Achieve Life Sciences, Inc. (ACHV) Earnings Call Transcript & Summary

Happy to have you here. My name is Thomas Flaten and I'm a senior research analyst at Lake Street. You'll see our disclosures up on the screen. I've been invited by the company to moderate the discussion with 2 KOLs in this space, and I'd like to introduce them now. Dr. Rigotti, perhaps you can get started?

Sure. Hello. I'm Nancy Rigotti. I am trained as a General Internist, Primary Care Physician. I'm a Professor of Medicine at Harvard Medical School and at Massachusetts General Hospital, where I started and still run a tobacco research and treatment center and helping people to quit smoking, so that they don't die of their tobacco use, has been one of my professional goals for many years. In terms of disclosures, I am the principal investigator of one of the studies that's ongoing, the Phase III study for the cytisinicline and have consulted for Achieve. In the past -- distant past, I have, which also consulted for Pfizer, but not now.

And Dr. Benowitz?

I'm Neal Benowitz. I am a Professor Emeritus at the University of California, San Francisco. I still have an active practice in cardiology. I'm also trained as a pharmacologist. My research over many years has been to study the effects of nicotine and tobacco in humans. And my -- conflict of interest, I have been a consultant of Pfizer for many years, but I'm not currently and have been a consultant to Achieve Life Sciences.

So why don't we get started? And thank you both and welcome. And for those of you in the audience, there is a chat feature, if you'd like to submit questions that we'll try to do our best to integrate as we go through the session. Maybe I'll start with a basic but incredibly important question, and Dr. Benowitz, I'll start with you. Why do we still care about smoking cessation?

That's a good question, one that comes up frequently, especially if you are in an area -- I live in San Francisco, and the smoking rates are very low. And people say, "why are you studying smoking?" However, if you look at the smoking figures in the U.S., 14% of adults in U.S. smoke, and that has been the same since more than 10 years. Every year, more than 50% of smokers try to quit smoking, and fewer than 5% succeed. Smoking is a cause -- or contributes to all of the 10 major causes of death in the United States. Cigarette smoking still is the most important preventable cause of premature disease mortality. Almost 0.5 million people die from cigarette smoking-related diseases each year. So for public health, one of the most important things we can do is find ways to help people stop smoking more quickly.

Dr. Rigotti, I know as part of your introduction, this has been part of your life for a long time. I'm curious if you have anything to add to that?

No. But I got into this exactly because I got -- when I was an intern and a resident, I got tired of taking care of people as they decline to die of their tobacco use, and I thought that we in the health care profession should be working upstream. I think the only thing I might add to that is that often, people like probably everyone on this webinar who graduated from college will -- don't know a lot of people who smoke. But that's because smoking is concentrated in lower socioeconomic groups and those who are poor and have less education and are more vulnerable. And that's where we still have huge gains that need to be made.

So there was some data announced in late October that seems to run counter to that where cigarette sales for the first time in 20 years increased year-over-year. So I'm curious then, we'll stay with you, Dr. Rigotti. If you have an attribution for that, do you think it was COVID related? Is it an anomaly? Is it permanent? Just curious to get your thoughts on that kind of [indiscernible]

Well, I think it's hard to know. But from -- and we're still waiting on the most recent prevalence data in the U.S. for 2020, although I've seen some early data that suggest that it's roughly the same as it was in the previous year in 2019 before COVID hit. And so that would suggest that perhaps maybe not more people are smoking, but the ones who are smoking might be smoking more. And that would be my interpretation. But that's just a guess.

Yes. So...

Well, I would just add that I can certainly tell you, from my cardiology patients, I've got many who are cigarette smokers. And when I asked them about quitting smoking, they say, "this is just a really stressful time for me, the ground side. I'm stuck, I'm bored." And so this -- it's really hard to quit and then they're smoking more.

So speaking of trying to quit -- sorry to interrupt. Speaking or trying to quit, and we'll stick with you, Dr. Benowitz, there are lots of options out there. But I was curious if you could just level set the audience on what the options for quitting are, or smoking cessation treatments are? And whether you believe there are new treatments that are required?

