Welcome to MNET's recent webinar on greatest hits that focus on opioid use disorder. Our presenter today is Dr. Mark Fishman. A couple of few housekeeping details, so please mute your microphone buttons that are on your left bottom. Also, make sure you are not using your computer audio and calling in by phone since it causes feedback noise for us. Please raise your hand by clicking on the button on your right, that's click on participant button and find the raise button. And type the questions in the question box at your right bottom. We are monitoring the chat box and we'll take up your questions after the presentation. So a brief introduction to MNET. What is MNET? MNET is an addiction medicine research network. It focuses on office-based addiction medicine, addiction psychiatry practices and other providers that are treating patients with substance use disorder. MNET adapts and leverages APA's PsychPro patient registry for practices to obtain patient reported outcomes and to conduct quality improvement in addiction medicine treatment. The objective of MNET is to engage practitioners in quality improvement, better understand patient characteristics, services and outcomes in real world and provide opportunities to participate in future research studies. What are the advantages of MNET participation? You will have opportunity to conduct quality improvement. You will be able to use patient data to engage with patients and track outcomes, inform quality improvement efforts, help track patient successes and present data to payers, policymakers and public. Participants will receive free access to PsychPro. It is free for non-APA members until next year, August. And PsychPro is always free for APA members. Participants also receive free tablet computer to collect patient data. They receive free access to CME-approved webinars in addiction medicine and clinical research. Participants also receive up to $1,000 honorarium depending on their level of participation and potential credit towards MOC Part 4 certification. How can you join MNET? The first step is to complete MNET survey to find out if you are eligible. For that, you will have to log in to psychiatry.org or you can write to MNET at psych.org. We will schedule some time to speak with you and answer your questions. So, our speaker today is Dr. Mark Fishman. He is addiction medicine psychiatrist. He is also medical director of Maryland Treatment Centers and assistant professor of Johns Hopkins Department of Psychiatry. He is a co-editor of ASM Patient Placement Criteria and chief editor for ASM PBC Supplement on Pharmacotherapies for Alcohol Abuse Disorder. Dr. Fishman, over to you. I will share your slide. Am I on speaker? Am I okay? Yes, you are. Good afternoon, everyone. It is a pleasure to be here. While we get the slides up, I will just say hello and appreciate MNET and Dr. Schwartz and gang inviting me. The reason I call this recent greatest hits, just by way of background, because it might sound like an odd title, is that for the last 15 years or so at our Maryland Society of Addiction Medicine meeting, I have been in the habit of presenting an hour or so of the past year's research findings in summary, two or three or four or six recent research scientific journal articles in a high-speed journal club format to be able to provide the members a summary of some interesting recent research findings. As presenters' prerogative, I get to pick what I call the greatest hits. There's always way too much to select from, so you can't show everything. When Dr. Schwartz asked me to present, I thought, well, I will focus on some of the recent work that has had as its central focus opioid use disorder. Not surprising. Lots of what we have been showing in the last few years has had that focus. I am going to show you three particular papers today. They are not necessarily from this past year. I think they are from a couple of years ago, but that's recent enough. Talk about what I think are important scientific and practical clinical findings in OUD. Here are my disclosures. I think the relevant one is the Alkermes disclosure. I have been a consultant for Alkermes. They make, as you know, extended-release naltrexone, which is one of the MOUDs. It doesn't feature in any of the studies I am showing today. I don't think it biases me. You guys will be the judge. That's that. Next. The studies I am going to show today are three. One is a public health conceptual piece on the opioid use disorder cascade of care. The second two are clinical trials that are FDA approval trials, in fact, phase three index trials for the approval of two of the formulations of extended-release buprenorphine. One brand-name sublocade that is currently available and commercially prescribed, and many of you may have experience using it. The other, CAM2008, which will be brand-name Brixadi when it is commercially available. We hope that to be soon, and we will talk a little bit about that. This CDC graph, I know you have seen again and again and again, so we won't belabor the scope of the problem, but just to remind everybody that OUD is, of course, a terrible public health problem. You guys as addiction medicine providers deal with this day in, day out. The notion that the problem is not going away, that it has been escalating steadily over the past decades. It is a central public health problem. In recent years, the acceleration of deaths over and above the concurrent acceleration in use and use disorder rates largely is from the prevalence of high-potency fentanyl analogs on the black market. You guys know all that, but this is why it is so important that we are able to band together, to do the learning we are doing today, and to treat these patients, and why I am focusing on these three articles. One, about a public health response and how we think about a 30,000-foot view of the big picture, and two, on particular pharmacotherapies, that is, extended-release buprenorphine. Here is this first paper, lead author Robin Williams in the Columbia Group, and it is called Development of a Cascade of Care for Responding to the Opioid Epidemic. Next. One of the things that is important about this slide is there is not going to be a ton of data, it is not a randomized trial, it is not an experimental design. As I say, it is more of a public health perspective to orient us to the bigger picture of how we might think of persons and then patients responding to interventions at a societal level along different stages of our interventions and engagement. Next. I want everybody to think about care as proceeding in steps. We call this the cascade of care, and the steps in the cascade are outlined here. You may be familiar about this kind of approach from other disease entities, for example, HIV, or HCV, or tuberculosis. The notion that we think about people entering at different stages and having different interventions depending on what stage they might be at. We think about primary prevention, the biggest net that we cast, and thinking about the general population, folks who do not necessarily have OUD, who do not even necessarily have opioid use, but they might have a variety of general risk factors, and we think about wanting to address them with general primary prevention techniques, how to prevent SUD writ large, how to prevent progression of SUD, how to prevent initiation of opioid use, and then later how to prevent progression to OUD. Secondary prevention, a somewhat smaller net, a subset of the first group, are those that have already been exposed to opioids, so do not only have general risks, but have the additional specific risk of having had some opioid use, some initiation of opioid use, but may not have progressed to loss of control of use, to developing a use disorder. When we talk about