Okay, good afternoon, everybody. Welcome to today's AOAAM webinar on Brixotic Buprenorphine Extended Release for the Treatment of Opioid Use Disorder by Dr. Antoine Deweyhe. My name's Julie Kmic and I'll be your moderator for this session. This is the fifth of a seven hour webinar series on hot topics in the treatment of opioid use disorder and stimulant use disorders. I'd like to introduce Dr. Deweyhe, who is a professor of psychiatry and medicine, senior academic director of addiction medicine services and addiction psychiatry fellowship at Western Psychiatric Hospital of the University of Pittsburgh Medical Center and co-director of the Tobacco Treatment Services of UPMC. His areas of clinical and research expertise and interests are substance use disorders, substance use disorders co-occurring with psychiatric disorders in adults and adolescents, psychiatric disorders in individuals with HIV and hepatitis C, smoking cessation and psychosocial approaches, particularly motivational interviewing and medication trials for co-occurring disorders, opioid and stimulant use disorders. He has demonstrated a record of expertise and experience in substance use disorders and well-established record of leadership and expertise in conducting multi-site clinical trials. He has served as a principal investigator, co-investigator or consultant on studies funded by NIAAA, NIDA, NIMH, AFSP and SAMHSA and as well as pharmaceutical industries. He served as a member of the Opioid Addiction Task Force established by the U.S. District Attorney in Allegheny County and the Opioid Addiction and Recovery Task Force at the University of Pittsburgh. He's currently the vice chair of the Pittsburgh HIV Commission and a member of the physician work group on medical marijuana for the Pennsylvania Department of Health. So welcome Dr. DeWahey, I'd like to turn the session over to you. Thank you so much Dr. Cmik for this great introduction and thank you so much also to you and Judy and the whole team for inviting me to talk about this important topic, you know, in the treatment of opioid use disorders. And I'm gonna be sharing now, okay, here we go. Okay, so we're good here? Yes, yes. Okay, so I'm gonna try to really be very much mindful of really the time frame that we have and give you enough time before we finish to ask any questions, to have any kind of reflection, thoughts, have a discussion. And Dr. Cmik has been also very much really experienced obviously, I would say even more experienced than me in the treatment of opioid disorders and has been a co-investigators with us here, you know, with one of the trials that we have, one of the multi-site trial that we have and I will discuss it here in a bit, so, all right. Okay. Okay, I wanna just mention here, you know, I know it was not mentioned that no, there is my disclosures are here and just wanna make sure that I point them out here. So in terms of the learning objective, I'm gonna go through a review of the background when it comes to the extended release, you know, of formulations, you know, I'm not sure why it's really moving here. And one of the things that I, do we have the next slide here? Yeah, okay, here we go. I wanna really kind of review a little bit to give you a background and talk about the injectable buprenorphine formulations and just very briefly review the other formulations that we know, but also refocus again on BRIC-SADE, the CAM2038 and also really discuss the trials that we have that we have been using BRIC-SADE and also what the clinical implications of it in terms of also the injectable buprenorphine formulations. I mean, obviously, as you know, this is kind of very much been evolving and the BRIC-SADE was recently got the FDA clearance, let's put it this way, obviously that's gonna be really, in fact, now, you know, obviously it's gonna be available and in the studies that we have initiated as a part of the NIDA clinical trials network, in fact, it was still not approved by the FDA. So in the midst of all these really trials that we have, we now, you know, the approval has happened. Anyway, so what, in terms of the background, as you know that the buprenorphine for opioid pharmacotherapy has completely transformed the treatment of opioid use disorders, adding obviously to the repertoire of recovery toolkit and becoming like a mainstream medicine. And the formulations, which are really the injectable, the extended release formulations, they marked another milestone in the treatment of OUD. And we know very well also that when you think about it, the sustained relief, the extended release formulation, they reduce, eliminate, having a large amount of medications that people would have to take on a daily basis. Obviously, we'll talk about also the challenges related to really kind of the issues that are, that have really interfered with the adoption, the easy adoption, as you know, with early on, you know, the sublocate. And which is really kind of fascinating because obviously the sublocate was a big, you know, transformation in the toolkit of treating opioid use disorders at the same time. It was, has not been really, there were a lot of complicating factors that have interfered with really implementing it and really diffusing it, I would say. And Braeburn, you know, pharmaceuticals have developed two separate products, you know, the subcutaneous implant, you know, probiophene, you know, and obviously the extended release, the brixoline. So what are the challenges really when it comes to really the treatment of OUD? And this has been really a big problem, you know, which has really in a way generated the discussion about the importance of the extended release formulations. We know very well the poor attention rates in treatment, and we need to really figure out what can we do to keep patients in treatment, to keep them retained in care for the longest period that we could, because we know very well that they would be at any point in time very much vulnerable to going back to using. And these issues were really basically, when you think about it, were related a lot to the buprenorphine formulation, the oral formulation, sublingual, you know, the formulations of the methadone or the Vivitrol with the limited kind of utility, you know, and the other questions that we looked at in our reading at trials, and I'll discuss it a little bit more, is that what are really the factors that influence when and whether patients with OUD can safely discontinue the medication? And we know very well a lot of people who have been on buprenorphine, let's say sublingual for years and years, they kind of, at some point in time, they kind of