Sure. So one of the most important parts of it, obviously, is counseling. And just as a background, when someone gets behavioral support, it doubles the quitting rates, no matter what else is going on. There are 3 major medication classes. So one, they are nicotine replacement therapies, nicotine medications. And these include patches; gums; lozenges; nasal spray; in some countries, drops. And we know that the best effect actually comes from a combination of patches plus even gum or lozenges together. Varenicline or CHANTIX is a medication that is highly effective. Unfortunately, there's a shortage now. It's not available because of a recall. But hopefully, that will be available in the near future. And then Bupropion, which is a drug that was developed for depression, but was shown to be effective for smoking cessation. And that's a second-line drug. But I think those 3 are the main medications that we can offer patients.

So it's well documented that most smokers who try to cut go through multiple attempts. And I'm curious, in your own practices, how many attempts it typically takes? And you mentioned CHANTIX, how prevalent that is. That's probably the one that people have heard the most of, whether that's from advertising or not. But curious to those 2 questions, how many times does it take? And do most people cycle through CHANTIX at some point?

Well, it's hard to get a good estimate of a number of times quit rate. I've heard 5 times, 7 times, which is as far as somewhat successful. But many smokers just say, "it's New Year's, my resolution is I'm going to quit." And they quit smoking for a day and go back again and don't even remember that as a quit attempt. But I think estimates is like 5 to 7x on average. In terms of the number of people who use medications, for varenicline versus others, I'm not sure of the data. Nancy may know better.

I think that the nicotine replacement is the product that is most widely used and has been most used, but still a substantial number of people have used varenicline at this point and Bupropion. I would say, my guess would be somewhere in the sort of 30% of smokers have tried varenicline and probably something similar for Bupropion, and probably twice as many of that have tried the nicotine replacement.

Got it. So there have been some -- there's a long-sorted story around CHANTIX, and we'll get to the most recent events in a minute. But do you have trouble convincing patients to take CHANTIX? Or do they come with concerns? Or are the concerns more on your end? Is it a combination of the 2?

Would you like me to take that? Or no?

Go -- oh, yes.

So I would say that because of the bad press that varenicline's had for many years, almost practically since it came on the market, there's reluctance both by patients and by doctors, even though the FDA had subsequently mandated a trial that demonstrated that it was not any more risky than any of the other products that are out there. The message has not entirely gotten to doctors, and it certainly hasn't gotten to patients. And so often, it is a challenge to convince patients to take it. They often have anecdotal stories about. And the thing that I hear most is either abnormal dreams, trouble sleeping, not so much nausea, which is another one of the well-known side effects, but really more kind of behavior change. Even though we know that from the data, that it is not more common in -- with varenicline than it is for, say, nicotine replacement, but people are quite concerned about that. And that's been a problem. So if we had a drug that was essentially like varenicline but didn't have the name, it would be an easier sell.

So just sticking with you, Dr. Rigotti. So earlier this year, CHANTIX was recalled due to nitrosamine contamination. So given that there was already bad press and some negative halo around the product, do you think that the recall worse than that? Has there been a noticeable change in payer -- sorry, patient and prescriber attitude store since the recall, do you think? I don't know what you've heard around that?

Well, my experience has been that there's a lot of prescriber frustration about it. Because more than the fear of, "Oh my God, there's a new problem that we didn't know about," I think most people aren't so concerned about the safety issue of this new fact, but rather just that they can't get -- they're not sure their patients will get it. And it's going to be more back and forth with the pharmacy and more things in their invest of their electronic health record. So it's just frustrating. I think for patients, I haven't -- I don't think patients are so worried about the risk. I don't think that, that's gotten so well communicated. But my guess is that it can be frustrating if you can't get the product.

Yes. And Dr. Benowitz, if I could go back to you. There's -- in addition to the CHANTIX noise, there's been a lot of noise around the e-cigarettes and vaping products, including the FDA rejecting over 6 million applications a few months back, at the same time as they approved a number of vaping products for approval. Just curious to get your thoughts on FDA's decisions, what you made of that in general.

