Can a genetic test tell who a new alcohol medication will help?
In May 2022, I spoke with William Stilley, one of the founders of Adial Pharmaceuticals and its chief executive officer (CEO). At 0:19, he explained that the company was founded on the work of Dr. Bankole Johnson, who has led psychiatry departments at several universities. Its lead product is a medication for alcohol use disorder in people who test positive on a genetic panel.
This is an archive episode, recorded when the show covered addiction and recovery broadly. The company was waiting on its first late-stage trial when we spoke, so what follows is William’s description of the drug and his expectations, not a report of results.
What makes a genetically targeted alcohol medication different?
At 3:00, I told William it was the first medication I had seen that came paired with a genetic test to show whether it would work for the person taking it. At 3:42, he said that, as far as the company knew, it was the first of its kind and the only product for alcohol use disorder in the last stage of trials anywhere in the world.
He added that only a handful of medications are approved for alcohol use disorder in the United States, and that few new ones are in development. Yet, at the time, the company still had to unblind its trial before anyone would know whether the drug worked.
Does a person have to stop drinking before starting it?
At 4:48, I raised a point that matters to many listeners. A sudden stop can be dangerous for someone whose body depends on alcohol, with seizures among the risks, and a community of people follows the Sinclair Method, using naltrexone to cut down gradually instead. So, I asked whether this drug could help someone who had not fully quit.
William’s short answer, at 5:33, was yes. In fact, people in the trial had to be drinking when they enrolled. He described an earlier trial in which people reached for a drink less often and, when they did drink, drank much less.
Why focus on heavy drinking days?
From 7:01, William explained why heavy drinking days are the target. In his view, most of the harm from alcohol comes on those days, and he said both the U.S. Food and Drug Administration (FDA) and its European counterpart accept a reduction in them as a basis for approving a drug. He thought the evidence that a drink or two a day protects the heart is weak and promoted by alcohol companies, and I answered that less is always better.
How would someone find out whether the drug is for them?
At 10:49, William described the test. A small panel of genotypes is checked, and a person positive for any of them would be expected to crave alcohol less. For someone who tests negative, he said there is no evidence the drug would help.
At 12:58, he explained that the company uses a blood test rather than a cheek swab, because the doctors it asked preferred blood.
Is alcohol use disorder really one condition?
At 16:59, after I asked about gray area drinking and binge drinking, William made his broadest argument. He does not see alcohol use disorder as one disease. In his view, it is many different conditions that all show up as drinking too much.
He described the steady all-day drinker, the person who goes years without a drink and then cannot stop, and the weekend drinker. He expected his drug to help only people with these particular genetics.
For those people, he described the goal as less craving and less urge to keep going once drinking starts. As he put it, the drug would let them make a choice rather than feel a need.
How would people take it, and for how long?
At 21:18, William said he expected the drug to be used much the way antidepressants are. Some people would take it through a hard period and stop, while others would stay on it.
At 24:53, I asked about long-acting injections or implants. William said the low dose could suit a depot form, but in his view people take a daily tablet most reliably, as part of a routine like brushing their teeth. At 26:10, I agreed from my own experience with the monthly buprenorphine injection for opioid use disorder, where patients sometimes arrive late. William added that a daily pill stays in the patient’s control, so they can stop it whenever they choose.
How does it work, and can people stop it safely?
At 27:15, William used a lock and key picture. Serotonin acts on several receptors, and his drug selectively blocks one of them, the serotonin-3 receptor. In his account, that receptor works upstream of dopamine, so blocking it may reduce the craving that alcohol helps generate.
When I asked whether someone could stop the drug abruptly, he said at 29:50 that he had seen no sign of a rebound effect so far. However, he was candid that the data were still blinded and that he might have to revise that view.
Could the company’s adenosine research matter for withdrawal?
From 33:44, I asked about a different line of research. People coming off benzodiazepines and other psychiatric medications can have withdrawal symptoms that last for months, and someone had suggested to me that adenosine might help balance the brain chemicals glutamate and gamma-aminobutyric acid (GABA).
At 35:07, William described adenosine as a natural balancing factor that helps the body settle after inflammation and slows the heart when it beats too fast. He made no claim about withdrawal. At 37:29, he made clear that this work is a separate chemistry program from the alcohol drug.
Who is William Stilley?
William Stilley is one of the founders and the CEO of Adial Pharmaceuticals. Its gene-targeted alcohol drug was known at the time by the code name AD04.
What can listeners take away from this conversation?
William’s central argument was that alcohol use disorder is probably several conditions, and that treatment will become more precise as each one is understood. Unfortunately, as he noted, very few medications were approved for it when we spoke. The conversation is a reminder that options which do not demand a sudden stop, or a public label, matter to many people who want to drink less.
How do I approach this today?