approaches and interventions for that group, it would be secondary prevention, how to prevent progression of already existing use from getting to a point where it becomes disordered use. Then in the transition to OUD, we narrow the funnel and think about the next group, and that is those that have progression of use and are progressing to the point of developing an opioid use disorder. Then there's the group of people who have an OUD, but may or may not have been detected, may or may not have received a diagnosis, may or may not have received an assessment, and then the intervention is how do we get them to be identified? How do we establish their quote-unquote caseness, although that's a terrible word? How do we get them at the front door of possible further treatment with an assessment? Then those that have been detected as having OUD, the next broad set of categories, how do we get them engaged in care? We want to find people that are identified as having OUD, and we want to initiate treatment. Among those who initiate treatment, in this room, we know that the main high effect size evidence-based treatment are medications for OUD, MOUD. Of those that have initiated care, a next step might be thought of as initiating medications for OUD. Of those that have initiated medicines, we know that these medicines aren't curative, so it's a matter of sustaining that treatment by retention in MOUD. One milestone that we sometimes talk about is six-month retention. Is longer better? Of course it is, but this is a standard measurement, partly having to do with what we are able to measure. In our field, we don't have the kind of longer longitudinal frames that we wish we could, one-year retention, five-year retention, 10-year retention. We'd be happy enough with six-month retention as at least a beginning marker of success. Then next step, of those who are retained in six months, how many achieve clinically meaningful remission? Another marker or benchmark of that duration might be 12 months. If you are in treatment with MOUD for six months, how many people are in a subset that have remission, and how do we enrich that? Next. As I say, this is a common public health framework. It's somewhat new as applied to SUD and OUD in particular, but it's a very common framework used in other chronic remitting relapsing epidemic-style illnesses. I mentioned HIV, HCV, TB, and one public health rule of thumb that has been used as a marker of the success of a broad-based public health initiative is the so-called rule of 90s, or 90-90-90. It's an aspirational metric whereby we hope or try to achieve that in the transition between each of the cascades or each of the steps in that long-term, long-term, long-term, long-term long cascade of care that we can transition 90-ish percent of individuals from one step in the cascade to the next step of the cascade. Obviously, 100 percent would be better, but that's unrealistic. Can we even make 90 percent? I don't know. But aspirationally, it's a reasonable goal because at those kinds of levels, we know from our experience in other illnesses that we can make significant progress to making a big dent in alleviating these epidemic public health problems. We've been very successful, for example, in HIV, in achieving very high rates of penetration, of identifying people with the disorder, getting them entered in care, once entered in care, initiating highly potent antiretroviral medications, and once initiating medicines, retaining them in care at a benchmark level, say, of six months. And so can we do that with OUD? Can we diagnose 90 percent of the people who have OUD and identify them as having OUD? And of the people that we diagnose and identify as having OUD, can we engage 90 percent of them into care? And of the people that we engage in care, can we initiate MOUD in 90 percent of those? And of the people we initiate MOUD in, can we retain 90 percent of those for six months, et cetera, et cetera? And that would be, again, aspirational, maybe overambitious, but we can dream. Can we achieve those metrics of success and in that way make the dent that we wish we could, that we know we must make in the opioid epidemic? And one of the things that this paper does, and I think so poignantly, is first to frame the puzzle, explain how applying this well-known public health framework to OUD would frame the puzzle conceptually, and then asks the question, well, how are we doing anyway? So let's look at some of the data. This is what it looks like. Looking from OUD to OUD diagnosed to engaged in care to MOUD initiation to retained for six months and having achieved 12-month remission, the tops of the bars are the aspirational 90 percent marks that I talked about. So, for example, taking the third from the left where it says OUD, if we were to have, if that's the number of people who our population prevalence estimates tell us have OUD out in the community, say 2.3 million-ish, then if we were to achieve the 90 percent rule of diagnosing 90 percent, then the top of the next bar, that's the fourth from the left, would be as you see it. But unfortunately, it's the blue that reflects our best current estimates based on the data we have. And the red is the gap of our underperformance, of our undershooting that aspirational 90 percent goal and proceeding to the right. Engaged in care, you see the blue and you see the red gap where we would be if only we were achieving 90 percent. And you can see that as we go on further down the cascade, our performance is not better. On the contrary, it's worse and worse. So we're not doing that well, right? But it's a nice way, I think, of framing the puzzle and framing a potential metric for how we might see ourselves as succeeding or not. And it also breaks down for us that it isn't just one thing. It isn't just one intervention. And from a broad public health point of view, it's different kinds of strategies for people at different levels of the cascade of care. Now, I think for those people on this call, myself included, who are providers providing addiction medicine treatment services, one, two, three and four are the key issues, right? And so that's why they're highlighted here, because this is a paper that's focused on us as the target population. Next. In order to get that, we're not doing so great now, but in order to improve, we need substantial and improved multi-component efforts at every step. And that's why we do what we do, because these are our people, these are our patients, and we want to be involved as part of the solution. All right, so that's paper number one. Next. All right, these next two papers are going to both be about extended release buprenorphine, two different formulations, and the background to these papers is as follows, right? We know, and we've talked about, that there is catastrophic morbidity and mortality from OUD, and fatal overdose is very high among those causes of morbidity and mortality. It's old news that buprenorphine has clear efficacy and effectiveness in treating OUD, but unfortunately, real-world outcomes are limited by all sorts of problems that we all know about. Problems with retention, problems with adherence, and especially over the longer term, right? We saw how poorly we're doing in that 90% aspirational benchmark from engaging people in MOUD to retaining them in MOUD. We're not doing very well, and we have problems additionally with possible suboptimal dosing, with diversion, with all sorts of things, insurance coverage, all sorts of things. One well-known strategy in chronic, remitting, relapsing illnesses where there are chaotic target populations is long-acting injectable formulations, right? You may know, for example, about long-acting injectable antipsychotics and schizophrenia as being a strategy for doing