wonder, you know, I want to get off the medication, I've been doing very well, I've been in recovery. So what is the best way to really do it? And I don't think we've had a clear answer about that. And so this is how the conversation was generated at the National Drug Abuse Treatment, the CTN, the Clinical Trials Network, and coming up with a study that looked at two phases, and I will discuss it in a bit, you know, the retention phase, called the RDD, the retention phase, and the duration discontinuation phase. So we want to really kind of, in a way, configure what we could do to really keep patients as long as we can to retain them in treatment. And for the patients who wanted to discontinue the medication, the buprenorphine, you know, what would be the best way to really do it safely and to really, what strategies you use, you know, pragmatically, and which is really, these are the answers we were looking for. Many of the CTN, the NIDA studies that have done over the course of the years, and we were involved in some of them, preceded the RDD study, and these are really the studies that have looked at buprenorphine for acute management of withdrawal, and they looked at a lot of the studies that have demonstrated that when people stop taking the medication after going through the withdrawal management, you know, that they never really, in a way, or very rarely sustain the ability to stay sober, you know, and not use any opiates. And there are a lot of them, basically, that looked at basic, also, you know, the multiple CTN studies. And so we're talking about really at least two decades of research before we came up with the idea, okay, what could we do here to really come up with like a randomized, pragmatic, prospective type of study, multi-type of study that could help us understand better the factors that play into the retaining people in treatment, as well as factors that really play in the context of the discontinuation phase. So long-term follow-up studies are so much important to focus on continuation of medications for the long-term to sustain remission, because we know from a lot of the studies that have been done for the short-term, they were really, in a sense, associated with very poor outcomes. You know, what I, let me see here if I, okay. Okay. Why don't I kind of go back here and then go back, okay, well, all right. Well, you know, the guys, as you're really familiar, you know, with the sublocate, you know, and the BRIC study, which was the CHEM 2038, you know, we know very well, I'm not gonna get into the details about the sublocate, but it was basically approved for the treatment of moderate to severe OED in patients who have initiated treatment with the transmucosal buprenorphine-containing coriolisate that has been followed by dose adjustment, I'd say seven to 10 days. And the question is that, you know, how are we doing with sublocate? Did it deliver exactly what it promised to do? And we're not quite really kind of sure about that. Obviously, there were complicating and challenging factors, but obviously, this is one of the medications that has some advantages. And here, what I wanna really mention is that we see a lot of fluctuations in patients who really, in a sense, wanna really initiate, you know, kind of move to really sublocate, but there are a lot of concerns that they would have. And these are the concerns that patients have, you know, with any sort of an extended release formulation. So, I kind of, can you see this comparison here, you know, between sublocate and prixali? But so before I go that, yeah, is it, okay. Okay, so the question is that, I mean, as you know, here, obviously, most of you are really aware, you know, of the sublocate, you know, some aspects of it, and obviously, you know, that it goes through really the differences, you know, between the sublocate and the prixali, you know, formerly known as the CAM2038. And with the sublocate, it's initiated transmucosal buprenorphine, as I mentioned, eight to 24 milligrams. But with the prixali, you know, the initiation of treatment is not already receiving buprenorphine, and we'll talk about that, or switching, in fact, from the transmucosal buprenorphine. Both of them are really subcutaneously given, you know, and the only formulation that has a weekly and a monthly, you know, schedule is basically prixali. For the sublocate, it's basically a monthly one. And the dosages, in fact, you know, with the prixali are really more and more flexible, you know, compared to the sublocate, you know, which is between 100 and 300 milligrams. The one thing is that, one I really mentioned here, that there is also, with the prixali, really the, where it can be really given subcutaneously is really, not just really the abdomen, but really, you know, the upper arm, the buttock, you know, the thigh. And so, and this is something, really, that is important to keep in mind. As I mentioned, you know, tentatively, you know, the FDA have started thinking about it. They wanted really more studies, and eventually, you know, it's been kind of clear, the FDA now. And this, these also really, the numbers that I have gave there is basically, these values, you know, are really kind of, I, you know, reflect basically the steady state concentrations, you know, compared to really the sublocate. So again, these are very important aspects because with our studies, and I'll discuss it a bit more, is that with our studies, you know, we can, we've been, in a sense, you know, with the weekly kind of, really, dosages, and I'll discuss here also the conversion aspect, which I've talked with Dr. Knick about it, that seems a bit challenging to really do, so we now take it into consideration, you know, the steady states. Okay. Okay. I don't know why I'm scrolling back here. Oh, here we go. We're at the right one here. Okay. So the, for the Brixadi, you know, as formerly known as 2038, you know, I don't know why, there is a mistake here, 2038, eight cell. And as I mentioned, you know, it's the once weekly or once monthly extended release, refilled small volume injectable buprenorphine. And so it has some kind of a really practicality here, and it uses like more a kind of a fluid crystal injection depot technology, which is really very easy to give in a way, and so it's really a low volume, lipid-based liquid with a dissolved active ingredient. And in fact, you know, when you inject and it goes into contact with the tissue fluid, the solution transforms into a nanostructure liquid crystalline gel that really effectively encapsulates the buprenorphine and releases it at a controlled and steady rate over the one week or one