Well, as this group probably knows, there's been a lot of controversy in the public health arena about e-cigarettes. Some people think that it's just another way to make people addicted to nicotine. It's another approach by tobacco industry, to hook people, their concerns about youth vaping. Obviously, those -- the concerns about youth are serious. On the other hand, there are very convincing data that e-cigarettes are less harmful than cigarette smoking. And if people switch completely to e-cigarettes, they can -- it increases the likelihood of quitting smoking. On the other hand, many people quit smoking to cigarettes continue to use these cigarettes for a long period of time. So I think there are differences of opinion. My personal opinion is that e-cigarette approach is what could be a very useful harm reduction approach. Like I say, quitting is stuck in the U.S. Other countries around the world, like the U.K., have found that e-cigarettes are actually the most common way that people quit smoking cigarettes. So I think there is some potential use. On the other hand, we will have some people who become addicted to e-cigarettes have a hard time quitting e-cigarettes.

So do you think there are a viable cessation treatment? Or is it -- does it really depend on the patient specifically? So some might quit, some might maintain the nicotine usage?

So there -- there seem to be 2 kinds of smokers. Ones, who use e-cigarettes to switch completely with the intent of quitting smoking. And they -- that helps them quit smoking. The others are those who use these cigarettes mostly when they can't smoke cigarettes because of bands of various sorts. And that's so, they use it as adjunct to keep on smoking cigarettes, and the quit rates can actually be lower. So -- and part of the problem in the U.S. has been messaging, because it's really not been solid messaging to say, if you use these cigarettes to quit smoking, then quit smoking completely and stay in e-cigarettes. That's just that been part of the U.S. public health message.

So would you recommend the e-cigarettes to a patient trying to quit traditional cigarettes?

What I do with my patients is I try to give them standard medication treatments first. If they failed that and they're interested in e-cigarettes, I say it's worth a try. I think it's less harmful than regular cigarettes, but you have to switch completely. You can't use both together. And then dealing with cardiology patients. So eventually, I say, "Well, look, you've been a nonsmoker for a year or 2. What do you think about trying to get off e-cigarettes?"

Which makes for a lovely segue into ORCA-V1, which is achieved a study for using cytisinicline as an e-cigarette vaping cessation product, and the IND was recently cleared. We're looking at a steady start here in early '22. So maybe Dr. Rigotti, I'll move it over to you. And I think Dr. Benowitz mentioned that nicotine addiction isn't common between traditional and e-cigarette users. Are there any other commonalities or differences in that patient group we should take into account? Are e-cigarette users as likely to be motivated to quit? And I know, Dr. Benowitz has presented a case of 2 types. But as you look at a study like ORCA-V1, I'm just curious to get your thoughts on the patient population you'll be enrolled.

Well, I -- first of all, I would agree with Dr. Benowitz, that there are different kinds of e-cigarette users. And there are some people, if they continue smoking, that's a whole different category. But of those who switch over and are vaping, then there are some who will want to stop and meet and ideally need to stop. And so I think that, that's a group who could benefit from something that will help them to quit. I also think that we've got a number of never smokers who are using vapes, who picked it up as kids and high school students, perhaps, or college students who have gotten to the point where maybe they don't want to be addicted to nicotine anymore. And that's a group of patients that will need help stopping vaping, even though they've never been smokers and they will need to handle their nicotine dependence.

So it's really on motivation to quit the product, less so where you came from and where you think you're going. You know you want to go towards quit, right?

Yes. I think there are plenty of vapers who want to quit and plenty of smokers who want to quit smoking.

Yes. And given that the group is a little bit different than the traditional smoking group, and if you look back at the ORCA studies to date that have been done, 1 and 2, how do you think about recruitment? Is it going to be more challenging to recruit patients into this since it's a little bit of a diversion from traditional smoking cessation studies?

Yes. Well, the recruitment is always the Achilles' Heel of all clinical trials. So it makes everybody nervous all the time. It certainly made us nervous when we were recruiting for the ORCA-2, but we recruited successfully and pretty quickly. I think, sure, it makes me a little nervous. It's because there's very little experience in doing a clinical trial like this. But I can tell you that as somebody who also runs a smoking cessation program, we're getting more and more people who are -- for our employees of our health care system, that we're getting more and more people coming in saying that either that they smoked and they quit. And they vaped, they quit, they vape and now they wanted to quit vaping. Or they have kids that they wanted to have helped get to quit vaping. So I think that there is demand.

Yes. And we've seen some success. We're obviously waiting for the ORCA-2 data, but we've seen early success with cytisinicline, not just in Europe, but also here in the U.S. I'm curious if you could just share with us kind of what your expectations are. You're obviously hoping for success, but what does that mean relative to maybe quit rates that we've seen with traditional smoking cessation products?