exactly the same kind of thing as it might do in OUD, trying to overcome problems with adherence, suboptimal dosing, diversion, all of those kinds of things. What about having buprenorphine, instead of in a daily sublingual formulation, in an injectable long-acting extended release formulation? Science fiction? Oh, no. We have at least two formulations, as I said, one currently commercially available and the other soon to be. Let's look at some data about those. Next. One of the things that you want to think about and that I often introduce in these conversations is not just the scientific evidence and not just the clinical implications, although obviously the clinical implications are the most important thing for us and for the field. I think it's also interesting to talk about design considerations as we learn to be better consumers of the scientific literature. It's interesting to put yourself in the shoes of the people who do this work, who design the studies, in thinking about how they come up with the methods that they do in formulating the research studies, because the way you design a study has obvious implications for the results. Are you answering the right question? You got to ask the right question in order to answer the right question. One of the things we want to think about as critical readers of the scientific literature is do we buy the conclusions that the authors make? Some of that comes from the way that the study was designed. You can think, let's say, you were trying to design studies to prove or support the efficacy of a long-acting buprenorphine formulation newly introduced. How would you design it? There's so many possible choices that it's impossible to do them all correctly. There's only pros and cons, and you make your best choice. One of the things we don't have time to talk about today, but one of the things that you got to remember is if you're doing a pivotal study for the FDA for a phase three approval to go to marketing, you also have another master besides clinical impact, besides scientific validity. You also have the FDA as the 800-pound gorilla who gets to sit wherever it wants and tells you how it wants the study to be conducted. All sorts of interesting factors. Interesting questions are would you be wanting to study patients who are early on in the course of their treatment, that is currently using street injection heroin and fentanyl? Would you be wanting to study stable patients who are already stabilized on buprenorphine and doing well? Or would you want to be doing something in between on stabilizing patients who are between the most severe and the most stable? There's pros and cons, depending on how you design the study. Would you want to compare your product to placebo? Would you want to compare it to sublingual buprenorphine as the comparator? That has statistical implications. You'd expect superiority compared to placebo. You'd expect non-inferiority compared to sublingual buprenorphine. Those are mathematical constructs that are beyond the scope of our discussion today, but they are different statistics. They also answer different questions. The FDA tends to like you to compare things to placebo. It's also easier to demonstrate that. We know that placebo isn't that beneficial for OUD, so it should be easier to demonstrate superiority over placebo. On the other hand, what about the ethical question? Do you want to enroll OUD patients in a study in which they could be on placebo and therefore potentially subject to catastrophic outcomes, so you have to design in what we call rescue procedures and think about ethical and safety issues? On the other hand, it's more real-world to think about a comparison to sublingual buprenorphine because we as practitioners presumably are going to be making that kind of choice. Should this patient be on a sublingual daily formulation, should it be on sublingual, or should the patient be on an extended release? On the other hand, that's not as easy to demonstrate, and you're going to have to work harder, maybe have a more complex design, maybe have more patients for more power, and use non-inferiority statistics, so that's another issue. Are you going to look at all comers, that is, anybody who's seeking treatment for OUD, or are you only going to look at people who have already failed sublingual, therefore enriching your possible response, on the one hand, to the new, novel extended release intervention, but also, therefore, enriching higher severity patients who are harder to treat? You're going to have to think about induction strategies. Are you interested in trying to meet the needs of real-world, fast initiation, or are you going to take an easier approach that allows slow induction, which will likely be more successful, but will not be as relevant to the needs of real-world patients? Are you going to just pick a single dose regimen, according to a strict, rigid protocol, which is easier to control the variables, perhaps, and easier to demonstrate the effect, or are you going to allow clinical judgment and dose adjustment more like real-world, so that it would have broader and more generalizable implications for the average practitioner, but perhaps be muddier from a scientific perspective? I don't have the answers to all these questions. I only raised them because, as consumers of the literature, it's interesting, as I said, to think about these design considerations. And now I'll show you what these authors actually picked. Next. All right, so study number one is the sublocade Indivior product. And this study actually came out second, but that doesn't matter. Both have been out now a couple of years. And many of you probably have now used sublocade. And it is, as I said, the product that is commercially available. Next. So the summary question for this study was, what is the comparative efficacy of two dosing strategies for monthly extended-release buprenorphine in patients who are active opioid users over a six-month duration of study treatment versus placebo? So remember, I threw out some possible design considerations. And you can see that they made some choices. They decided on a placebo control. They decided on active opioid users. They decided on a treatment duration. They chose six months. And they're going to test two different strategies for dosing this novel product. Next. And I say novel because it was novel at the time. Now we've all had the experience or the possibility of the experience of using it in real-world non-research settings. So this was a multi-site study over 36 US sites. The enrolled cohort was 505. Everybody got a short, open-label run-in of sublingual buprenorphine, titrating up the dose from 8 to 24 milligrams a day. That makes sense in the sense that you wouldn't want to give anybody a extended-release injection of a substance that they haven't at least had one previous exposure to, to make sure that they tolerate it, that they're not allergic, that they're not going to have anaphylaxis. Because once you give them a monthly shot, you can't take it back. And it was a 2 to 2 to 1 randomization with the following three arms. A extended-release buprenorphine dose of 300 milligrams for six months. So that is six monthly doses of the 300 milligram strength versus two months, consecutive months of 300 milligram doses, followed by four consecutive months of the lower dose of 100 milligrams versus six monthly placebo injections. One way of addressing the ethical issue of can you give people with OUD a placebo is you give a fewer number of people placebo. And that was done here by having half of the number of people have in any of the two active arms have placebo, and total only a fifth of the entire population having a placebo. So that ameliorates it to some extent. In order to help with the