month's period. As the whole really formulation itself, the depot slowly biogrades in the subcutaneous tissue. And so it's really kind of very easy to administer when you really think about it, so. So again, it's the only, you know, it's the, when they looked at the phase three efficacy and safety, they evaluate the range of weekly and monthly doses, and it was really titrated to effect in a blinded fashion. And so, and Brixadi met the primary endpoint of non-inferiority, which is really crucial. I'll talk about it in our, one of our studies, which is with pregnant persons with opioid use disorders, and looking at the inferiority, whether the injection of the CAM-2038, the Brixadi, versus the sublingual, you know, because, you know, first of all, you want to make sure it's not going to be really kind of in a way performing, let's put it this way, less than the sublingual, you know, buprenorphine. But fascinatingly enough is that it met the primary endpoint of non-inferiority for responder rates versus the daily single sublingual buprenorphine naloxone, which really played a very major role in initiating one of, in giving like, in a way, more like the clearance to proceed, you know, with one of the clinical trials that we have. And this trial was include real-world patients, you know, when 26% tested positive for fentanyl prior to study randomization, 71% using heroin at study initiation, and 52% using injectable opioids at the study initiation. And the key secondary point, whether, was it superior? So that was really the question. And which is really also kind of fascinating, you know, when it demonstrated superiority to the sublingual formulation. And in, but specifically in the percent of negative opioid assessment from week four to week 24, which speaks to the importance of really continuing with the medication for some significant period of time. So again, this kind of goes back to the point that I made earlier about the, because of the poor retention rates of treatment that you would wanna really kind of continue, which gives it a lot of advantage, you know, the weekly and moving to the monthly injection. So it's the only basically injectable buprenorphine that was studied against, you know, the standard of care. And they did not see in the clinical trials any opioid overdoses on people receiving Bruxadi. And when you think about the safety profile, which is always very important to discuss with the patients, you know, too, you know, what's consistent with the known safety profile of oral buprenorphine, with, as you know, the exception of the mild to moderate injection site reaction was a lot of people, it becomes like a more, some sort of really not a serious or danger, but really uncomfortable that sometimes really in a way produces this aversive reaction after a few times when they end up, patients end up with injection site pain or really, you know, some, you know, even, you know, erythema or pruritus, or even, you know, a lot of patients, you know, would describe that they have some really bumps, you know, in their, whether they're really abdomen. So when you think about really the most common adverse reactions, which happens in close to 5% of patients, so it's kind of really very limited from our experience here with it. We have seen very limited really side effects. And the patients, you know, one, what, what patients, you know, usually report is that, that they struggled with really kind of start 3D after they moved to the monthly dose that they have some kind of an unusual symptoms, you know, that we're not quite sure whether these are withdrawal symptoms or mostly some kind of discomfort, but something that does not interfere necessarily was really the fact that, well, we want to stop reading the medications. Well, we've, we've kind of, in a sense, you know, discussed with the patient the possibility that this could really potentially happen. And, and I think this is one of the reasons why some patients, you know, are really reluctant to go on the extended release formulations in general. So the, there is an ongoing recent trials with BRIC study. The first one that I want to talk about is the MOM study, which is a CTN, the clinical trials network from 9 to 0 to 80, a pregnant woman with the OUD. So it's a pragmatic multi-site randomized trial. We have one, our site is the pregnancy recovery center at McGee hospital here in Pittsburgh, and it compared two buprenorphine formulations, which is the sublingual formulations in the CAM2038, you know, which is a BRIC study. And obviously we know very well the sublingual is efficacious with a lot of disadvantages in pregnant women. And most of what we're thinking about that were really potentially problematic is the poor adherence treatment dropout and the negative maternal and fetal effects that are associated with the peak and trough, you know, cycles of the buprenorphine. So in a sense, the CAM2038, you know, formulation, obviously addresses these challenges. And our study has been conceptualized as an inferiority study in the sense that we're, you know, want to see whether really in at least that, you know, the CAM2038 is not inferior to the sublingual buprenorphine. So we're finished basically recruitment and we're still following up. It's a long-term study. We're still following up patients, even patients after they deliver. And hopefully very soon we will have more data. In fact, you know, one of the data that we have so far is looking at also the history of, in that kind of a context, history of traumas. You know, there is a lot of obviously data, obviously you want to look at the data related to the primary objective, which is evaluating the impact of the CAM2038, again, Brixadi, compared to the buprenorphine sublingual and particularly on the maternal infant outcomes, you know, and the secondary trial objective was really looking at the mechanisms that would improve maternal infant outcomes. So we're hopeful that it's not going to be inferior to Brixadi than the extended release. And Al-Ata, you know, the patients that we've been seeing in that study, they have been tolerating very well Brixadi and that they really, we've never had any issues in a sense, you know, the patients, you know, deciding that, that said, I'm not going to continue that, you know, so rarely, you know, and then this is something obviously you can always negotiate with patients to understand the reason why they don't want to stay on the extended release formulation, you know, and once they are really randomized, obviously. And, and interestingly enough, we didn't, as I mentioned, we, we've had people tolerating it very well with no