Well, I hope that it's as good as the best we have. I certainly do, or even better. That would be great. We certainly need a magic bullet. I think that the reality is that we are not going to ever have a magic bullet that's going to help everybody to quit. We need newer products that can be helpful. The best -- the way I think about it is how much -- what's the increase in quit rates compared to not using the product. And roughly, if something gives you a 50% increase in quit rates, that's pretty good. That's roughly what nicotine replacement gives you, maybe 50%, 60% increase if you use a single product. Bupropion is more or less comparable. Varenicline is more like a doubling or more than a doubling of quit rates. That's what we're dealing with. If we could get something that was a doubling, that would be great, but even less would still be useful because people need different products. We need a range of products just as we have a range of medicines for hypertension or infections.

Sure. And Dr. Benowitz, if I could turn to you and maybe back up a little bit. I think we've kind of skirted it around this issue a little bit. But maybe I could get your thoughts on nicotine as a chemical and what its negative health impacts are? And why stopping nicotine because now we've gone from traditional cigarettes to vaping? Just curious to get your thoughts on why users should seek to stop using nicotine as a drug.

Well, then there is a lot of controversy about that question, too. There are some people who hold that nicotine is a little more harmful than alcohol or marijuana. And if they're legal, they should be able to vape as long as they're not smoking. That said, there are some concerns with nicotine. The first concern obviously is addiction. So our addiction means it's hard to quit when we want to quit. It costs money. They're using a product at times when you rather do something else. So it is loss of control is a negative aspect to it. There are reproductive concerns with nicotine. So if you're pregnant, nicotine is not good for your baby. From the cardiovascular point of view, there are potential adverse effects nicotine could contribute to fail heart attacks or fatal strokes, didn't seem to cause coronary disease, but because of its effects on adrenaline, it could make an event more lethal. There are concerns about playing a role causing diabetes, which is one of complications about cigarette smoking. So -- and youth, their concerns, although it's hard to know how really is hard, but based on animal studies that nicotine can affect the maturation of the brain, can still the maturation of the brain, can impair brain function. So there are a number of concerns that are such that, especially in cardiovascular disease, I would rather my patients get off nicotine when they can. But I think for most people, they just don't like to have to be hooked [indiscernible]. It's just not -- that's a lifestyle most people would like.

So when -- if you prescribe nicotine-replacement products to a patient who's seeking to quick smoking, how often do they persist on those nicotine-replacement products? Generally speaking, I'm sure there's a wide variety, but do they then become hooked on the nicotine and need a product to help them get off a nicotine-replacement therapy? Or how do you think about that?

Well, some do. But first, you have to understand, nicotine addiction is more than just the nicotine. It also has to do with how you get the nicotine. So if you inhale nicotine, it gets to your brain in higher levels faster. It's much predicting that if you use nicotine in a patch or a gum or lozenge, particularly smoking or vaping is more addicting than NRT. That said, there are probably 10% of people who continue using NRT for a year. And we encourage that if someone needs to do that, not to smoke. We think the risk is much, much lower than cigarette smoking. So that's really encouraged.

Got it. Switching from the vaping space into the traditional smoking space. Just last week, the company announced that the Safety Data Monitoring Committee completed the final review of the ORCA-2 Phase III study, where they indicated there was no safety or adverse event issues and that compliance with medication was excellent. Obviously, this tells us nothing about the efficacy. We're going to have to wait a few more months for that. But from my perspective, it reinforces the tolerability profile of cytisinicline. So maybe Dr. Rigotti, I'll switch back to you. Could you maybe walk us through, just at a broad -- at a kind of a 50,000-foot level, the importance of tolerability and having a reasonable adverse event profile in the context of patients who are seeking to quit smoking? So I know there's a lot of words, but...

Yes, sure. Got it. So -- but essentially, when some -- you're trying to help somebody quit smoking, you're trying to help them to change something that, while they want to do it, there's ambivalence because they're also giving up something that's been a friend to them for many years or whatever. And so whenever you're trying to get somebody to change their behavior, especially behavior that are ambivalent about changing, you want to have these 2 side effects as possible in the medicine that you're giving. That's been the strategy that people have -- that we've used for hypertension -- hypertensive treatments, for diabetes treatments, for all kinds of cholesterol treatments. And so obviously, having a drug that doesn't give you a negative effect and give you an excuse to stop using it and going back to your habit is really important. And that's why that's so important for smoking cessation medications.