My thinking has kept developing since this conversation was recorded. Today my practice is built on one idea that runs through all of it: when the body has adapted to a substance, the safest way off is usually gradual, with the smallest steps the person’s nervous system can tolerate. Physical dependence is not addiction.
For alcohol dependence I use the Sinclair Method. The person takes naltrexone about an hour before drinking, and over time the drinking itself becomes less rewarding, so the urge fades gradually instead of being fought every day. It does not require stopping on day one, and it does not rely on willpower or meetings.
Like a slow taper, it lets the brain change at its own pace. For many people that makes it a more humane path than a sudden stop, which can also be medically dangerous for someone whose body depends on alcohol.
Call 911 or go to an emergency department if there is a seizure, confusion or hallucinations, or thoughts of self-harm. For thoughts of suicide or any mental health crisis, you can also call or text the 988 Suicide and Crisis Lifeline.
This page is educational. It is not medical advice, and listening to the episode or reading this page does not create a doctor-patient relationship. Decisions about starting, continuing, or tapering any medication should be made with your own physician.
Full transcript
A note from Dr. Leeds: my guests speak from their own experience and expertise, and the terminology they use is their own. Whatever the topic, this show holds to one distinction: physical dependence on a prescribed medication is not addiction. This transcript is educational content, not medical advice, and nothing here creates a doctor-patient relationship.
Read the full transcript (42 minutes)
Dr. Mark Leeds [00:02] William Stilley, welcome to the podcast. So you are one of the founders of Adial Pharmaceuticals and the CEO. Tell me a little bit about the work that you guys are doing.
William Stilley [00:19] Well, Adial Pharmaceuticals was founded on the work of Dr. Bankole Johnson, who has been a head of the Department of Psychiatry at the University of Texas, University of Virginia, and the University of Maryland. And he has been in the field for almost 30 years, or actually, I guess, about over 30 years at this point. And we are focused on developing medicinal treatments for addiction. And in particular, we have a lead product, which is for alcohol use disorder in genetically targeted patients. We have, if you get a genetic test, if you’re positive, the drug will be expected to help you reduce your craving for alcohol so you can reduce or eliminate your drinking. And in addition to that, as a pharmaceutical company, we also have a pain product, which is in earlier stages. It’s shown a good efficacy in animals that are very similar to opioids, actually, without being an opioid that we would expect to be non-addictive. So that’s to help people not become addicted in the first place. And then because we have that science platform and a number of other disease states such as diabetes, asthma, and cancer, but we are planning on partnering those with other companies that have focus in those areas.
Dr. Mark Leeds [01:33] Okay. Yeah, and maybe that could be like a topic for a whole other podcast because that’s a really interesting subject, kind of the holy grail of pain management to find the medication that can work without getting people addicted to it. So that’s also really interesting.
William Stilley [01:49] Yeah, I would say just a quick comment on that is, you know, it’s been known, it’s in a class of chemistry called purines targeting what’s called the adenosine receptors. Adenosine is a, I call it a primordial molecule in the body, a neurotransmitter very similar to serotonin that does a number of things. And there’s one well-known adenosine blocker called caffeine. And caffeine is known to work towards pain, but the problem is caffeine hits this one receptor. So there’s four adenosine receptors. It’s one that has cardiovascular and wakefulness effects. And because of that, you can’t give high doses of drugs that have an effect like caffeine. But we’ve worked out a way chemistry-wise to not have effect on that receptor, but have effect on the receptor where caffeine affects pain. You know, caffeine is in Excedrin. It’s in Anacin. It’s been known for decades to work for pain. So we believe we have a product that’s about 200 times as potent or as powerful as caffeine, but does not have any of those effects that you would not want to have, you know, at high doses. Think about if you had, you know, 10 cups of coffee, what does your heart do? You don’t want that when you’re having a drug that can be taken chronically.
Dr. Mark Leeds [03:00] Yeah, definitely. And actually, now that you bring up adenosine, I saw that adenosine mentioned in your profile on LinkedIn, and I want to come back to that definitely. There’s some other things I wanted to ask you about related to that. But, yeah, first I wanted to definitely ask you about the product that you have for helping with alcoholism. And I think it’s like the first genetically targeted treatment that I’ve seen. I don’t know if there’s others on the market, but it’s the first time I’ve seen anything where this is a medication a person can take. But there’s also a genetic test paired with it to make sure that it’s going to work for the person that’s taking the medication.
William Stilley [03:42] Yeah, so first of all, you mentioned that it’s the first one with Genetically Targeted. As far as we know, that’s true. Also, as far as we know, we’re the only product in Phase III trials right now, which is the late stage, you know, the last stage is before you go for an approval anywhere in the world. And so not only are there only a handful of drugs, three actually, that are approved for alcohol use disorder in the United States, there’s not much in development. So, you know, we’re hopeful that we can bring something that the market absolutely, the market and the patients, you know, absolutely need. And the drug has actually completed its first phase three trial. We did it in six countries, and we are in the process of wrapping up that trial, you know, doing the site inspections and all that before we can unblind the data and have the results. So at the moment, we’re, you know, kind of holding our breath, waiting to see what the results of the trial are. But that was a two-year process that took many years to get to in the first place. And so it’s a really exciting time for the company and hopefully for humanity.