major issues. So there is the, another ongoing trial, which is the clinical trial network from NIDA, which is, I've already talked about it, the CTN-100, the retention duration and discontinuation study. And the whole point of it is optimizing retention duration and discontinuation strategies, as I have given you the rationale for that, I mean, the poor adherence treatment, dropout, and it's prospective, and again, pragmatic multi-site trial that has two phases, as I mentioned, you know, the phase of the retention and the phase of the discontinuation. And Dr. Khmik has been involved as a co-investigator in our trial. And I want to thank her for the work she's doing, you know, with us here on the study. And she's been referring also a lot of patients and seeing a lot of patients who are following up. And so the, one of the things that in terms of the retention phase, you know, is open to have patients initiating treatments and testing different doses and formulation of buprenorphine, and particularly the standard dose, high dose, and the extended release. And as I mentioned to you in the informed consent, it was really the CAMP2038, and a lot of patients have asked, you know, was it approved by the FDA? Now, you know, obviously, you know, we can tell them very clearly, it was in the process of being approved, and now it is really approved, including with that, the high doses, I'm talking about up to 32 milligrams, you know, with that, looked at the standard dose and also the extended release. And this also include as a part of really the retention phase, a digital app delivering contingency management and cognitive behavioral counseling, focusing on the primary outcome of retention and, you know, in treatment. And again, and with all NIDA studies, you know, obviously, you want to look at patients, you know, drug use, whether we have outcomes, obviously, this is really very crucial, whether people stop using or reduce their using. And at the same time, we know very well, if people would be retained in treatment as long as really possible, that the chances, you know, for them to really kind of work the recovery, you know, with all the support that they need, you know, are they going to potentially either reduce or stop using completely. But clearly, you know, the retention, the importance of the retention is a primary outcome. In terms of the discontinuation phase, these are patients who have been open, you know, it's open to the patients who are already in stable remission. For example, today, we randomized a patient who has been on buprenorphine sublingual, eight milligrams daily for a couple of years. She hasn't used any opiates and doing very well on that dose, you know, and then deciding that she's really ready at this point in time to really kind of discontinue and choosing to discontinue the medications. And in a sense, we're testing different type of tapering strategies for buprenorphine, whether with the sublingual or extended release. In fact, she ended up being randomized to the extended release to the Brixadi. And in addition to that, also a digital app that was focused on resources to promote recovery. So the key issue is, you know, that we're looking at from the discontinuation is that the effects on the primary outcome of relapse-free discontinuation of the medication. At the same time, I mean, like for example, the participant that I saw today, you know, that, you know, you look at the patient's history and everything, you know, over the course of years, even they have been really in a way exposed to different treatments, whether sublocate, whether even, you know, the oral naltrexone, you know, and even extended release, you know, naltrexone, and either like, for example, two doses here and there, like for example, sublocate, two injections and stop. So I think if we think about it as with the discontinuation phase is that to go at the patient's pace, you know, and really doing it very, very gradually and slowly. So I think this is what's been really kind of missing when we really work with patients, you know, and you know, and Dr. Tmick has been very much involved in really developing really the programs, you know, when it comes to opioid use disorder, whether in the methadone clinic or the buprenorphine clinic is that the long-term follow-up with patients and really meeting patients where they are. And so I think, you know, we need more of that kind of a sort of a culture that kind of really promote that type of approach, which unfortunately a lot of programs do not provide much of that really thinking about it. So in terms of this, again, continuing with the CTN 100, you know, so the, as I mentioned, the first phase, you know, that the focus on the maintenance, you know, patients prescribed buprenorphine or naltrexone XR. So we've had patients who have basically have been on really the extended release naltrexone and they continued with that, you know, for that they chose to continue with that. And we, on a monthly basis, you know, and what we're looking for, and I talked about the primary outcome briefly, is that we want to really achieve a minimum of six months maintenance on the medication, which when you think about it, even six months in the context of really treating a chronic medical illness like opioid use disorder might not be even enough. But again, we have, we follow patients for the long, you know, for long, long-term at the same time, a lot of these patients have been already involved in our really clinic and treatment, you know, or in the other side, which is really at mercy, you know. So, so my point here is that, you know, providing as much of that follow-up, long-term follow-up is really crucial. And for the, for the clinical approaches, as I mentioned, you know, for patients choosing buprenorphine treatment, you know, we're talking about the different doses, as I mentioned, you know, the standard dose and the extended rate and the higher dose. And, and as I mentioned also that the patients who really decide that to really stick to the Naltrexone XR will not be randomized, but they would really receive either the app that I talked about or the usual psychosocial treatment and medication management sessions. So that the, as I mentioned, and this is going to give us that pragmatic study is going to give us a better sense of more and more data, as much as we can collect to better understand really what could be done, what sort of 3D strategies in terms of medication aspect, or even which a lot of patients would stick just to the medications without really necessarily being involved in any formal psychosocial treatments. And, and we know very