So then if we -- and I'll stick with you, Dr. Rigotti. If we make it more specific to cytisinicline. So we've seen the [ TASK ] Study, the CASCADE study, the AURORA study in New Zealand, has consistently shown a favorable adverse event profile for cytisinicline. And in AURORA, in particular, we saw there was a stark contrast between CHANTIX, varenicline and cytisinicline and favor cytisinicline. So when you look at that product specifically and try and put it into the context of the smoking cessation market, I think you've answered the question, but maybe we can be more specific to cytisinicline? How do you merge that into the overall smoking cessation market?

Okay. So I would say that I think the main comparison is people are thinking of comparing with varenicline because their mechanism of actions are very similar. And what we've seen is that there's less nausea, less sleep disturbance and less concern about the abnormal dreams in most -- in the clinical studies that have been reported out so far.

So do you think -- and I -- the CHANTIX failure rates are pretty well documented. Do you think that there's kind of a twofold impact? If you have less side effects, you're more likely to stay on drug, therefore, more likely to succeed? Is that a logical sequence? Whereas because you can't tolerate CHANTIX, you don't get the benefit of the efficacy, therefore, you fail more. Is that a logical conclusion that we can draw?

Yes. Yes.

With a favorable adverse event profile, you have longer duration of treatment, better shot at better efficacy, is that...

Yes, that's the way we think about it.

So -- and Dr. Benowitz, I'll switch back to you. So ORCA-2, the ongoing Phase III, study has 2 active arms, 1 with 6 weeks of treatment and 1 with 12. I'm curious just to get your thoughts on the importance of having those 2 arms, particularly as you look through the differences patients have in quitting and giving them our window versus getting them off cigarettes quicker. I'm just curious if you could provide some context to the list on that.

So it's an important question because the standard treatment duration for medications for smoking has been 12 weeks. Now cytisine, as it was called in Europe, where one of the trials have been done, use a 25-day treatment course. And actually, that treatment course did as well as the 12-week NRT course in the trials that compared the 2. So one question is does cytisinicline work in a shorter period of time compared to standard treatment? On the other hand, we know from other trials like for varenicline, that in highly-addicted smokers, if you give them treatment beyond 12 weeks, they actually do better. So it would have been done even going to 6 months or a year. It's trying for some people if they stay on longer, it will be better. So this trial will be very informative to know, one, is 6 weeks as good as 12, which would make shorter therapy an advantage; or is 12 weeks are really important, and this should be dosed the same way as other medications. So I think it's a really critical question, will be answered by ORCA-2.

And just in your clinical experience, people who quit sooner, are they more likely to stick with it? Or does it depend from patient to patient? So if someone can stick with the drug for 12 weeks. They have a better chance of a permanent quit. Does it -- is there any rhyme or reason to how long it takes people to become abstinent?

Well, it's complicated because sometimes people, when they decide they really can't quit to stop the medication. So it's hard to know how much of it is the medication versus just what's going on with their own behavior. We think that longer duration of treatment works better. And for some drugs like varenicline or CHANTIX, and would be true for cytisinicline as well, is that if you keep on taking the drug even while you're smoking, your quit rates increase over time. And the reason is that these drugs both block the rewarding effect of nicotine from cigarettes. So they give you some nicotine-like effect with respect to withdrawal symptoms, which is -- makes you feel less stress from nicotine withdrawal. But at the same time, your cigarettes are not as satisfying. And that's important because after why I say, well, what should I smoke a cigarette and not even enjoyable. And so that -- it may take 6 weeks or 12 weeks before you get to that point.

Right. And I think it's important to stress, and I think you made this comment earlier, Dr. Benowitz, the importance of behavioral support during a quit attempt. I think it'd be helpful just to reiterate that now in the context of speaking of a Phase III study and efficacy data, et cetera.