Dr. Mark Leeds [04:48] Yeah, yeah, definitely. One thing that I’m interested in with alcohol treatments is that there’s a large community of people that are interested in harm reduction treatments, treatments that don’t require the abrupt cessation of alcohol. You know, because when someone stops drinking cold turkey, suddenly, you know, they get all kinds of trauma to the central nervous system and risk of, you know, bad things happening, you know, like seizures and other things. So there’s a community that follows something called the Sinclair Method where they, instead of stopping alcohol abruptly, they kind of taper off of alcohol by taking naltrexone. And it doesn’t always work for everybody. Is this a treatment that a person can take if they haven’t quite fully quit drinking alcohol? Yeah.
William Stilley [05:33] So the short answer to that is yes. And in fact, in our trial, patients had to be drinking when they came into the trial. And so a significant number would, actually a very significant number, would drink during the trial. What we’re hoping to show and what we showed and demonstrated in the Phase 2 trial, which is the 283-patient trial that we had previously run, was the patients picked up the bottle less often. By the way, that was almost half as often. And when they picked it up, they were able to put it back down. By the way, that was about a 60% reduction in how much they drank. So they drank almost half as often, and when they drank, they drank almost 60% less, which is a really meaningful health benefit, societal benefit, work-life benefit.
Dr. Mark Leeds [06:22] Yeah, and that’s a very high number, especially in addiction treatment, where, you know, with abstinence-based treatment, you know, where there’s no medication-assisted treatment used, the success numbers and, you know, they’re very, very low. I mean, you know, people talk about 1%. I’ve seen some studies and maybe 10% to 15% at the upper limit of success of, like, rehab and psychotherapy and going to meetings, you know, things where there’s no medical treatment involved. And then the right medical treatment can make things really jump up. Like you said, 60%. I mean, that’s a huge number with alcohol addiction treatment.
William Stilley [07:01] Yeah. And by the way, you know, we believe, you know, that will, as I said, be a benefit. And there are data now that are pretty compelling that the almost all damage due to alcohol is due to what they call a heavy drinking day. And in fact, you know, the data are so strong that the FDA and the EMA, which is the European FDA, both published on it and said they will accept what’s called a heavy drinking day. And reduction of those as being something to get a drug approval. And so the data are that if you can reduce those days, reduce or eliminate those days, you can have a meaningful effect on somebody’s life. And if you think about it, you know, and by the way, the definition according to the U.S. FDA is four or more drinks in a day for a woman, five or more drinks in a day for a man. And, you know, intuitively, if you say, all right, you have a male, he drinks one, two, three, four drinks, Yes, he should not get behind the wheel after three or four drinks. However, is that day going to create a lot of harm in his life? Is he going to do what I call the drunk stupid things? But also, is he going to get blood levels so high that he’s going to get tissue uptake that’s going to cause the 200-plus diseases that are caused by alcohol, really do damage across the body? And the answer now, the data are there, that he won’t. If you can reduce those days, those are the days that cause the harm. There’s actually even a small amount of evidence that one or two drinks a day can actually be cardioprotective. Personally, I think that evidence is weak and promoted by the alcohol companies, but there’s not much evidence that one or two drinks is particularly harmful.
Dr. Mark Leeds [08:40] Yeah, less is always better, definitely. So now if a person – is there any benefit or could a person take this drug with naltrexone, or would they be exclusive? Would it be that for a person maybe one works and the other doesn’t work? Or, like, how would that work, like, between those two medications? Because naltrexone, I know, is one of the approved drugs, and it’s being used kind of, you know, not huge. I mean, it’s kind of not used that often, but it is being used currently. And a lot of people who are failing on naltrexone are looking for other alternatives.
William Stilley [09:15] Yeah, so naltrexone is a pretty tough drug. You know, it’s got a lot of side effects. But, you know, it has been demonstrated to work. People aren’t particularly excited to be on it. There have been studies in the past where the drugs have been done in combination. They do work through different what they call mechanisms, so they target different receptors. And it would not be surprising if people could take them both together. We are not running that study, so in this call here I can’t make any claims about how to be used or whether it should be used, but that’s absolutely something that people have hypothesized, that they may work either additively or synergistically.
Dr. Mark Leeds [09:54] Okay, so that would be off-label. That would be up to the medical practitioner prescribing to make that decision if they want to try that or not. Okay, and what’s the name of this drug?
William Stilley [10:08] So currently it has a codename, you know, which most drugs do as they’re in development. It’s called AD04, so Alpha Delta 04, you know, which comes from Adial being our name, and then it’s numbered number four. So that’s what we go by right now.