masking, everybody got after the run-in of pretreatment with sublingual buprenorphine, got a continued five-day taper with sublingual buprenorphine so that there wouldn't be sudden cessation of the lead in buprenorphine. So it would be harder for the investigators and the patients to know. Part of the background treatment was a weekly counseling session. Patients were seen, participants were seen weekly for assessments. And the primary outcome, and here's another design consideration, what is it that you're going to measure your success by, right? Every study has to pick a primary outcome. You have to pre-specify it. And you're kind of betting, your big gamble is that you can meet the primary outcome and show that your experimental intervention is better on that metric. Not that that's the only metric. Not that that's the best metric. But it's the metric that you pick because both you think you can meet it and because you think it's most convincing and meaningful. And you still get to use secondary outcomes. And I'm going to show you a mixture of both. You still get to show people other ways in which you did or you didn't meet the mark. But you're putting most of the eggs in the basket of your primary outcome. And for this study, the primary outcome was the proportion of the weeks of the study that were weeks without opioid use. Another way of saying that is the percentage of abstinence weeks. How many weeks were abstinence weeks? But not over the whole course of the study, but between weeks 5 and 24. So the notion, why would you start late? Why wouldn't you count weeks 1 and 4? Well, because we know that for many patients, there is a period of stabilization during which they're figuring out the medicine. You're ramping up the dose. They're still dabbling. They haven't quite stabilized yet. And we're giving them a discount, if you will, for those first few weeks. And we're expecting that it's going to, quote unquote, kick in about in a month. And then we're looking for weeks of abstinence or the proportion of weeks of abstinence from week 5 to 24. Next. So here's the summary of the result. The primary outcome, mean percentage of abstinence weeks 5 to 24. And we have three columns. We've got the column number one for the entire six months being 300. We got the second column for two months of 300 and four months of 100. And we have the third column for six months of placebo. And you can see that both of the dose approaches to extended-release buprenorphine beat placebo by a mile. That probably doesn't shock you, right? A couple of things to see is that although placebo did horribly and although extended-release buprenorphine did very, very well, you notice it's not 100%, right? And that doesn't shock you either. You guys have treated real patients. And we know that these are good medicines. In fact, they're very good medicines. But they're not curative, right? These are not surgical cures. And so even when we have very good treatments, seeing numbers like 40%, glass half full, glass half empty, right? It's great, but there's room for improvement. But this is both a statistically significant and I think clinically very meaningful result. Another outcome, a secondary outcome, was how many patients met the threshold of having at least 80% abstinence weeks. So between weeks 5 and 24 were at least 80% of those weeks abstinence weeks. And here again, the two different approaches to dosing extended-release buprenorphine were much better than placebo and not different from each other. Another metric is study completion. How many people make it out the other end and are retained for 24 weeks? That's very relevant to our own practices because we're thinking about retention as being very highly correlated with success. And not surprisingly, being on active medication much better than placebo. And the two different approaches to dosing the medicine not different from each other. And also in terms of the number of doses received, right? That's a nice metric of medication adherence. One of the things that we would expect about an injection, as we're contrasting it to sublingual daily dosing, which is what we do for most of our patients, we'd expect that we'd get an improvement in adherence. And here we did quite well. Almost five out of the six doses in both of the active treatments, significantly better than the placebo doses. Next. And here is a graphic representation. This is the survival curve of retention in the study. Remember, I showed you the absolute numbers as being significantly better at the end of the study. In both of the active treatment conditions compared to placebo. And this is watching that decay or that survival curve over the course of the entire time. Next. Here is the results of abstinence as a survival curve. So before we were looking at retention. Now we're looking at the percent of participants that were abstinent in every given week. It might not be, it's not really a survival curve, because it might not be the same patients that are abstinent in any particular week. They might move in and out of the abstinent versus non-abstinent categories. But again, it's a very dramatic difference. You see that by the end of the study, it's nearly zero, as you would expect in the placebo group. And we have the numbers of between 40% and 50% in the active intervention and not different from each other. Next. This is an interesting way of looking at the data. And it takes a minute to absorb what we're looking at. It's a measure of who meets what threshold of a certain outcome. And the outcome here is how many weeks were abstinence weeks. So they call it achieved abstinence. In the way I think of English grammar, I would call it abstinence achieved. But either way, the point is that you can think of the percent of people that achieve at least 20% weeks abstinence, 40% week abstinence, all the way up to 100% weeks abstinence. So if you go all the way to the right, those that have achieved 100% abstinence are cumulatively abstinent the entire study. It's zero in placebo. And it's not very, very high in the active intervention either, as you might imagine. It's something like 17% or 15% here, but significantly better than placebo. And all across the range of the heterogeneous possibilities of outcome, you get significant superiority to placebo and no difference between the two dose regimens on average. Oftentimes, one way that we read a graph like this is to look at the 50% mark right in the middle as the median response. So how many people achieve 50% abstinence? Or another way to look at it is to look at the 50% participant level horizontally. So what is the achievement of 50% of the population? And as it is here, by coincidence, it's about the same. About 50% of the participants achieve about 50% abstinence. And you might ask yourself, how does that compare with your usual clinical experience with sublingual buprenorphine? That wasn't studied in this study. When we get to the next study, which is a comparison to sublingual buprenorphine, we can ask that question more directly, but you can at least speculate. My view is that it's probably better, but again, not directly observed or studied in this study because sublingual buprenorphine wasn't in the design. Next. Here is the dosing kinetics, the blood levels. I think it's very important looking at this, and we're going to look at it again in the next formulation as well, because it gives you a feel for how much medicine gets into people. What is the blood level of buprenorphine that's experienced by this formulation? You can learn a lot from these graphs. It's the two different dosing strategies, 300-300 versus 300-100. By the way, you guys may know, since you probably have had some experience in using this product, that the FDA indication, the formal labeling