Yes. So behavioral support is important because people -- they've been smoking cigarettes for years and years and years. And they use cigarettes to modulate a mood and arousal throughout the day. So smoker has a cigarette first thing in the morning. It's like white coffee does for coffee drinker to get going. They have a cigarette because nicotine helps them concentrate on the tasks throughout the day, work or whatever. They use a cigarette when they're stressed and they're anxious to make them less stressed and anxious. They use cigarette before they go to bed to help them relax. Now many of these effects of nicotine are just reversing the withdrawal symptoms. But the smoker just comes to think, this cigarette is really necessary for me to cope with daily life, unlearn that. Counseling helps, gives you tools to do that, to find substitute behaviors and to get away from depending on nicotine for daily coping.

And do you think that is -- that behavioral support needs to be delivered personally? Or do you think there's a whole host of new apps that impose some level of cognitive behavioral therapy for eating choices, lifestyle behaviors? Do you think apps would work as well? Or does this need to be an in-person type of interaction?

There's a wide spectrum of approaches. The most extreme approach, put people in the hospital for a week. That does really well, but that seems pretty extreme. On the other hand, there are quit lines where are people just encouraged to call quit line to get counselling. But then there are apps -- mobile apps, the bright promising data from those. And there are clinics and hospitals and from various health organizations. So there's a wide spectrum. I think the patient needs to be offered these different things and care to do as much as they have time for.

Dr. Rigotti, let me bring you in. As I've mentioned a couple of times, the ORCA-2 Phase III data is due here in a few months. And I was hoping maybe you could help us set some context. Obviously, we don't know what the data is, but maybe we could start with kind of a general question. Clinically meaningful is that it's a term we use a lot. But in the context of smoking cessation, what in your mind is a clinically meaningful result from a study such as this?

Well, I think I kind of touched on that earlier when I said that if you increase the quit rate by 50% over what the placebo group got, that would be pretty impressive. You could even argue that less given how bad and how dangerous cigarettes are. But to be in the -- to be comparable to the existing drugs, you probably need to increase the quit rate by 60% to maybe 2.2% or twice the 2.2% twice. 2.2% full net 220% would be an increase that would be really impressive. So as I said before, we don't have the magic bullet, but we do have things that do help.

Yes. And so specifically with respect to cytisinicline, there's obviously efficacy and safety. And I'm sure you would prefer for it to score excellently on both. But as you think about -- and you mentioned this when we've mentioned the side effect profile relative to CHANTIX. Now you just mentioned efficacy. But as you think about what's approvable from FDA's perspective is one thing, but then what's also relevant to you as a clinician that would help you recommend this product to the patients. So you mentioned safety. We talked a little bit about efficacy, but maybe you could create like a nice little package of thought around what that label would need to look like to make it usable.

Well, I think that ideally, it would be that this is more effective than what we already have and with very few side effects, no more or perhaps fewer than what we already have. But even if it were comparable in efficacy and had very few side effects, especially if you have fewer side effects than other drugs that it's comparable to, that would be a very good thing. And that's obviously, in a way, what you're thinking of, I think, is the comparison with varenicline since those are the most similar products. And already, it looks like we probably will have data that shows that it's less that's more easily tolerated. The question is just exactly where the efficacy goes. But the fact that you've got tolerability is really important.

Yes. And just there was a question from the audience, and I want to make sure we hit on it that is there any reason to suspect that cytisinicline will not be effective in patients that have previously been treated with varenicline or CHANTIX?

I don't think so because there have been studies with varenicline where they took people who had been on varenicline had failed varenicline and then were interested in trying and they wanted to see whether it was worth trying again. And in fact, they showed that varenicline could be effective on a second trial and a third trial. And it's partly because people are at different places in their lives when they're trying to quit smoking. So they may -- while they may have tried varenicline or they may have tried cytisinicline, they may not used it at a time when they weren't just ready to quit as they are now. Or maybe they learned something from that previous quit attempt because repeated quit attempts that you learn from it, it's like learning to ride a bicycle. You then get better at abstaining.

Right. So Dr. Benowitz, so I'll turn to you. So how do you think about -- again, based on the data that we have on hand today, and I know it doesn't include ORCA-2. But assuming it pans out the way that we expect it to, how do you think about integrating a product like this into daily practice? And I'll ask that two ways: one, for yourself, but also in a nonacademic setting, the kind of day-to-day primary care provider, how would you think about it for yourself? And what would you recommend to someone who might look to you for guidance on how to use that?