Dr. Mark Leeds [10:25] Okay. Okay. So and now it’s – I remember reading about it. It’s something about that there’s maybe a protein or something like a serotonin transport enzyme or protein or something, and that’s coded for by a certain gene. And I think is it if a person has that gene or that protein that the drug will work for them?
William Stilley [10:49] So the answer is yes. So we have a panel of four genotypes. If you are positive for any of those four genotypes, the drug would be expected to help you reduce your craving for alcohol, to reduce or eliminate your drinking. And so before you would get the test, so in the trial that we’re running that we’ve just completed, patients, we come in, they get tested. Originally, we had done tests across multiple, all genotypes and done studies. Now, this trial is you come in, get a test. If you’re positive, you were included in the study and you were either given drug or placebo. And so we’re trying to show a differential between those two groups. In practice, out in the market, what will happen is patients will get a genetic test. If they’re positive, then the drug would be expected to help them. If they’re not positive, there is not any evidence that it would help. And I’ll note that if you’re not positive, insurance companies probably won’t be willing to reimburse for it.
Dr. Mark Leeds [11:46] Okay. Yeah, that makes sense.
William Stilley [11:48] But for those that are positive, we would fully expect reimbursement of both the test. Well, first of all, testing, we expect to be reimbursed by insurance companies. And for those that are positive, we would expect the drug to be reimbursed by insurance companies. It’s sort of on the money side of the business for the insurance companies, if you can reduce alcohol consumption, you reduce a lot of costs. And so this is really a win-win-win all the way around. Not only does it improve human health, help the patients, which is the whole goal of the medical system, but it’s always easier to get the money to flow if it makes sense that way. So this is something that we think could really roll out quickly, be actually even pushed by the insurance companies because they know it’s going to help patients, which is their mission, and then to save them money. So what a great way to go out and help society.
Dr. Mark Leeds [12:47] Yeah. So is a genetic test, is that like one of those cheek swab things where you swab your cheek and then send it off to the lab?
William Stilley [12:58] So it could be done as a cheek swab, but we have currently done it as a blood test. And we actually talked to doctors and asked them which they would prefer. And it turns out because, you know, when you go into the doctor, you’re already taking blood for your cholesterol and all that. They actually preferred the blood test. They already do that. And the cheek swab is actually something that most doctors don’t do in their lab. Though with COVID, a lot of people are more comfortable with that. I expect blood tests to be the primary method. You would get the blood test, send it off. A few days later, you’ll get the results.
Dr. Mark Leeds [13:30] Okay. And would that, like the genetic profile, would that be kept on file or be useful, like if a person needed further genetic testing down the line, or would that just be very precisely only for this purpose?
William Stilley [13:44] So we would expect our test, you know, in order to have a test that is used to identify a person for a particular treatment, that’s a treatment-indicating test it’s called, you really have to make sure it is on to, you know, it’s accurate. And so when you get these mass testings where you get huge amounts of genotypes, there’s a lot of errors in those. And so when you do a test like this, you really do specific. You look at just those genes. You make sure that when you get it, you have a high, high probability. We try to get really as close to 100% as you can that the answers are correct. And therefore, so when they go and take this blood test, they will get results on those four genotypes, and that’s it, at this point at least.
Dr. Mark Leeds [14:29] Okay. Okay, perfect. And then I think I read something about that there’s some hope that this drug might also help with other addictions, maybe even opioid addiction. I don’t know if that’s something you can talk about or if that’s being studied also.
William Stilley [14:46] Yeah, so the answer is yes. Hypothetically, it should, and I say that, though, with some support. Based on the way it works through the serotonin-3 receptor, there are some other addictions that we believe it also might help. And, you know, by the way, people immediately always ask me, oh, will it help with smoking? And I would actually say, no, I don’t think so, because that works through the serotonin-3 receptor. We do not believe it is involved in smoking addiction. But opioids and gambling, I think, is a really good one. And then there’s a couple others that may be sex addiction and potentially obesity. So obesity trials are very difficult. So I think, you know, once we have an approval in the first indication, we would immediately go out and try to generate data showing, you know, or seeing if it will work in opioids and gambling and then look at others after that.
Dr. Mark Leeds [15:39] Okay at least in the beginning when it’s approved and people are using it for alcoholism you know they may see some other beneficial effects you know maybe gambling less or not you know maybe lose a little bit of weight or eat less less binge eating
William Stilley [15:54] That’s we’re hopeful that’s the case
Dr. Mark Leeds [15:56] Okay okay great and now as far as like you know a lot of people who have issues with alcohol that they’ve kind of been pointing out by their family as being the alcoholic in the family. And then when they’re in recovery, sitting around the table, everybody in the family is drinking. And, you know, I mean, there’s a huge problem with, even beyond the problem of alcoholism, alcohol use disorder, there’s a major issue with what people are calling gray area drinking, which is probably like every college student or a lot of them. You know, people that they don’t drink every day and they don’t consider themselves to have an alcohol problem. But on some days, you know, when they do drink, they get carried away. You know, they drink to get drunk and they just keep going. Maybe they have a compulsion to keep going. And so I don’t know if you call them a binge drinker or gray area drinker. Is this something that could benefit the larger population? Would insurance possibly cover that for someone who doesn’t want to be labeled as an alcoholic or alcohol use disorder patient, but they want to get ahead of the problem before it becomes a bigger problem?
