All right, thank you, everyone, for joining. My name is Frank Briswell. I'm one of the biotech analysts at Oppenheimer. Our next company presenting here is Achieve Life Sciences. From the company, we're lucky enough to have CEO Rick Stewart to present. In terms of format, what we're going to do is a fireside chat. We're just going to run through questions. If you want to send any questions, please do in the Q&A tab at the bottom of the screen, or you can email me as well. With that, thank you very much, Rick, for joining. Maybe just a quick background on Achieve, and I think the history here is very interesting. Yourself and Achieve would be helpful. Thank you. Thanks for having us, Frank. The history of Achieve is interesting because the drug was originally found about 10 years ago by myself and Tony Clarke in Bulgaria, of all places. The drug has actually been used for many years in Central and Eastern Europe. Its original design had many flaws. We spent a considerable amount of time actually redesigning the dosing and duration of treatment to get us to where we are today. I think the key, as far as we're concerned, is that we see cytisinicline and Achieve as the solution to the nicotine dependence crisis in the U.S. and globally. I think we've got the benefit of a lot of history related to the compound, which we've been able to capitalize on. By redesigning it, we believe we've improved both the efficacy and the safety, and most importantly, the compliance of the drug. Can you? Okay, on that note, can you just help us understand a little bit how you found this in Bulgaria and what cytisinicline is? Sure. Yeah, cytisinicline is an alkaloid. It's a partial agonist of the alpha-4 beta-2 receptor. Really, what it does is to block the uptake of nicotine, of the nicotinic receptor, but also it provides some of the buzz or the receptor excitement that's associated with nicotine itself. Yeah, we've had a history of actually identifying off the record, off the radar screen drugs. We were behind Huxley Pharma with 3,4-diaminopyridine, which is actually now Firdapse. We were also behind Fintepla, which is fenfluramine for Dravet syndrome. We've got a long history of finding these drugs. This is the most important one because it is the first new treatment for nicotine dependence in nearly 20 years. There are 29 million smokers in the U.S., and there's approximately 11 million vapers. We believe that this is the most important drug we've ever worked on in terms of our ability to save lives. Roughly 500,000 Americans die every year from smoking-related diseases. The annual cost is somewhere around about $300 billion a year in treatment and lost productivity. Yes, this is a really important drug. I think the exciting time is now, given the fact that we are filing the NDA with the FDA next quarter. Okay, ahead of that, just to get up to speed on the data, can you help run us through a little bit? In the past couple of years, you've had a lot of data from cytisinicline that goes into this filing. Can you help us understand, just go through the data so far and the filing and what had happened? Just a little update. Absolutely. Yeah, we've run two large-scale phase 3 clinical trials, the ORCA-2 and ORCA-3 trials, and hugely successful in terms of odds ratios. That is, the probability of a patient quitting relative to placebo. On average, in the 1,600 patients in the phase 3 trials, they have an odds ratio of 5.5, which means they're 5.5 times more likely to quit on cytisinicline than they are on placebo. That's important because the nearest competitor only had an odds ratio of 2.3. Our efficacy is more than double that of the previous nicotine-dependent drug. I think the side effect profile is probably amongst the biggest differentiators. I mean, historically, the predecessor drug had a reputation for nausea and vomiting, abnormal dreams and nightmares, sleep disturbances, and headaches. It really wasn't a great combination of side effects to encourage somebody who wanted to quit to actually be compliant. We have very few side effects. It's largely benign. We do think that both the combination of the superior efficacy and the superior side effect profile is the real differentiator with the drug. At the moment, there are no branded competitors in the market. There is no one for us to share voice with with respect to the physicians. Can you help us understand a little bit? You talked about superior efficacy. Wasn't there back in the day a head-to-head with Chantix here that was done? Do you think this is something that you would need to look at, or it's pretty understood what the data is here and physicians know how to kind of interpret it? Yeah, we have never conducted a direct head-to-head clinical trial. I believe there's been an academic study, but perhaps not with the same rigor you'd expect as far as regulatory review. Yeah, I think that obviously Chantix generated revenues of over a billion dollars at peak. That was with the side effect profile that I just described. We're pretty confident that with our very benign side effect profile, superior efficacy, we should