well, a lot of patients utilize, you know, support recovery support, you know, in different ways, but it's just the idea is that, that we want to really keep patients as long as we can in a long-term study, long-term really treatment, sorry. So, and this study really offers that and really kind of see what really, you know, what kind of a sort of a clinical implication we could really give practitioners about really the, you know, the particular strategies in terms of treatment, but also what keeps people the longest in terms of the, you know, in terms of treatment. And again, I want to be really clear here is that, you know, what they're having also multi-site study will give us also a different idea about different demographics, different places, because, you know, for example, we have a lot of patients also have polysubstance use, which is really the norm, you know, obviously there are some exclusion criteria at the same time with, in regards to some substances of use, but let's kind of keep in mind that in real world and real, you know, patients, you know, that you're going to see most likely polysubstance use. So, you have to figure out how to navigate that. In the discontinuation phase, there is no predetermined length of treatment because we work with the patient collaboratively to decide about that. You know, obviously we've had patients who moved more quickly with the discontinuation than really others. And we've seen a lot of people basically throughout that discontinuation phase, if they were to be randomized to Bruxadi, that the fear or the anxiety that they might need to really, they might need to take an additional oral, you know, sublingual, you know, buprenorphine to really hold them for that really kind of week or a month after they were discontinued. And again, that's why we work collaboratively with the patient to see how they are feeling. And so it's really kind of, when you think about it, it's really very much of a real world type of really clinical trial, you know. And the end point, obviously, is stopping the medication, not using opiates within, you know, the six months following the discontinuation. So, I, you know, I was going to, you know, mention something, you know, and I was talking with Dr. Kmic about that. Let me kind of, you know, it's about really the question of, you know, which is really a challenge, how to convert people from sublingual to Bruxadi. In fact, I left also the, under the references, the, you know, the package labeling. The package labeling basically give some kind of relative conversions from the sublingual formulation to Bruxadi. And, and one of the things that they recommend is that, you know, you start, you know, with 16 milligrams, but I'll tell you, if patients have been on even higher doses, you know, you know, 25 or 24 milligrams or 32, which we don't usually see as much, you know, but the point is, you know, that you would really, it depends on the type of population you're really dealing with, that you don't want to really give necessarily, you know, you know, bigger dose or something. And, and again, as I mentioned, you know, there's always the, the idea that you can really supplement, at least at the beginning, you know, when you're, you know, you started the conversion process, you know, with sublingual formulation. So the, you know, some patients might need two doses, three doses of that. There is also about the labeling, you know, about giving, you know, an additional like eight milligrams using the, you know, three to five days after the 16 or 24 milligrams, you know, I mean, if it's well tolerated, you know, so I think it's just a really very much of a clinical judgment on how to really approach it. And with the RDD, obviously we've seen people may need to go higher clinic and then a big part of, as I mentioned, also the anxiety about really how to approach it. And we have a lot of patients who are really kind of, in a sense, been exposed to treatments really before with medication for quite a while on and off or something. So you would want to kind of look at it as in terms of each patient, you know, like more case-based, you know, by case-based, you know, like, you know, approach. And this is kind of similar when it comes to really kind of also the switching, you know, from, you know, people are on a bigger dose, you know, like 24, 32 milligrams. And for people who have also hard time really starting the treatment, you know, I think, you know, that, you know, this type of populations, you know, you might need really much smaller, you know, obviously in terms of the dosage, you know, like you can start with the weekly up 16 milligrams, you know, and see how it goes, you know, and again, the smaller amounts of extra eight milligrams, you know, and with the, this is for the, I'm talking about the weekly, for the monthly, you know, you might want to, you know, starting with 128, you know, milligrams is kind of similar, you know, with a similar amount of really 96 milligram dosages. The issue is that in terms of the conversion, you know, and it's kind of somewhat very challenging, you know, but again, that's why you need to really take it based on each patient's profile, you know, in terms of clinically and, you know, like you continue with the weekly, you know, and obviously when you really move to the monthly, you know, then you can really kind of go off from 64 to 96, you know, if it's needed or 128, you know, for the discontinuation, obviously it would have been, you don't want to keep really kind of going up in a sense, you know, and, but I mean, but I mean, again, as I mentioned, you know, that, and this is going to really be playing a very important role in figuring out the pharmacist, how, because we've had pharmacists who just started asking, you know, here PMC, you know, what would be really the best kind of, what should we start, you know, with orders? What, what is, if you want to initiate the medication, you know, how much would you start on, you know, and so I think it's just really, in a sense, as I mentioned, you're more of a clinical judgment and, and again, it depends on really the challenges that can happen with any particular populations. So some perspectives and questions to reflect on, you know, the whole benefits, risks, and benefits and all the stuff in that we talk about in terms of the extended relief formulation, such as really Bruxadi, it depends a lot. I mean, when you talk about really, you know, the, in a way the academic detailing and who you discuss it with, whether I talk about the patient practitioners, communities, manufacturers, and, and how can we determine the profiles