William Stilley [16:59] So the answer we would expect to be yes. You know, it’s really insurance companies, once a drug is approved, they don’t get in the way of what the doctors do as long as it checks the couple of boxes. You know, in this case, it’s going to need to check the box that they’re genetically positive. If they do that, then we would not expect limitations on how it can be prescribed. And doctors, as you mentioned, can do what’s called off-label use. So they could actually prescribe it for other things. But absolutely, if it comes to drinking where somebody has not, you know, checked all the boxes to be an alcohol use disorder patient, you would expect it to be able to be used. And, you know, when you talk about the person sitting around the table with alcohol around, what it appears to us is that, you know, based on what we’ve seen is that patients actually have less of that drive. And, you know, when you talk about alcohol use disorder, everybody says, you know, oh, you’ve got this disease. And I would actually disagree with that. I would say that you have one of the many diseases that present as overdrinking and are called alcohol use disorder. And I think right now we see this overdrinking and we call it one thing. But, you know, in fact, in the future, or I should say not in fact, but in the future, I believe that it’s going to be better understood what’s going on in the brain. And we’re going to understand that this isn’t just a disease, but multiple, multiple diseases. And it makes so much sense because you think about it when you see people, you know, in the world. There are some people that they get up every day and they just need to be drinking and they’re drinking. And I mean, there are literally people that start in the morning and they might drink 20 or 30 drinks in a day, but they do it at low levels and they never get so drunk that it’s maybe even that noticeable. A lot of times these are the people that by the end of the day, they start to get noticeable in the morning and they were able to function. Then there are some people that can go years without drinking. Then they have just that one drink or that one, two, three, and they can’t control. And the next thing you know, they’re on drink 12. And that bender may last a day or that bender may last six months and then they can come off it and be fine and you know and then there’s the weekend drinker and then there’s the just at night drinker and all these different patterns of drinking is what they’re called indicates that you know this is not just one disease there’s different things going on here and the history of humans and our interaction with alcohol is long and complex that it makes sense that we have developed multiple pharmacologic pathways that can drive our addiction. So in these patients, with these genetics, we think we are going to help them reduce their craving, which means when they’re around the alcohol, they will have less desire to seek the alcohol. And then when they have the alcohol, they’re going to have less desire to continue to drink. So it allows them to then make the choice rather than have it be a need. That’s what it appears to us. And we think, you know, this is important. I’d also say we believe that, you know, and I believe that in the future, us or others are going to figure out some of the other genetics involved and figure out ways to treat those. And so for the two-thirds of the patients that we can’t treat, there’ll be, you know, treatments for them. And then some of the patients, they probably have multiple drivers, you know, maybe ours works and then something else will also work. And, you know, I’m hopeful as we, you know, computing power gets up, the imaging power gets up, and we’re really starting to understand how the brain works, that we’ll be able to bring a lot more help.
Dr. Mark Leeds [20:44] Yeah. Yeah, that’s incredible. I mean, that would be great to have, you know, just be able to say, like, you know, these are the genes that a person has that code for different proteins and just really, like, look at the mechanism a lot more clearly and know, like, what’s going to work for different people. That would be great. So as far as the medication, is this something that would be used for a certain period of time? Like, would it be used for a week, a month, or could it be taken indefinitely for years?
William Stilley [21:18] So I think that this drug will probably be used much like antidepressants are used. And again, saying that all people are the same, I think that’s always a tough thing to say. And I think what will happen is some patients will have a difficult time in their life. They’ll go on the drug. It will help them get where they want to be. Maybe they take it for 18, 36 months. They rotate off. And maybe again, a few years later, they have some difficulties, and they go on it again for a period of time. And then there’ll be others who go on it, say, this is just working for me, and they’ll just stay on it. It’ll be a lifetime medication that they just take every evening when they’re in front of their medicine cabinet, something to that effect. But, again, much how antidepressants are used today.
Dr. Mark Leeds [22:08] Okay.