at least match that, if not exceed it significantly. We're building this into a blockbuster. We believe this could well be a blockbuster. I think added to that, of course, is vaping. Back in the day, Chantix didn't have a vaping indication. That's our next phase 3 clinical trial that we'll be working on. Altogether, we think that with a superior side effect profile, superior efficacy, that we really have a great potential for this becoming a blockbuster. I think one of the key elements to this is to realize that nicotine dependence is a medical condition. This is not a lifestyle issue. This is not a lack of willpower. This is a nicotine dependence is a medical condition. It's the third most addictive drug after heroin and cocaine. We need to be treating the nicotine dependence just in the same way, almost as obesity was, say, five years ago. Five years ago, before the GLP-1s, people tended to view obesity as a willpower issue, should be dieting and exercising. That's clearly not the case. The same applies to nicotine dependence, where this needs to be really treated as a medical condition. Yeah, so it seems like safety is extremely important here, especially on the differentiation versus what Chantix had to deal with. Can you help us understand? You've had your data. The safety looked good. It seems like the FDA wanted to see additional safety. Can you just remind us where you stand on that? There was a press release just yesterday to touch on that. Absolutely. We put out a press release early in January saying that we had met 300 patients with six months exposure to the drug. Yesterday, we put out the announcement that the Data Safety Monitoring Committee had also met, and there were no major issues at all. Our next milestone with respect to long-term exposure for cytisinicline is reaching 100 patients at 12 months. We're expecting that to happen also in the second quarter, although it won't be included in the NDA. There won't be enough time. We've got an agreement with the FDA that we can add it subsequently. Can you help us understand from the NDA filing, how much time should we expect here, maybe for PDUFA and launch? Yeah, I mean, typically, it's around about a 12-month to PDUFA. We're currently anticipating a product launch probably in the third to fourth quarter of 2026. A huge amount of preparation for that is taking place. Clearly, it is a huge market that we're addressing. If you look at the number of primary care physicians out there, there's in excess of 460,000, but only roughly 47,000 actually write prescriptions for generic varenicline now. The top two deciles are roughly 7,000 physicians. What we're going to be targeting are the real committed varenicline writers as our target physician population. Similarly, we'll be targeting the committed quitters. We've got the characteristics of both of those. Increasingly, the difficulty is being to actually access the physicians face to face. I think the world has evolved fairly significantly away from, frankly, a salesforce on the ground. We have a highly sophisticated and well-thought-through digital data-driven strategy, which has both a push and a pull element to it, where we're able to communicate digitally with the physician and then receive kind of feedback from them in terms of how they're responding to our channel approach. We're actually adopting an omnichannel approach where we're not just relying on emails or webinars, but we're actually utilizing the feedback we get from them. It may well be negative feedback. It may well be that they're not reading emails and so on. That's information that is valuable to us in terms of altering the channel that we'll be using for them. Again, with that limited number of physicians that we're accessing, we believe we can be highly successful in the product launch. Similarly, raising the awareness in the patient population. This really is the first new smoking cessation treatment in nearly 20 years. I think the reputation of the predecessor is one that kind of allows us the opportunity to really optimize the messaging. How familiar would you say your physicians, when you speak to them about cytisinicline and having a new potential branded therapy out there for smoking cessation, how familiar are these docs with the data and ORCA and the ORCA trials? Or is it going to be a big educational lift? I think there's two elements to that. I think the first is the feedback we've received from physicians is a great degree of frustration that there are no better treatments for nicotine dependence. That is really clear. I think the second element to it is a growing awareness of cytisinicline. We had a number of publications recently, and there's more to come. I think it's part of this digital awareness strategy that we're working on. For the 7,000 or so target physicians, highly committed writers, it's a process now of, once the drug is approved, increasing the visibility of cytisinicline and, most importantly, the benefit to patients. That's part of the whole digital strategy in terms of generating, first of all, awareness of the drug. Secondly, interest in