Well, first, I want to just say that one of the important things about ORCA-2, I think, is this simplified medication regimen compared to how the drug was developed in Europe, where it was very complicated, tapering over 25 days. The ARCA trials that basically have looked at a standard dosing 3 times a day for 25 days, simple regimen. And [indiscernible], one thing that I've certainly had to deal with, others have as well is the nausea issue. So people start and nausea is very common. You have to titrate the dose up, and people have a hard time. Sometimes they just quit because of nausea. So the cytisine drug, I'm going to use the term cytisine just because that was in the news for years and it's easier, too. Doesn't seem to do that. Nausea is very minor effect. And so people can just start taking the full dose. There are no complicated dosing regimens. So for me, it's a very attractive approach to say, just start taking this pill 3 times a day and then pick a quit day. Or even if you can't clear in a quit date, keep on taking medication. I would tell people it's going to probably make a cigarettes less satisfying to you, you be able to quit later on, maybe, but just it's a pretty safe drug. So to me, for my practice, it would really be quite a useful thing to have. And I think physicians would be very responsive to a very simple regimen and simple instructions for their patients.

And when you have a patient who comes in that's maybe -- and I don't know how many first-time quitters you see, but would you consider this as a go-to first line, if I can use that term treatment option? Or would you start them on a nicotine replacement therapy first? Or maybe in the context of other modalities, how do you stack this up relative to those?

Yes, well, in my practice of cardiovascular disease, every 1 of my patients has already been told that you could quit smoking and have tried and failed. So it's all of them. So I think this would be a very attractive a first-line drug. And again, even now, what I do with smokers, even if they're not ready to quit, I say, okay, here's the medication, now I'm making it easier to quit over time, start this medication. And then when you're ready to quit, then just help me quit. And I would do the same thing with cytisine.

So those questions, Dr. Rigotti, I just ask Dr. Benowitz, maybe I can get your take on them too. Where you see it in the context of the broader smoking cessation market and also the question about first line. And that might not apply because you might see patients who have tried multiple times as well, but if you could...

Yes. Well, most smokers have tried to quit already, and most of them have failed many things. So I could say, first of all, that a new drug on the market that's available to help with a recalcitrant problem like this is going to be very popular and very attractive to start with. And then if and when people have positive experiences, both the physicians and their patients, that will help get more people interested in doing that when it starts to have a good word on the street, if you will. So I think it -- whether it will be the first-line drug, I think it could be. It a little bit depends on how high the efficacy is. But it certainly is going to be 1 of the desired drugs, and there are a lot of people who failed the other ones.

Is there anything you see that could stop cytisinicline? Again, I know you're projecting a little bit forward. But from being a preferred product, would it be a safety issue, an efficacy issue, maybe both?

Well, I think I mean either -- I mean a safety issue could be really a killer as it was with varenicline. But compared to varenicline, which was a new product on the market, cytisinicline has been out there and used in Eastern Europe for decades. And there are thousands of -- tens of thousands of people who've used it before and apparently with very little problems. So I don't think we're in a situation where we're likely to see something that we hadn't anticipated. Unlike most new drugs, this drug, this so-called new drug, it's really not new. And so we have a lot of experience. So that, in a way, makes it safer for us to think about.

So all -- if we project forward the current cytisinicline profile, which appears to be equivalent based on efficacy but more tolerable, all else being equal, and I'll get back to payers in a second, is there any reason a doctor would choose CHANTIX over cytisinicline?

Probably not.

Yes. And you mentioned, Dr. Rigotti, payers earlier, that the recall it caused some wrinkles with payers. Obviously, by the time cytisinicline hits the market, CHANTIX won't be generic. Do you...

It already is generic.

Right. Yes. Correct. But do you anticipate having any issues with brand versus generic? And I know the government has imposed certain mandates around covering smoking cessation products. Do you anticipate that being an issue?

Well, I think that the price of the product will always be an important issue. And I can't speak to what that might be. I know that it is very cheap in Europe as cytisine and would hope that it would remain cheap. Because one of the advantages of this product, besides helping those of us in high-income countries like the United States, is that there are a huge number of smokers around the world, in fact, from, I think, it's 80% of the smokers in the world actually live in low- and middle-income countries, and they don't have access to any medications at all. And there's a huge market out there.

Perfect. And so let's -- maybe we can switch the perspective over to the patients. I'll flip over to you, Dr. Benowitz. So one thing that we don't talk enough about, I think, is the fact that cytisine is a naturally derived product. How do you think that resonates with patients in general versus having a purely synthetic compound?