is the dosing strategy on the right, two months of 300 followed by 100 ongoing. You can imagine why they chose that. Remember, there was no separation in the efficacy of the two different strategies. In general, if two different doses give you roughly on average the same outcome, we generally pick the lower dosage as presumably being safer, fewer side effects, more conservative. Now, having said that about the average response, that of course doesn't tell us about heterogeneous response that might be different between different individuals. Just as you know from your own sublingual patient experience, that some patients are fine with lower doses like eight milligrams a day, plenty of your patients need significantly higher doses, and your clinical experience is that you learn that with customization and patient-centered care over time, adjusting the dose based on individual response, not based on average response. We have choices here. Even though the general clinical labeling is for 300-300 followed by 100, there are plenty of patients who, as you get experience with the product, you will learn really do better with a higher dose and that's an option. Look at the different blood level response that you get with the different doses. Couple of things that are very notable. One is that you don't reach steady state for several months. Over time, you can see each dosing cycle, that's every four weeks of 4, 8, 12, 16, 20, you see that the blood levels are increasing. The steady state is not reached well into say month 5 or 6. Earlier in the 300-100 scheme, maybe by month 3, you get steady state. But with 300-300, you're still increasing your cumulative blood levels without steady state into month 5 or 6. That's one important thing to know about this formulation. The other important thing to know about this formulation is look at the variation over the course of the month. When you first give the injection on week 0, go back, on week 0, week 4, week 8, you get a spike. We get very substantial blood levels, but then it rapidly attenuates and then continues to gradually attenuate over the course of the month. Most of that happens in the first week, but continues to happen in subsequent weeks, 2, 3, and 4 to the end of the month. People have progressively attenuating blood levels over the course of the month, and one wonders, although this study didn't address that, one wonders whether there is variability over the course of the month, both in terms of subjective experience of drug effect, of side effects, of craving, and also in terms of actual outcomes, like prevention of opioid use, blockade of ill effects, subjective effect, overdose, when the blockade is attempted to be overcome, etc. Just interesting to see when the patients might say things like it's wearing off, if in fact they say that, that that might be supported by the pharmacokinetic data here. What do we conclude? Monthly XR is more efficacious than placebo. It seems to perform as well or better than the typical metrics that we know of for sublingual buprenorphine, although those weren't examined in this study, and it has the anticipated conceptual advantages of other long-acting injectables from the other examples that we know, like from long-acting injectable antipsychotics and schizophrenia. The labeling recommendation is a seven-day sublingual lead-in, that is stabilized people on a dose of sublingual buprenorphine for seven days to get them to the point where they receive an injection on day 7 or 8, then two months of 300, then maintenance ongoing on 100. We can discuss at the end if we have time, that many people have gone off label and adopted a strategy of giving most people continuing doses of 300 because lots of patients appreciate and seem to need higher dosing. But as we say, that's customizable for patient-centered care. This is early stages in penetration and dissemination. Very encouraging news from the field, lots of acceptability from patients, lots of good results as you might imagine from dealing with adherence to people who had known clinical pharmacological response to buprenorphine, but have troubles taking it in a way that's going to be successful. Lots of clinicians, lots of patients are finding this to be a very advantageous strategy. I give this a solid two thumbs up. This was the conclusion I gave it when it was just a research result now that we're a couple of years into clinical experience. If I had a third thumb, I'd add the third thumb. All right, next. The next study is the other formulation of extended-release buprenorphine. This was originally called CAM20038 in its experimental stages. It's going to be marketed by Braeburn, and it is going to be brand-named Brixadi. The summary question for this study is, what is the comparative efficacy of weekly extended-release buprenorphine for three months, followed by three months of a monthly extended-release buprenorphine formulation in active opioid users with sublingual buprenorphine as the comparator? Next. This was also a multi-site study, 35 US studies and of 428. It was a one-to-one randomization to two arms. Injections of extended-release buprenorphine, as I said, three months of weekly followed by three months of the monthly versus daily sublingual. The way that you disguise it is you add double dummy placebo so that the patients that are getting the daily sublingual buprenorphine also get placebo injections and the patients that are getting the injections get daily sublingual placebo, and neither the patients nor the investigators know which is which. There was one dose of sublingual lead-in, not the seven days as in the other. The notion again, you got to get at least one dose into somebody before you give them a long acting to make sure they're not allergic. It was a complicated lead-in. Week 1, they got a weekly injection of 16 milligram strength and then day on four got an eight milligram booster and then went up to the 12 milligram and on and on. Eventually, the idea was that they got stabilized on the 128 milligram monthly dose for the second three months. Although the numbers don't correspond in an instantly intuitive way, that's about the equivalent of 24 milligrams. In the sublingual group, they were titrated to a target of 16 milligrams, but there was investigator flexibility up to about 24 milligrams. There was some supplementation allowed, but it wasn't used much. There was a weekly counseling background and the primary outcome not too dissimilar from the primary outcome in the other study was percent abstinence in weeks 1-24. That's very similar to the other, although you remember in the other study, they didn't kick in measuring percent weeks abstinence until the fifth week. This looked at the entire 24 week or six month duration. There was another interesting primary outcome, I guess co-primary outcome, which was a synthetic construct of who is a responder. This is complicated. Lots of people end up trying to invent their own definition of good response or positive response or who is a responder. In this case, what they said was in order to be a responder, you had to be opioid negative at week 12, opioid negative at two of the three weeks between week 9-11. I said that backwards. Opioid negative at two of the three weeks 9-11, then opioid negative at week 12, then opioid negative at five of the six weeks in month 3-6, including at least one point in month 6. That's very complicated to get your head around. But suffice it to say that it's some semi-arbitrary metric of saying lots of key milestones in the course of treatment were abstinent weeks, although not necessarily all of them. It's good response short of the requirement for full abstinence, but it's a binary or dichotomous. Yes, you meet this standard or no, you don't, whereas percentage