of patients and hopefully from the studies that we've had, you know, that we can determine some particular profile, which, you know, like what would be really, you know, in a sense, the ideal candidate as patient or not ideal necessarily, but really the candidate that would potentially be a good candidate, even, you know, would benefit from treatment with Bruxadi. So I don't think we have a, maybe Dr. McCormick could really also eventually, you know, jump in and give her perspective, but I'm not sure if there is any clear sense about that. But obviously, when you think about the patient, what the patients want, you know, we know that very well, that they want the life to be much easier to deal with, want to focus on recovery. They don't want to, you know, we had a lot of patients don't want to take any more really, you know, pills, films, you know, all this stuff. And, and it does reduce the stigma at the same time. So patients are not going to come on a regular basis, you know, to treatment, you know, let's say they've been on a monthly injection and, but they don't have much of that really contact in terms of really seeing the practitioners, therapists and everything that could, you know, in a way, lead up to some kind of concerns, you know, because patients would start feeling a little bit more isolated if they are not actively involved in their recovery. And, and also the issue of having to deal with some kind of annoying side effects as we talk about the injection site, the rotation. So they ask themselves, you know, why should I switch if I've been on, you know, medications for years and I've been stable and I've been doing well, so they question that, do so. Always discussing the risks and benefits, you know, and in terms of really waiting for some more clinical trials that tell us about, you know, superiority of outcomes. We don't have that, you know, yet in a sense, obviously from the phase three, superiority of outcome was more what they, you know, the assessment, the, you know, that I talked about in terms of, you know, the opioid use, but we don't have, you know, one of the things that is really kind of you would think about is that there is no medication diversion that so, so these are from, from really in terms of the system issues and making sure, you know, that it's covered under the insurance, you know, that you're going to have to really kind of also justify, you know, what, what made you decide, you know, Brixadi versus Reno sublocate, you know, and all this, you know, and, and I think the only question is always about, you know, it's too early to determine, you know, whether we should, you know, making a call for Brixadi, you know, and, and as I mentioned earlier, and Dr. McMick can share also her perspective and her experience, you know, with the sublocate, you know, it's been kind of really, you know, not as really navigating the implementation or the, because it's a kind of a clear innovation, you know, obviously these extended release formulations, but in terms of really the, you know, the diffusion of innovation has been always a major challenge, how to really kind of integrate it into treatment programs, you know, and, you know, I, I, across, I think there is still not much of really, it depends on the setting and, and as you know very well, also in the context of treatment programs, you know, there are still a lot of really treatment programs that are very much, you know, let's put it this way, kind of stigmatizing, you know, the fact that patients, you know, are on really medication for OUD in general, you know, and, and with a lot of really, whether practitioners or even therapists advocating for, you know, the fact that you don't want to take a drug, you know, to treat a drug problem, you know, and, and so, so again, there's still a lot of, we can't, we can't really kind of, in a way, dissociate that kind of a conversation about the extended release formulations, you know, that it's still going on, you know, even though with all the, really the advances when it comes to the buprenorphine, and I believe, you know, there is a talk on the evolution of buprenorphine, you know, which I think should be fascinating, you know, how the buprenorphine treatment has evolved over the course of the years, it's still really, the stigma is a big, big issue and you want to always figure out ways to be dismantled that, you know, and again, maybe one of the options could be, you know, that the extended release formulation such as Bruxade could really, could really potentially have some sort of a positive impact, but I mean, still not totally, we still kind of should not really, in a sense, really let go of the fact that we have great medications that could potentially work. The question is, and as you know, particularly with the extended release formulation, Bruxade, you know, until we have more and more of really the outcomes, you know, is that how, how are we going to implement it more and more into programs, you know, how can we decide, you know, to really go with, you know, sublocate versus Bruxade, you know, and as you know very well, I've talked about the whole other extended release buprenorphine, you know, is that obviously it requires a lot of the training and the whole implants and all the stuff, so, which is really kind of obviously much more really complicated from that aspect, so. I think that's it, you know, and I have some of the references there, you know, and I put also the the labeling back here, just, you need any more information, you know, about any particular, you know, area, you know, then we can definitely, I told Dr. Cmick, I can send that, you know. Thank you very much. Thanks for listening. Yeah, thank you so much. We do have some questions. I wanted to get through here. So, one of the questions was revolving around the MOMS study, and it was a statement that they would have thought it would be important to increase the buprenorphine dose during pregnancy due to the increased blood volume. So, was that something that happened during the MOMS? Were you able to increase? You know, yeah, we have some flexibility with that, yes. We do have some flexibility because we realized particularly, you know, with the elimination that can be really happening more quickly, yes. The challenge is, you know, that, you know, with obviously, if they were to be, if the patients would be randomized into really the extended release, you know, then you can have some kind of really, in a way, flexibility in terms of the dosage thing, you know, because one of the things that we've experienced, the MOMS, is that a lot of really also patients, you know, once