I think people are attracted to that idea. They had the idea that natural products are safer, has been around in people's minds for a very long time. One of the things that's been popular in the studies in Australia, for example, is smokers like the idea that this was on a plant product, flower they might have in their garden. I've been involved in research with native Alaskans who are very interested in sort of natural products and staying away from synthetic things. And so these ideas are very attractive to people. So I think that will be a plus.

And do you...

I would actually add that there are cigarettes that have been advertised as being natural and that it's marketed as a positive characteristic.

And sticking with the patients, do you think the FDA seal or approval has -- does that have -- does that resonate with patients? Does it being FDA approved versus something you can pick up at the gas station matter to patients when they're thinking about NRT they can buy at Target versus something that is prescribed? Do they -- does that factor into the calculus on their part and your discussions with them?

So well, first of all, the ones you can buy at Target are still FDA-approved. They're approved for over-the-counter sale. Certainly patients, but even more so physicians are very much influenced by what FDA approves. So I think -- and the idea of prescribing something, we know that even for NRT, if a physician prescribes it and it's done in the context of any sort of counseling, the outcomes are much better than over-the-counter. People think of it as a more serious prescription. So cytisine is available in that way. I think the physicians will find it very attractive and smokers as well.

Yes. And also, it will probably be covered better by insurances physicians prescribe it. There are some insurance companies that will pay even from a over-the-counter nicotine replacement with the physician prescription. And I think that that's increasingly going to be the case.

And do you -- and I know things have changed since the ACA was implemented, but how often is cost to consideration for patients in this? It might be covered, but it might be with an onerous copay. How often does that come up as a challenge for getting patients onto a prescription product?

It certainly -- it can be a major challenge, especially for a lot of the population of smokers because they often are lower income. And it is -- what might be affordable for somebody in the middle class, it's not affordable for them. So that's really critical.

Great. And then just one kind of final on the stack ranking. So you have varenicline, Bupropion and cytisinicline based again, we're projecting what we think the ORCA-2 data will look like. But I've taken away that cytisinicline would rise to the top there based on what we know today. Is that a fair summary of what we've talked about so far?

I think it's -- you mean in terms of -- are you talking about efficacy or are you talking about the overall?

The overall.

I think so. I mean, I think that it's -- when we think about the ranking and making, we think of -- varenicline is the single best product that we have. We then think of -- and probably combination NRT is similar. And then we have Bupropion and single NRTs sort of in the second category, effective but not quite as effective. I could see that I don't know, and I really kind of been reluctant to make any guesses ahead of time, but I would hope that cytisinicline would prove to be in the top tier. And I don't see why it couldn't be.

Dr. Benowitz, your thoughts?

I agree. Again, I think a lot of it will depend on the safety profile because varenicline is most effective, but some people have side effects and will have concerns about it. Again, if the drug comes out that works as well as varenicline, but it's got fewer side effects, I think it could be -- do very well.

And the -- I think it was you, Dr. Benowitz, mentioned that only 30% of the patients will take CHANTIX or another drug to quit. I might have gotten that wrong. Do you think the side effect profile and the negative halo around varenicline really contributed to that? Do you see that a product like cytisinicline could be -- could penetrate the market much better or help more patients, however we want to phrase it?

Well, I do. There were many concerns about varenicline that were not well founded, but have concerns about causing cardiovascular problems, causing seizures, causing people to become psychotic. There were many concerns that these have been dispelled by large clinical trials, but many people have in their mind that varenicline is a dangerous truck. So having cytisine available without that baggage would be useful.

Dr. Rigotti, you feel the same way?

Absolutely.

Excellent. Well, we've come to the end of our time. We're a little bit over. I think we've gotten some great questions from the audience, and I appreciate your guys' thoughts on the product. Is there anything that we didn't cover that you think is important to share with the folks on the call or the webinar just before we end?

Only that I think most physicians think that we need more drugs to help deal with this problem.

Yes. Dr. Benowitz?

No. I don't have anything to add.

Excellent. Well, with that, I want to thank you both for your participation, the kind and thoughtful responses. I thank the company for bringing us all together, and I hope this was informative for everyone on the line. And with that, we will end the session. So thanks, everyone. Thank you, guys.

Okay. Bye.