of abstinence weeks 1-24 is a continuous measure. Here's the data, the primary. This is study retention, sorry, not the primary outcome. This is how many people are retained. We've got pretty good retention for a buprenorphine study, just shy of 60 percent at six months with no separation between the sublingual and the injectable. At least we've got non-inferiority. By the way, that was the primary strategy here, not to have to prove that sublingual was worse. I mean, not to prove that injectable was superior to sublingual, but to make the point that it's at least as good, and then have the intuition that perhaps adherence advantages confer the extra boost. Next. Here is week-by-week opioid negative rates, and we can see that they are about the same. Although on a couple or three of the time point outcomes, there actually was superiority. Those are the ones that are circled. Although that wasn't the predetermined outcome, it was a non-inferiority goal, and they met that goal. Next. Here is that same slicing and dicing in looking at who achieves what level of success at different percentages of being opioid negative. Not surprisingly, all the way to the right at 100 percent, very few people achieve that milestone. But if we take the strategy of looking at the median level of participants here at 50 percent, we see that you get a significantly better response actually in the injectable, and the entire curves do separate with statistical significance. Next. Here's a summary of the different outcomes. That main outcome of mean percentage of abstinence, weeks 1-24, they did not separate, but it met the standard of non-inferiority. When they did look at it the way the first study did by taking out the first four weeks, so they looked at mean percent abstinence weeks 4-24, that's the bottom column. It did separate and they achieved superiority that the extended release did better than the sublingual. The percent responder, the two different conditions didn't differentiate, but they did meet non-inferiority. In the study completion that I showed you in that first outcome slide, there was also no statistical difference, so there was no separation. Next. Now, I know we're running out of time, but I just want to take a look at the kinetics because I think this is very interesting in trying to understand and appreciate what our patients experience subjectively and potentially how they might respond. This is not from that paper, this is from an earlier preclinical paper looking at pharmacokinetic attributes of the same product, but it very much illustrates some important features. The first thing I want you to see in panel B, in the upper right-hand corner, is just to look at what happens when our patients take sublingual buprenorphine. This has nothing to do really with these two studies I showed you, it's just a background about the experience of taking sublingual buprenorphine. We generally think about sublingual buprenorphine as being a single daily dose product, and that's certainly how most of the initial studies were done. We would like, in our imaginations, to have medicines like single daily dosing of blood pressure medicines. Patients take their medicine in the morning, and they can't even tell they're taking it, and they go about their business, and they go through the course of the day, and they don't even know they're on medicine, but yet they achieve important outcomes in abstinence and recovery, and it's like they're not taking anything. On the other hand, our patients are reinforced through their street drug use, and their loss of control, and their substance use disorders to be very reinforced by taking things, taking opiates, taking other substances. We've all heard the expression in relationship to medicines we prescribe, doc, it's not working, I don't feel anything. Then we say, well, that's great. We try to spin and we say, that's wonderful. That's the whole point. We don't want you to feel anything, we just want you to get well, like with your blood pressure medicine. No, doc, you don't understand. I know it's working because I feel something. In fact, I know I'm protected, say in the circumstance of buprenorphine, I know I'm protected because I can feel it working. By the way, one of the advantages of agonist treatment or partial agonist treatment like buprenorphine might be the reinforcement of partial experience of an opioid agonist feeling, and you might say, well, is that real recovery? Well, on the other hand, taking a medicine that you like taking and that reinforces it's taking while it protects you, might be an important feature of a medicine, especially in early recovery, where the advantages and the successes of early abstinence and recovery are few and far between and slow, and most people even feel worse at first when they stop using drugs, not better. Liking your medicine might not be such a terrible thing. This panel gives us some of the data behind some of the subjective experience. First of all, this is blood levels at steady state of a single daily dose of sublingual buprenorphine. You got three lines at 8, 16, and 24 and the shape is exactly the same, just different amplitude for the different doses. The first thing is that you see is even at steady state, you start the day at a relatively low blood level. In fact, below one nanogram per mil, which is where this is, is a blood level at which many people will experience withdrawal or discomfort. When the patients say they wake up feeling icky, they're not making it up. Some of them will feel that way, and it's based on the pharmacokinetics. Then when they take the dose, you can see right away there's a very significant peak as they absorb the medicine. You're not surprised that they say, wow, I feel that. I have a subjective experience, and you're not surprised that it is reinforcing as an opioid effect. Then the third thing to notice is that it decays over the course of the day. You can see out of 24 hours that it gets lower in a way that might be appreciable to some patients, and might not be appreciable to other patients. But it might be a phenomenon that would lead patients to want to do divided dosing. Lots of our patients say, I really do want to break it up into two doses, into three doses, and it might be because they notice that as their blood levels go down over the course of the day, either they don't feel as protected, or they have mild subjective withdrawal or semi-withdrawal experiences, or they want that reinforcing spike. All of those things may be part of the subjective experience package that lead to those behaviors. Now, contrast that with panel C, and here we're looking at the Braeburn-Brixiety product, a single dose. You got various different dose levels, but the shape is all the same. And you see, not surprisingly, that there's an initial spike, and that it decays over the course of the month. So one of the things that we might have to contend with is patients, despite the advantages of these extended release formulations for adherence, for constant coverage, for protection against aversion, all the pros, they may also have this subjective experience later in the month of not having as much of a subjective experience of high enough blood levels, or they may not notice it. I mean, it's much more gradual, right, than the experience of the 24-hour cycle that we looked at before in panel B of the daily sublingual dosing, but it is a significant change. As you can see, it goes from somewhere like around 9 nanograms, and then by the time the end of the month is where again at about 1 nanogram or 2 nanograms there, and so that's a significant change over time. And contrast that in panel D, where you see both the weekly dose, day 0, 1, 2, 3, 4, 5, and then on day 6, a sublingual dose given on top of that, and