William Stilley [22:09] I’ll note also you mentioned getting labeled and all that previously, and I’d meant to address. One of the great things about something like this is, and I’ll note that the side effects of the drug so far appear to be very limited. We’ll know more once this trial is unblind and we can do a real good comparison in a large group of patients between drug and placebo. But this is a drug that we believe you can go into the confidence of your doctor, take the genetic test, find out, you know, if it’s for you and take the drug. And you don’t have to step forward and label yourself if you don’t want. You know, it’s up to you. Some people, you know, AA really works for some people, and that method really works for some people. But it’s also a barrier to a lot of people getting treatment. And so we think that, you know, this can really expand who can get treated and take away that part of treatment for those that aren’t willing to do it.
Dr. Mark Leeds [23:11] Yeah yeah I was imagining like you know parent with their kid going off to college I mean parents are getting you know the vaccines for kids to so they don’t get you know these cancer causing you know sexually transmitted viruses and you know maybe I can imagine a parent you know worried that their kid might go off and maybe like a kid drinks a lot in high school and then they’re going off to college and the parent might say well but you know let’s get you tested and if you test, you know, properly, we can get you on this medication and just reduce the issue of the possibility of you getting carried away with drinking or, you know, having some negative outcome from drinking too much in college.
William Stilley [23:53] Yeah I would so I’m going to say that when it comes to changing the behavior of college kids and getting them to take a medication daily to stop them from drinking I think that there will be some some limited use in that manner it would not and by the way I don’t have any data on this is just me and you talking, I think that it will not be the most useful place for the drug. I think when you look at who is being really harmed by those with alcohol use disorder, it’s as you continue on into adulthood, you’re trying to be a functioning member of society out in the workforce or at home with the kids and lost control. You know, you just lost control. The alcohol controls you rather than you controlling the alcohol. And, you know, our belief is that this can can help, you know, offset that balance or that imbalance.
Dr. Mark Leeds [24:53] Yeah. And it might be maybe it’s too early to think about this. But have you looked into like long acting injectables or even dissolving implants that might last for a month or six months at a time?
William Stilley [25:08] So the answer is absolutely. And given that we have actually a very low dose of the drug, it could be useful for what they call a depot, which is something you inject either as an implant or a gel that elutes over time. As far as getting people to comply, though, the data are that daily oral medication is the easiest to get people to comply. Because, you know, let’s say you have to go in every month for an injection. Well, you’re supposed to do it, you know, within a three-day window and people forget. And, you know, oh, wait a minute, that was last month. Oh, that was three weeks ago. You know, they found that with birth control pills. I mean, it’s a birth control implant that is sometimes, until they went to the really long duration one, that it was difficult to get people to comply with the exact regimen you needed in order for it to work. And so, you know, an oral daily tablet is something humans are really good at taking because we get into our routine. We just take it when we brush our teeth.
Dr. Mark Leeds [26:10] And that makes sense because, yeah, we’ve seen that with the monthly buprenorphine injection for opioid use disorder that, you know, you think it’s going to be a great treatment because people are covered for the whole month. And then they don’t show up there for their appointment until a week or two later. Sometimes because of the shipping, it doesn’t show up on time. So, yeah, in the end, the regular daily use ends up being more reliable.
William Stilley [26:37] More reliable, but the difficulty there is that in the control of the patient, which means they can stop and do something else if they want. So it’s an interesting tradeoff in that situation.
Dr. Mark Leeds [26:48] Yeah, definitely. So as far as like antidepressants, like things like Prozac, Prozac, Paxil, Zoloft, Lexapro, selective serotonin reuptake inhibitors, they work by making more serotonin available in the brain. Does this work similarly? Like does it make more or less serotonin available or does it work differently than those kind of antidepressants?
William Stilley [27:15] So it’s absolutely differently. Like you said, you totally characterized that properly, you know, correctly. What our drug does, so serotonin hits seven receptors, potentially more, but there are seven known receptors. And a receptor is like a keyhole in a cell that makes a cell do something. And serotonin is like a skeleton key that goes in and acts like a key in all of those seven keyholes. But you can develop keys that only hit one of those receptors, and they’re called selective compounds. So we have a selective compound. The second thing is you can have keys that go into the keyhole but don’t do anything. Those are called blockers. So people have heard of beta blockers, for instance. They block the beta receptor. So you can have a molecule that goes into the keyhole, and what it does by hitting the keyhole is it stops serotonin from being able to get into the keyhole. So our drug is a serotonin-3 blocker. So it goes into the serotonin-3 receptor, doesn’t do anything, but it stops that activation by serotonin. And serotonin production can be driven by alcohol and some other pleasure systems. And the serotonin-3 receptor is known to work upstream of a molecule called dopamine, which is also called the reward molecule. So that’s what gets you to crave things or helps. It can be involved in the pathway of craving. So we are blocking the serotonin-driven craving that alcohol helps generate is the way we believe this works. And so when you think about a reuptake inhibitor like those antidepressant drugs, I would call that using the nuclear bomb or the big exploding cannon, where what we are doing is really a rifle shot. We’re a sniper going in and taking out just that piece you want. And it’s one of the reasons we believe we have so few side effects in this study to date. And we can be, you know, more more effective by hitting just that piece.
