 year for the advisory vote on the frequency of future advisory votes on named executive officer compensation.

The fifth proposal is the actual advisory vote on the compensation of our named executive officers or say-on-pay vote itself. As required by the Exchange Act, we are asking our shareholders to approve on an advisory or nonbinding basis, the compensation of our named executive officers as disclosed in this proxy statement. This proposal, commonly referred to as a say-on-pay vote, provides our stockholders the opportunity to express their view on our named executive officers' compensation as a whole.

This vote is not intended to address any specific items of compensation or any specific named executive officer, but rather the overall compensation of all of our named executive officers and the philosophy, policies and practices described in this proxy statement. This is the company's first say-on-pay vote. The Board of Directors recommends that stockholders vote for the advisory vote on the compensation of our named executive officers for 2025.

Before proceeding to the voting, we will check to see if there are any questions submitted about the proposals before we open the polls. Angela, are there any questions?

Greg, there are no questions related to the proposals submitted for the meeting.

Thank you, Angela. The time is now 10:10 a.m. Eastern Time, and the polls are now open for voting. In order to vote during the meeting, you may click on the Vote My Shares button on your viewing page and follow the prompts. If you have voted your shares prior to the start of the annual meeting, your vote has been received by the company's inspector of elections, and there is no need to vote those shares again during this meeting unless you wish to revoke or change your vote. We will now pause 1 minute for stockholders to finish their voting.

[Voting]

The time is now 10:11 Eastern Time, and the polls are now closed for voting. Will the Secretary please report the preliminary results of today's voting?

Greg, based on the preliminary report of the Inspector of Elections, I hereby declare that each of Dr. Abel De La Rosa, Greg Duncan, David Keefer, John C. Thomas, Jr., Dr. Melvin Toh, Dr. Richard Whitley and Alan Yu has received the affirmative vote of more than a plurality of the shares present at the meeting and entitled to vote on the election of directors, and each of them has been elected to serve as a director of the company to serve until the 2027 Annual Meeting.

I hereby declare that the appointment of FORVIS Mazars LLP to serve as the company's independent registered public accounting firm for the fiscal year ending December 31, 2026, has been ratified by the affirmative vote of at least a majority of the shares present and entitled to vote on this proposal. I hereby declare that the amendment to the company's certificate of incorporation to increase the number of shares of common stock and preferred stock has been ratified by the affirmative vote of at least a majority of the shares present and entitled to vote on this proposal.

I also hereby declare that the advisory vote on the frequency of future advisory votes on named executive officer compensation or the say-on-frequency vote has been approved to be 1 year based on the affirmative vote of at least a majority of the shares present and entitled to vote on this proposal.

Lastly, I hereby declare that the advisory vote on the compensation of our named executive officers for 2025 or the say-on-pay vote has been approved by the affirmative vote of at least a majority of the shares present and entitled to vote on this proposal. I will turn the meeting back over to Greg for final comments.

Thank you very much, Angela. I hereby request that the final report of the Inspector of Elections be filed within the minutes of today's meeting. Our final voting results will be filed with the SEC on a current report on Form 8-K within 4 business days after the end of today's meeting. This concludes today's meeting. As there are no other matters to be considered, the Annual Meeting of Stockholders of Dogwood Therapeutics, Inc. is now adjourned.

I want to thank you again for your attendance at today's meeting and for your interest in Dogwood Therapeutics as we work to develop novel new medicines to treat cancer and chemotherapy-related pain and neuropathy.

The meeting has now concluded. Thank you for joining, and have a pleasant day.