they really move after the weekly, you know, to the monthly, you know, is that they might, you might want to cut shorter than the monthly, you know, like maybe three weeks to really avoid potentially having some kind of, you know, withdrawal-like symptoms or, but yes, we, there is some flexibility with that, yeah. Because, I mean, this is the real world. Also, you're seeing, you know, patients, you know, that you don't want to be kind of rigid about really how the approach, I mean, you know, the whole point of it is that also, as I mentioned, the outcome on the maternal infant, you know, which we follow through, you know, very, you know, very closely, you know, and yeah. Hi. Somebody also wondered if you ever supplement with sublingual buprenorphine while they're on the BricsANU shot. I'm sorry, say it again, I couldn't hear you. Do you ever supplement with sublingual buprenorphine when they're on the BricsANU? Well, we could, yes, we could, yes, yes, and we've done with a few people, yes, with the, yes. Well, because, you know, now when you think about it, also, we know traditionally it's been like more, you know, the, you know, the treatment has been, you know, with, you know, the monoformulation, but yes, we kind of really, you know, can really definitely, and we've, you know, and we kind of tell patients, you know, more like, you know, you know, in a sense, based on, like we, like patient, it's customized to the patient's, you know, kind of a context, you know, in terms of a few doses here and there, or something which, which we believe, you know, would not necessarily interfere, you know, with, you know, with the holes, you know, with potentially the outcomes that we're talking about. Oh, would you be able to use Brixadi in patients for chronic pain management? Oh, that's a very good question. I don't know if I have, well, you know, if, if there is a chronic pain, you know, I'm, I'm not quite sure how you can, the dosing, the, you know, the aspect or I don't know, theoretically, I mean, you're talking about chronic pain without opioid use or like with the history of opioid use disorder or. You know, they mentioned just with chronic pain, I would think with opioid use disorder for sure. Yes, but like a chronic pain with, no, I am not sure separately for chronic pain. I, I'm not aware of any, I'm not, I'm, I don't know. I mean, but I can definitely, you know, I'm trying to think, you know, if it's been looked at at all or whether they probably assess during the treatment of the opioid during, you know, really the opioid use disorder. And we're going to have some data from our study on that part, you know, that people who have been treated for chronic pain, but whether also, I'm not sure if there's going to be some really looking at potentially secondary outcomes in terms of how really being on Brixadi for the opioid use disorders and people who have the co-occurring chronic pain, you know, would potentially work, you know, or not. I'm not sure. There's a few questions about like the dosing. Do you mind if I just share my screen so I could just. Yeah. Okay. Sure. Yeah. Okay. You want to stop sharing? I think I stopped it. Okay. That's good. Okay. So you're seeing patient selection cropped on the screen. I'm sorry. It says patient selection on the screen. No, you're not sharing right now. No, no. That's why maybe I should stop it here myself. Oh, I know. Try to share now. Got it. And now it's like a bunch of my slides. Okay. Good. Okay. Now you see patients. Yeah, we can sign them. Thank you. Thank you. So this is just some of the information about how you would start somebody. So for weekly people only have to tolerate four milligram dose to start it. And then, or if somebody is already on transmucosal buprenorphine, you could start them monthly. You can only start people who've been on transmucosal or on weekly injections. So somebody was asking, I think about like dosing and everything. So let's say somebody is not on buprenorphine. You would give them that test dose of four milligrams just to make sure they don't have precipitate withdrawal. And then they'd get that 16 milligram injection for the weekly. And then after that, let's say three days later, the complaining that they're really symptomatic still given another eight milligram injection. So their weekly dose is 24. And then let's say they're complaining about that withdrawal again, or severe cravings. You can give them another eight milligrams for that total of 32 in that first week, but you have to wait at least 24 hours after the last injection. And this is what I think you were talking about too, about like how you would start somebody with the daily doses with their corresponding. So I think this is a question that was in the chat here. I'm wondering about like what they're on. Yeah. Sublingual. So you can see this table. If you're starting on the weekly, what corresponds here and if you're going to give them monthly. But of course with monthly, as we talked about, they have to be on the transmucosal more than just like that one four milligram test dose. And then let's say you want to go between weekly to monthly. The corresponding slides. And then a couple of things that I was thinking about while you were talking to you is that syringe is a little bit different than the, somebody had asked, is it 0.5 and 1.5 for the volume? It's different for each dose, but the syringe is different as well. And we've noticed in the study that patients tolerate this injection a lot better that it doesn't burn. So I have patients who, you know, want to ice or they want some, I've heard other people have given like some lidocaine injection around the spot where they might give the sublocade shot, but this one burns maybe for two seconds at the most, if at all from the patients that we've given it to. And it has a little bit different syringe. You have to put the plunger in and screw it in and then you inject it perpendicular. And then to the, to the, um, and then the guard takes the syringe back. So, um, it's pretty easy to administer. I've given it a few times and it's pretty simple. And these are the spots you can administer it. Now, somebody had asked a question about the arms. They had asked why you just, um, it's only after four doses. I think it says the package insert says that people should only get it in the arm after four consecutive doses. Yeah. And you can alternate basically. And, uh, you don't want to give it at the same place, you know, and I think somebody asked about the, for the refrigeration to, you know, no, it does not require to be refrigerated. Right. Now there's a question in here that says