Dr. Mark Leeds [29:18] OK, yeah, I think that’ll, you know, put a lot of people’s minds at ease, you know, that are worried about antidepressants. And, you know, in recent years, you know, people are finding that they may be more harmful than, you know, than what they thought. You know, they’re not such benign drugs that we thought before. And, you know, and there’s no. Can someone stop this drug abruptly if they want to? Like, is there, like, a withdrawal syndrome? Like, would they have to, like, taper off of it, or is it totally safe to take it for a period of time and then just suddenly stop taking it?
William Stilley [29:50] So our belief is, based on what we’ve seen so far, is that patients should be able to stop without any, you know, they might not have the help the drug is giving them, but they won’t have a worsening effect, which is what you have in some drugs called a rebound effect, something like that. We don’t see any evidence of that at this point. And that includes during the phase three trial. What happened was every patient was on drug or placebo for six months and then 30 days after that they were again contacted either by phone or in person and there was a whole questioning to make sure that was not happening. And at this point it doesn’t appear that’s happening with either drug or placebo group particularly. So they were having other side effects that are kind of withdrawal syndrome, I should say. But I have to caveat saying we don’t know who is on drug or placebo. And if every little problem turns out was on the drug group, I might have to reverse what I just said.
Dr. Mark Leeds [30:54] OK. OK. But yeah, from what I’ve read about it seems like a very safe drug. And we’re looking forward to it being something that people can take safely long term. Now, the next thing is I think anyone listening to this who is looking for a solution to reducing their drinking is going to be really excited and want to know how soon can they start taking it. Do you have any idea when people might expect to be able to actually get a prescription for this?
William Stilley [31:25] So depending on how this trial comes out, the earliest it could possibly be would be probably the beginning of 2024. That would put us a little over a year and a half. Currently, the regulating authorities have stated, and it’s not specific to us, but, you know, in general, you need two phase three trials to go for an approval, and they have not at this point waived that. So that would mean, you know, more like 2025, probably closer to the end of 2025. In drug world, that’s actually fairly quick. For a patient in need, of course, that seems like a lifetime, time, but we’re doing the best we can to move that forward as quickly as possible. Given the devastating nature of this disease, and not only that, but the increase in the disease and the problems related to it, I mean, they just announced, the NIH just announced a few weeks ago that the number of deaths last year is up 25 percent, number of deaths due to alcohol is up 25%. And I just saw a thing in the past, like 48 hours, that said that the number of people in the emergency rooms due to alcohol has gone up almost a similar number. So those that go into the emergency rooms without fatality. So this is a problem that not only was terrible, caused over 200 diseases, quarter trillion dollars of damage to U.S. Economy. I mean, the Lancet has said it’s a leading indicator of death in people in their prime. And it was already a devastating disease. It’s gotten way worse during the lockdowns. So, you know, and in fact, the number of people killed by alcohol during the COVID pandemic is more than the number of people killed by COVID. And the lockdowns have absolutely increased that. And so this is so anyway, with all that said, is there a possibility for an emergency use authorization, something like that? We will absolutely be exploring that, you know, attempting to make a case if the data from our trial, you know, support such a case. And, you know, so that would that’s something we still need to be determined.
Dr. Mark Leeds [33:44] Yeah. Yeah. The sooner the better. I mean, that’s definitely I mean, you know, 2024, 2025 is not that far away. But there’s definitely an urgent need for this. So, yeah, that would be great. You know, the sooner the better that it’s available. So, yeah, I wanted to get back to you mentioned adenosine, and that came up in another conversation, which is a whole other thing. Patients that are coming off of psych drugs, in particular benzodiazepines, have a lot of issues with withdrawal symptoms and sometimes protracted withdrawal that can go on for months and months and in some cases even years. And someone had mentioned to me that there may be a mechanism that’s of interest that could help people by, I guess, the balance between the neurotransmitters glutamate and GABA. And this is, you know, I don’t know if I was following it properly, but it was pointed out to me that adenosine might be a balancing factor between those two. And I mean, is this something that might even have some benefit in that area of helping people with other conditions? I mean, it has nothing to do with addiction, but maybe helping people with that kind of a thing of benzodiazepine withdrawal or maybe even other kinds of drug withdrawal symptoms.