the drug. It usually takes six to seven touch points with an individual physician to actually get them to write a prescription. We are not completely excluding face-to-face intervention with sales reps, but they will not be ours. It is not quite a contract sales organization, but we can target an individual sales rep for as little as $75 to actually go visit a physician who we believe would need a face-to-face discussion. Add to that a discussion as well. There are many, many tools that we can use to actually raise the awareness of the benefits of cytisinicline, both at the physician level and also at the patient level. We really have targeted the patient level very, very clearly. We know the characteristics of those people who are ready to try a new treatment for nicotine dependence. Those are the ones that we're going to be targeting in the first instance. Okay, so it's fair to say, based on this digital approach, 7,000 docs, that in the U.S., you guys are going to attack the market yourselves or you're planning on doing so. Can you discuss a little bit XUS thoughts here? Yeah, sure. The European opportunity is one that is clear. Unfortunately, the European market is not homogenous. Yes, we've got interest. Ironically, it's Germany, which is the biggest market in terms of smokers. So far, we've had the highest level of interest coming out of Spain. We've had a number of touch points with Spain. We prefer to have a single global approach to partnering than kind of segmenting it geographically. We continue to have discussions on a global scale in terms of we need somebody with more horsepower than Achieve to actually optimize the revenues of the product. Yeah, we continue those discussions. I think where it becomes really interesting as well is the impact on some of the comorbidities that are associated with smoking and increasingly with vaping. We start to look in the areas of respiratory. COPD is a really interesting area where 80% of COPD patients have the disease because they were smokers. Of the 16 million smokers in the U.S., 6 million of them are current smokers. If we can actually get some of those to stop smoking, we can reduce the number of exacerbations and reduce the number of hospitalizations, which individually cost about $22,000 per visit. I think that the scope of cytisinicline in terms of addressing some of the comorbidities is to be explored in the future. Yeah, that's great. On the digital side, it seems like attacking the docs makes a lot of sense. On the DTC side, I feel like this is something where consumers and being in front of them would make a lot of sense, especially the ones that tried and probably discontinued because although it can ultimately lead to death, these patients, a lot of smokers, are relatively healthy patients. Any side effect could be really a big turnoff. The safety here is extremely important. Is there any thoughts about educating the consumers? No, absolutely. It's part of the whole digital strategy as we kind of divide it into two elements. First of all, the physicians. Secondly, the patients. Round about 53% of all smokers attempt to quit on an annual basis. We're talking somewhere around about 18 million quit attempts a year. Yes, the ability to influence some of the decision-making for patients is critical. Again, they've probably gone on some kind of journey. They'll probably have gone cold turkey at some point. They will probably have tried nicotine replacement therapy at some point. They've got to the stage where they need to do something to actually aid the quit attempt. They go to a prescription, go to the physician, get a prescription. Frankly, there are no other branded nicotine-dependent drugs available, a generic varenicline and little else. I think that positions as well. The awareness at the patient level is going to be critical. Again, we're going to be using the same drivers or similar drivers to what we're doing with the physicians as well. Stimulating awareness, whether that's as simple as a dropdown on a Google search or whether it is, frankly, radio or even magazine advertising to stimulate the awareness with the patient population. To give you an example, one of the patients in our clinical trials personalized this significantly because she asked to talk to the entire company. There are only 22 of us, so it wasn't a big hall, put it that way. She came on Zoom, and she thanked us for the fact that she had been smoking for 30 years on average, three packets of cigarettes a day, had attempted to quit more than 20 times. This was the first time she'd ever been successful. She actually read us a letter from her daughter thanking us for keeping her mother alive and that her mother will be there for her wedding, for the baptisms, and so on. It really does personalize what it is we're trying to do here. We were pretty taken by that. Oh, that's great. On the vaping side, is there any reason to think that this wouldn't work as well in vaping? What's the difference between nicotine dependence for cigarettes and vaping? We've already run a phase two study in vapers, and that was successful. It