contrasting the smooth decay of declining blood levels versus the big peak of taking a daily sublingual dose, and so it contrasts, I think, in a poignant way what might the subjective experiences of patients, some of them might not notice, on some it might confer no difference in terms of blockade or using behavior, but there might be others who say, no, no, that's not enough for me, and I really want to feel the daily spike or peak levels, and it also might inform the notion of whether for some patients as the monthly dose wears off towards the end of the month or the weekly dose wears off towards the end of the week, whether a supplemental strategy of giving them extra sublingual in response to their individual subjective experiences might or might not be helpful, but when I hear patients say this, and I sometimes do hear it, it's important to remember that they're not making it up. At least a subgroup of them have these experiences, and it does reflect the actual pharmacokinetics. All right, next. So to conclude, for this study, the weekly than the monthly formulation is as efficacious as on the primary outcome and on some secondary outcome indicators superior to sublingual buprenorphine, so I certainly give this a two thumbs up, and that was when I saw this just as a research result. I've actually been using this formulation in another research study, so I've had my own personal experience with patient use, and so again, if I had a third thumb, I'd give it three thumbs up now. It's, I think, highly acceptable and feasible, and the patients appreciate it, and it seems to be effective. I don't have as much experience, and it's not commercially available yet, but hopefully coming soon to a drug store near a pharmacy near you. It has a great deal more dosing flexibility than the first product, and I'll show you that there are four weekly doses and four monthly doses. That gives you a lot more options for customizing care for an individual patient. The product that we looked at first has only two doses, the 300 and the 100. Both are monthly doses. Is one better than the other? Not so much. They're just different, and they have different advantages. Just to tell you a little bit about where this is in terms of availability, it was hung up at the FDA with provisional approval for a while in an intellectual property dispute between these two manufacturers, one saying, it's mine, no, it's mine, no, it's mine, you know, the usual craziness. That dispute has now been resolved, but there is still a residual manufacturing difficulty that they are resolving with the FDA, and so it's not yet commercially available. It's not yet on the market. It's expected out sometime in mid to late 2021, although we don't know the exact details of what it's going to take to resolve their manufacturing problem, but for my money, the big message is let's get it on the market pronto and have more choices for our patients. Next. I just want to show you this side-by-side comparison of some of the features of the two products. They are both subcutaneous injections. The sublocade product has a higher volume. It's two milliliters, so it's given as a subcutaneous abdominal injection. Many of you will have done that. Most of the patients tolerated fine. You might wonder, you know, about does it give you a lump on the belly button during bikini season, but most people don't care about that. The other is a somewhat smaller volume. It's only one mil, so you have slightly more flexibility in terms of site of injection, and so it can be given on the abdomen, but it can also be given in the subcutaneous skin of the thigh, the buttocks, or under the arm and the triceps area, so some patients might appreciate being able to try different places. As I said before, there are more options with the Bruxade product. Is that a pro or a con? Well, it might depend on who you are and who your patient is. To have these different formulations and customizable mix and match choices might be a flexibility advantage for the specialist, but it certainly makes it more complicated. On the other hand, the two speeds only is simpler for the non-specialist, but doesn't offer as much flexibility and customization, so pros and cons. Thinking about how quickly you can get a person up to speed. So remember I said that the labeling on the sublocate is seven days of lead-in followed by a first injection, so if you follow the labeling, you can do it in a week. You can give the first injection of the monthly formulation on day seven, and it isn't even clear to us that that seven-day lead-in is necessary. That's what the FDA made them write in the label because that's what they did in the study, but if you can get people to tolerate sublingual buprenorphine over a fewer number of days, and we know we can, then there's no reason you have to wait seven days, and lots of people, including myself, have gone faster a little bit off label and given it on day three or day four, right? There's no harm in that. They're already tolerating. They know, so that's quicker, whereas with the Bruxade product, you need to go through a series of weekly injections to get to the monthly injection, and so that can take two to three weeks to stabilize on the highest dose monthly injection. Again, that's not very long. They're still covered by medicine. It's not that they're waiting three weeks to have adequate doses of buprenorphine in them. They're just waiting three weeks to have monthly coverage in the monthly injectable. Both products, as I showed you, have some moderate to high degree of plasma-level variability over the dosing cycle, as we saw in the Pharmacokinetics. There is a increase in steady state over time, as we saw. That is, several months to steady state with subsequent injections in the Sublocade product, not so much in the Bruxade product, which seems to get steady state pretty quickly within the first monthly dosing cycle, and as I said, simple, but less flexibility versus high flexibility versus more complicated. Next. So, which product is better? Yes. As far as I'm concerned, the more choices we have as practitioners, the better off we are. If we have multiple different tools, then we can customize them for individual patients, get hand feel in our own practices for what works for whom on what day of the week, in what phase of the moon, and get a sense of how to do good treatment matching. None of that research has yet been done. We need comparative effectiveness trials. We need treatment matching trials. That all will come, but while we're waiting for that, that's what we do as physicians. That's what we do as medical providers. That's what we do in our practice. We get this experience, and we learn from our patients. Next. So, what's next? Well, one is, you know, when are we going to get the Brayburn Bruxade product? Soon, we hope. And some interesting questions for next steps. Many of you have seen the work of upstream initiation of buprenorphine. So, lots of work being done across the country in initiating sublingual buprenorphine in emergency departments, in hospital, in jails and prisons. Well, what about initiating extended release buprenorphine in those settings, where you'd not only get the advantage of having people on the medicine, but get the adherence advantages? Another interesting question that deserves study is, what about a tail when the medicine is discontinued, right? The last day of the injection cycle, your blood levels don't go to zero. They taper on their own in a gradual way. So, that might mean that for patients who want to intentionally discontinue medicine, not that we're encouraging that. We want patients to stay on medicine as long as they can, but some patients will vote with their feet and will say, I want to discontinue medicine, no matter what