the package insert states that patients on Brixadi should only receive it in the upper arm after four consecutive doses. Do you know the reasoning behind this? Um, I'm trying to remember, you know, because we, uh, because we alternate, we don't usually give, and I'm not quite sure what's the reasoning behind that. Did they, I'm trying to remember. If we haven't in the RDD study, we haven't, that's not a site that we're giving the shot to. Um, and I can't remember the rationale as to why that we've been doing it in the abdomen and then in the thigh. This is what we've been alternate. Yes. Correct. That's the best spots. You know, one of the things that you mentioned about the burning sensation, uh, which is really can happen for like maybe less than a minute or something, you know, I mean, obviously it can be a little bit of a turnoff for a lot of people. It's like, Oh God, you know, this is really, but it's not really, again, it's not really significant. People really forget about it very quickly in a way. Yeah. Um, we do have a comment in here. It says, I think that the confusion about the initiation strategy will be a major barrier versus supplicate, which has only one initiation strategy. The sublingual lead-in versus extended release at the outset, weekly versus monthly, starting higher and titrating down versus titrating up, risking long period of subtherapeutic doses, et cetera. That's one of the comments from one of our participants here. Do you have any, any further thoughts on that? I think that's, so the question is, you know, uh, when I really kind of, because I, it seems like basically, you know, supplicate, you give 300, 300, then you go down to a hundred. Correct. Yeah. 300. This one, you can, you know, you got, if somebody is not on anything, you give them four milligrams, then you can give them the 16, the eight. Exactly. Yeah. And so it's a little bit more of a confusing schema or doing the 16 milligrams weekly for a while, then getting them on to the monthly or going from monthly to weekly. Um, I think the, the comment is just like, it's a little bit more confusing, so there might not be as well. I think it just, I think it offers also some flexibility. You're right. There is some kind of confusion about it. I think, you know, at the same time, that's why, you know, it has to be reading more case by case, you know, in terms of, you know, how you could really navigate the, the, you know, the dosage, you know, and, uh, I think, you know, that's, that's why, you know, obviously the study, you know, the RDD and even this, I mean, the, uh, this continuation phase, as well as the retention phase will give us better idea of what would be, what sort of a strategy, strategy, you know, would be the best, you know, to approach that kind of really a challenge, you know, so yeah, but that's really very good question, you know. I think part of it too is, um, the nice thing about like those lower doses and weekly and stuff like that is if you do have somebody that wants to come off, that could be a strategy that's good and find out more with the discontinuation study. Somebody had asked about the MOM study, is it just weekly formulation that was being tested or were they on a monthly? Well, it's both basically. Okay. Um, let's see. Since we use buprenorphine for pain in the buccal and transdermal formulations, I would imagine we could use it in the injectable formulation as Bruxade. However, are there very specific handling requirements for it similar to sublocade? And does the DEA require a specific process be followed similar to sublocade? Is there a REMS program is basically what I believe is being asked here. And I think there was a question about 3D, basically the insurance aspect, you know, obviously, you know, we're going to see how this is going to evolve. Now it's been approved by the FDA, you know, what, you know, how, I think we're going to need to really kind of, in a sense, you know, justify what are the advantages. I mean, this is what we always do, you know, with different kind of, you know, medications that, you know, are really FDA approved, you know, it's like, it's going to be something that we need to look to really kind of see how it's going to evolve. But we started, obviously, you know, we need to really kind of make sure, you know, that the process in terms of how do we get, you know, which pharmacies, you know, to reach out to, you know, and our system basically here, you know, the UPMC, you know, is going to need to really basically intervene, you know, to help, as I mentioned earlier, with the dissemination of it, you know, I mean, obviously, you know, that practitioners would need to really have more experience with that, you know, so. Yeah, I think, so, as far as one of the differences, too, this doesn't have to be refrigerated, but if you are going to have it in your office stored, you're going to have to do the same kind of procedures, and there will be a REMS, too, I'm sure, where you can't give it directly to a patient, there is a REMS, actually, so it can't be handed to the patient. Yeah, yeah, we get it from the, when the patient is randomized to it, we get it from the pharmacy directly and do it, yes. Yeah, okay. But it's got to be also another tricky, you know, technical, logistical aspect, you know, and. Yeah, okay. Well, we are right on the six o'clock hour, so I think we're going to wrap up for today, and I just wanted to thank you, Dr. Dwehi, for presenting on the BRICSANI and the studies that you've been involved in, it's been very enlightening, and hopefully, you know, we'll see this being used in clinical practice. I do have some patients that I know are interested in it because of, they don't like the burn that they get with the sublocate, so they're looking forward to this one. But, but yeah, it's great to have another agent that we can use for patients, the more the better, I think. So, this is going to conclude today's webinar. Please complete the survey on the AOA education page where you registered for the webinar to get your CME credits, and our next webinar is on Wednesday, September 20th at five o'clock eastern, and we have Dr. Brad Stein speaking on the evolution of buprenorphine prescribing practices and efforts to increase MOUD access. So, again, thank you, everybody, for joining us, and thank you to Dr. Dwehi. Thank you. Thank you, Dr. Dwehi, thank you, everybody, for joining us, and thank you for inviting me. All right, take care.

Brixadi

extended-release formulation

buprenorphine

opioid use disorder

medication burden

improved retention

MOM study

pregnant women

CTN-100 study

dosing and administration