was 160 patients. Now, it did show a lower level of efficacy than it was a much smaller clinical trial. I think in the broader population, this is a much younger population. On average, in the smoking cessation clinical trials, the age was roughly 55 years old. They were taking, on average, a pack of cigarettes a day for the last 30 years. In the vaping phase two trial, on average, they were 33- 35 years old, had been vaping for about eight years. The difficulty with vaping is the nicotine load. Again, on average, a cigarette's got somewhere around 10-12 milligrams of nicotine in it, whereas, frankly, it is unknown how much nicotine there is in a vape. Estimates range from 30-36 milligrams per dose, for want of a better word. There's a heavier nicotine load. There's probably a higher nicotine dependence in the vaping population. I think where we're really focused on is this much younger population. People in their 20s and 30s are now experiencing a lot of wheezing. They're restrictive in terms of their exercise routines. You're starting to see the early signs of some level of respiratory disease. That's coming from two sources. The first one is propylene glycol is often contained in vapes. When you superheat propylene glycol, you get formaldehyde. Formaldehyde is a known carcinogen. In addition to that, of course, the flavorings and colorings were never intended to be superheated. The fine particle size is actually getting into the deep lung of vapors, whereas cigarette particles are only in the upper part of the lungs. We are starting already to see the impact of vaping. Certainly, you've seen the newspaper articles about high school students in the bathroom. They're all vaping. When they can't vape in the classroom, they're now using tobacco pouches as well. This is a bit like whack-a-mole. We believe we're going to be highly successful with smoking cessation, moving on to vaping cessation. Ultimately, we'll start to look at tobacco pouch. They're all to do with nicotine dependence. Okay, great. In terms of supply, this is such a large market. Where does cytisinicline come from? Is it synthetic at all? Or how do you feel supply-wise? Yeah, it's extracted from the seeds of laburnum trees and other plants that contain cytisinicline. It's a fairly complex extraction process. It's an area that we're examining. We've tried to synthesize cytisinicline on at least three occasions. I believe now we're starting to make some progress. My belief is we won't be reliant on botanical sources in future. That provides us with an increased level of flexibility in terms of the supply chain. Yeah, we're also looking at supply chain redundancy as well in terms of both drug substance and drug product. Overall, we've got a very robust supply chain. That's really been developed over the last two years. Okay, great. Can you help us just on the financial side? What's the picture of the company? Where does the cash stand right now? Yeah, end of Q3, we had $43 million in cash. That is enough to see us through the NDA submission and beyond into the second half of the year. We are starting to look at funding the commercialization strategy as well in terms of royalty funding, etc. We are keeping our options open in terms of the longer-term commercial spend. Yeah, that is pretty much where we are. In terms of catalysts, obviously, the submission, is there anything else? You talked about the phase three. Can you just help us in terms of 2025, what should investors be looking at for Achieve? I think NDA submission is clearly a major catalyst. NDA acceptance, 60-74 days later. Subject to financing, the vaping phase three towards the end of the year. I think you'll see a lot more visibility in terms of the data from the clinical trials. I would like to think that at some point, we'll have some news on partnering XUS. I think the key in my mind right now is to optimize the value of the asset in the US and whether that is achieved doing it itself or working in collaboration with a bigger partner. Yet to be seen. Okay, great. No, that's super helpful. Thank you for the history and your personal history with finding drugs sometimes that have been overlooked. I appreciate it. Is there any kind of closing comment that you'd like to share? Anything I should have asked that wasn't brought up? Yeah, I think we're really excited for this near term. With next quarter, the NDA will be filed. I think we can create significant shareholder value from the NDA submission, the acceptance, and moving forward. In the right hands, we believe that cytisinicline for nicotine dependence is a blockbuster drug, potentially in excess of $2 billion in revenue. I think we should never overlook the role of cytisinicline in those comorbidities. Again, we're not experts in respiratory or COPD or those areas. Again, we'd be looking to a partner to really exploit that opportunity as well. Overall, I'd say my final comment will be we're going to be best in class in smoking cessation and first in class in vaping cessation. Great. Okay, thank you very much. Really appreciate your time here, Rick. Thank you, Frank. Thanks.