William Stilley [35:07] That’s an interesting thought. So there is some evidence and data has been generated around the – so there are four receptors, the A1, A2A, A2B, and A3. So the 2A receptor, the adenosine 2A receptor, has been shown to have effects in animals, in cocaine addiction. So there is some potential use there. As far as, you know, other things for adenosine, it’s really a primordial molecule that, and I used that word before, that does a number of different things in the body, and in particularly related to the inflammatory system is one of the areas that when you talk about, you know, the other neurotransmitters that you mentioned there, it would not be surprising to me if you And by the way, it works in general. You activate and it downregulates the immune system. So it’s the body’s natural way. Adenosine is one of the many factors, an important factor, in helping the body return to normal after an inflammatory storm has kicked off. So cytokine storm occurs, adenosine is generated. It helps then turn it back off. So the body is able to do its job with the inflammation and then go back to normal. Without adenosine, it would be difficult to return back to normal. And so that’s what adenosine often does is it’s a balancing factor. Like in the heart, what it does is when the heart starts beating too fast, adenosine gets generated. It activates the receptors, which slow the heart back down. So it’s the natural way that the heartbeat is regulated. It. So, you know, I’d actually be interested in maybe an off-podcast discussion to think about that more after I have a little time to look into what you’re mentioning.
Dr. Mark Leeds [37:07] Yeah. And as far as, like you said, you were talking about looking into, you know, researching this medication for using it for pain. Is it the same medication you’re talking about for pain management, or is that a different medication?
William Stilley [37:21] So are you talking about AD04 or the adenosine?
Dr. Mark Leeds [37:25] Oh, okay. So AD04 is not the thing that helps with adenosine, right?
William Stilley [37:29] Correct, correct. The pain drug and the adenosine piece, that is a whole different chemistry program. We have one of the world leaders in the field of chemistry of adenosine. He invented his first adenosine drug that went into human trials in the 1980s. Who has really made a breakthrough in getting these drugs into the human body and into tissue to allow it to do the job that it can do.
Dr. Mark Leeds [37:57] Oh, okay. So this other research that you’re doing with a whole entirely different drug could have major impacts in a lot of different areas, even beyond pain management.
William Stilley [38:10] Correct. And by the way, we currently have six different drugs or drug candidates that we’re developing. The pain one is the furthest along that’s shown good effect in animals. We expect to be in human testing, potentially the end of this year, but most likely first quarter of next year for that drug.
Dr. Mark Leeds [38:30] Yeah, I mean, if you’re able to look into that, like helping people with psych drug tapering and withdrawal, and especially benzodiazepine tapering and withdrawal symptoms, you know, which especially when they’re protractive, like things like akathisia, you know, the movement disorder, which is torturous to people. I mean, if you can find a way, maybe look into that of how you can help people with that. That would be really incredible.
William Stilley [38:55] Well, you know, there’s a drug actually called istradefylline, which it does work through the adenosine mechanism. And it’s useful for Parkinson’s. So when you talk about movement disorders, it actually helps with that. And by the way, historically, one of the best treatments for Parkinson’s disease was two cups of coffee. So, you know, it’s been long known that adenosine blockade can help with movement disorders.
Dr. Mark Leeds [39:22] Okay. Oh, that’s interesting, you know, because, yeah, people going through this, it might be counterintuitive thinking, you know, like something that involves rebound anxiety, they might avoid caffeine. And it might actually, in one sense, help a little bit, possibly. But, of course, like you were saying, you know, using something more targeted that doesn’t give you all the side effects of caffeine would be better.
William Stilley [39:44] Right. And caffeine, as I mentioned, is what’s called non-selective, meaning it hits all of them. Plus, it actually has some non-adenosine effects. It’s not a particularly strong drug, but it hits a number of things with adenosine being the most important of what it hits. By the way, that’s how it keeps you awake.
Dr. Mark Leeds [40:03] Yeah, so it sounds like you’ve got this really great product coming out soon and then some really unbelievable potential and some great things coming out in the future that you’re also working on. So definitely, now is your company, is it public? Is it something like people can invest in, you know, hearing like how great things are going?
William Stilley [40:24] Yeah, so Adial Pharmaceuticals is a public company. We’re listed on the U.S. NASDAQ. The ticker symbol is A-D-I-L, so Alpha Delta India Lima. And, you know, we’re excited to be moving forward with all this.
Dr. Mark Leeds [40:41] Okay. Yeah, and I don’t want to start making stock recommendations here. But, yeah, that’s definitely, you know, something to look at. And, I mean, it sounds like you’re doing a lot of unique things that no one else is even, you know, close to replicating. So, you know, it’s, you know, not like some of these other products you hear, like, you know, like with one called psilocybin, you know, it seems like there’s a ton of companies researching that, racing to get it out first, and who knows which one to pick. But you guys are doing, like, completely unique stuff that no one else is really doing.
William Stilley [41:15] And it’s called, you know, with the adenosine work, it’s, you know, novel chemical design. So these are brand new drugs. You know, psilocybin has been known for, you know, millennia potentially. And, you know, it’s a potential treatment, but it also does a number of things. So hopefully something good comes out of it.
Dr. Mark Leeds [41:36] William Stilley, CEO of Adial Pharmaceuticals, thank you for joining me today.
William Stilley [41:41] Yeah, Dr. Leeds, thank you so much. It’s been a pleasure.