you advise me. So, would it be easier to do it with an auto taper, as we know that some subgroup of patients have trouble tapering sublingual buprenorphine? And will it be safer? Because for the patients who suddenly drop out of medication treatment with either methadone or sublingual buprenorphine or naltrexone, we know that they rapidly lose tolerance and are vulnerable to relapse and overdose and overdose death. So, will a tail of gradual taper of the medicine on its own confer a penumbra of safety in which there will be enduring coverage, even though the patient isn't taking medicine? And then for patients who decide they want to transition from a buprenorphine product to extended release naltrexone, how do we do that with an extended release in which we know it lingers in the system? And so, some people are looking at studies, are doing studies to try to determine that, but for sure, it isn't right away. And most people are estimating that it should be at least several months for patients that want to make that transition. And then, as I brought up before, what is the role of sublingual supplementation when patients say that it's wearing off at the end of the dosing cycle, or it doesn't feel the same to them, and how will we learn what are appropriate strategies? What about real-world conditions? So, we've looked at boutique research under very circumscribed and controlled conditions. We want to see what this is like out in the community, what you experience. That's part of the point of AMNET, right, is getting your feedback and outcomes in your own practice and with your own patients. Will we see reduced leverage for supply? You know, some of us will use access to sublingual buprenorphine as a way of reinforcing touch points, come see me, let me monitor, let me see how you do in order to get your medicine. Here, if we're giving patients monthly injections, will we lose those touch points? Will there be less dosing of psychosocial treatment? Will that translate to worse outcomes versus better outcomes? We don't know because, you know, it wasn't real-world conditions that were studied even in the second study that compared to sublingual buprenorphine. I already asked what about patient selection and treatment matching strategies, and what about assertive community treatment-like interventions, just as we do in schizophrenia with long-acting injectable antipsychotics in which home delivery for non-adherent or chaotic patients is a mode of intervention. What about a strategy of doing home delivery with these injectable buprenorphine products, and that remains to be examined. Regarding the casket of care, is there a target for primary prevention or secondary prevention, and especially how are we doing in preventing prescription opioid use disorder? So that's a great question, and, you know, each cascade of care from illness state to illness state has to customize what the intervention for a particular step in the cascade would be, and what a realistic target would be, and it'll be different in tuberculosis than it will be in OUD. But in thinking about primary prevention, you're exactly right to mention access to prescription opioid analgesics as a very important intervention, and we've done a decent job in the past five years. The House of Medicine finally woke up and smelled the coffee. I don't know why it took so long that prescription opioid analgesics are problematic, not only in terms of their side effect profile, but also that they're not that effective for chronic pain in the first place. So that lesson learned, or re-learned, if you will, has helped quite dramatically, and you may have seen that in 2019 we did start to see a flattening of the curve, although during the pandemic in 2020 and 21 we have an uptick again, and so I don't know what that will mean for an enduring trend, but the intervention of limiting supplies has been a help. Presumably the intervention of educating people broadly in the population about the side effect profile and risks of opioids will have been a help. The pursuit of other strategies for the treatment of chronic pain, both safer but especially more effective non-opioid strategies, will be a help. Another very important strategy for prevention, perhaps better considered a secondary prevention strategy in my mind, is thinking about OUD as an advanced or more malignant stage of the broader spectrum of SUD writ large, and that is to say that most people who initiate non-medical opioids and have loss of control of non-medical opioids with progression to an opioid use disorder have had prior loss of control of a non-opioid substance. That's not 100%, that's not everybody, plenty of people in the minority who've had their first SUD as an OUD, but the majority of people have had a non-opioid SUD first, and so that suggests that a very, very critical OUD prevention strategy, and especially in young people, is identification and intervention upstream prior to initiation of OUD interventions in earlier SUDs, and for young people, that means typically nicotine, alcohol, cannabis, and so I think it's vital to think of that as a major prevention strategy as well. I don't know if that answer is helpful in answering your question. I'm sure it is. We have one more question, probably the last question we can take, given the time constraint. We are already over time, but the last question from Dr. Richard Soper is, does DEA or FDA categorize injectable buprenorphine as an opiate? Does it come under pharmacy inventory limits of opiates like SL meds, sublingual meds? So, each of these medications will have their own REMS plan, that is a risk mitigation plan, and it complicates our use and the logistics for access. We don't yet know what the REMS plan is going to be for Bruxade, because it isn't formally released, but the REMS plan for sublucade is is a little complicated. You know, you can't get it through your local pharmacy, you've got to get it through a contracted specialty pharmacy, so practitioners have to do the extra work of establishing those contracts. There will, as always, be insurance-based special prior authorization, and those will be local from place to place, from one state Medicaid program to another, from one commercial insurance program to another. Then there are the rules of how it gets delivered, and so you can only get it delivered to the address at which your DEA license is registered, so it's complicated if you work at more than one physical clinical location, because your DEA is registered at one of them, and so the medicine gets shipped to location A, but you're treating a patient at location B, that becomes a little complicated. Obviously, the reason is because people are trying to prevent diversion, but I think that becomes an impediment to patient access. I don't know the answer about inventory, whether there are strict inventory limitations, and one of the things that is complicated, though, is that you're supposed to only give the medicine to the patient for whom it was obtained. Unlike sublingual buprenorphine, in which we can have our own stock supplies and then supply them to patients as they show up, you have to order individually for the particular patient, and that so far seems to take a little bit, so you can't evaluate a patient today and start them tomorrow. It takes a little bit of time to do the ordering, do the prior off, do the shipment, etc., etc., so there are still some bugs to be worked out, and as often is the case, bureaucratic protections have unintended consequences, and in this case, I think patient access suffers.

extended-release buprenorphine formulations

efficacy

opioid use disorder

Sublocade

dosing strategies

abstinence weeks

Brixadi

sublingual buprenorphine

responder status

real-world settings

delivery processes