Indivior Pharmaceuticals, Inc. (INDV) Earnings Call Transcript & Summary

That's a great question. I'd ask Richard, why don't you go ahead and share the mic with Christian, who understands completely kind of the adverse event profile. He has the call center that manages those as they come in. So Christian, could you talk to those?

Yes, we currently have a really good safety profile. The only thing that you see at the beginning of treatment are some injection site reactions, which is complete for an injectable of that sort. But these original side effects are actually resuming over time, so significantly decreasing all the time. So there is certainly no drive there to stop treatment due to an inside effect. We have a very, very safe profile.

I think the other thing to remember, [indiscernible] is these are not patients who are typically needle naive, right? Just based on the nature of the disease space in which they've been engaged. So while there are some minor adverse events early on, they're not a barrier to treatment typically. Any other questions before we take a 15-minute break? Up there, we got James back.

Two follow-ups, if I can. The more than $1.5 billion, how much do you need to spend on further education and how material is that? My understanding is sometimes patients don't want to take SUBLOCADE, they worry is soon to work. So they're kind of used to having that kind of day check and if they don't, they're worried to my relapse, but then they get a positive experience afterwards. And my second question is, can you give us a feel on how much of that will be the USD 1.5 billion versus and rest of the world. Just given the fact you talked about, I think, 36 countries [indiscernible] SUBLOCADE how material that could be as we look out over the horizon as well.

Thanks, James. I think the education is a key. I think it's built into the base assumptions that we'll talk in the operating model that Ryan will provide some more granularity that really robust unmatched scientific generation that Christian has, his team, both the R&D team and the medical team take that to disease state conferences really educate with regards to those the papers that are put out. And then, of course, the medical science liaisons whose job it is in a very compliant fashion to engage on the new breakthrough science in the disease space. So there is a big component of it because this science is transformational, but it's built into the base. I think your second question was with regards to the U.S. versus rest of world. Richard, do you want to talk through that?

Yes, certainly. So I think the numbers you saw there really were predominantly the U.S. I think the rest of world is a great opportunity. But as we highlighted earlier, U.S. really is where the majority of the opportunity sits. So the $1.5 billion really is driven by the U.S.

And I think for us, it's the rest of the world is just increased confidence on why we say it's greater than $1.5 billion. All right. With that, it's 10:11. Jason, how long would you like to break for?

[indiscernible] get back there.

Okay. So 10:30 then. Thank you, everyone. [Break]

Good morning. My name is Glenn Tyson, and I'm Senior Vice President of Sales and Marketing. I'm here today to talk about PERSERIS, I'm happy to do it. PERSERIS represents a meaningfully differentiated product in the category, and we believe that it represents a meaningful diversification opportunity for the company. PERSERIS is targeted to achieve $200 million to $300 million of net revenue at peak. We believe in this potential, we're going to talk today a little bit about why we're so confident in that. It comes in 3 areas that we're going to talk about. One is that it's attractive growing dynamic market. Two is that we are leveraging a highly differentiated product profile, that provides real benefits to patients and the clinicians that treat them. And lastly, we'll be diving into a little bit around the executional excellence, which really gives us the confidence of where we are today and why we believe that we'll be able to achieve the $200 million to $300 million net revenue. First, let's talk about the market. For those of you that are aware, every market entrant that has come into the long-acting injectable market has helped to drive up the growth -- the rate of growth within the market. You can see over the last 20 years or so, all of the products that have come in to the long-acting injectables for the treatment of schizophrenia. And each one, as it's come in, has also contributed to the growth. You can see that when PERSERIS came in and the growth continues there, we believe that the growth will continue. And we'll talk about some of the reasons why in a few moments. The 5-year CAGR is about 18%. And excuse me, 15% and that's representative partially due to volume and partially due to value. That being said, with the market growth and now approaching almost $5 billion. It is still a very low penetration rate. So what we mean by that is the number of patients or the percentage of patients with schizophrenia that would be appropriate for long-acting injectables and therapeutic that are on a long-acting injectable is only about 18%, and that's calculated based upon patient months and the units that we see in the market. So there still is great room for penetration here and another reason to believe in the category. It is not a generic market at all at this point, all the products that are in the long-acting injectable space are branded. The market is divided largely into 2 molecules. I'll talk about the differences here in a second. First is the risperidone, paliperidone side of the house. Why do we group those together was because paliperidone is the active metabolite of risperidone. So in the case of PERSERIS, which has risperidone as the active after metabolism, it breaks down into paliperidone and risperidone. So paliperidone is the active metabolite of risperidone. And therefore, we categorize the products that have that as the active in the same bucket. So risperidone paliperidone and the aripiprazole patient is also there. What's the difference between the two? Well, they're both effective medicines for the treatment of schizophrenia. But there are different aspects of the medications that are attractive to the clinicians who are trying to treat, let's say, the positive symptoms of schizophrenia. What are the positive symptoms on. Those are the ones that you would most commonly associated with schizophrenia, that being hallucinations, delusions, paranoia, those are the things of positive symptoms, it schizophrenia that are most well treated by Respira. That's what's understood in the market, and you can see that in the way that's utilized. And that is why you see that the risperidone, paliperidone side of it is a larger share. So within that side, there are a fair amount of competitors. We are [ 6 ] to market. We allege our brand in this space. So we're certainly not the market leader. We're a challenger brand. There are well-established products on this side. And you can see them there, [indiscernible] in the INVEGA family. And on the aripiprazole side, there are 2 products there. It is Abilify Maintena and ARISTADA. PERSERIS is competing in the overall market, but you can see here that it's advantageous that we're in the larger side of the market, where we have clear differentiation between the products that exist -- and we'll get into that differentiation shortly. Another attractive part of our story here is really that in the 1-month LAI category. So you could ask the -- what's happening with the various different durations of treatment for some of the other LAIs. But the 1-month LAI portion of the market is the lion's share of it and growing. In 2015, once-monthly, long-acting injectable schizophrenia accounted for 68% of the market. And today, it's 84%. It's really important that we understand the patient. I think at Indivior that is really, really high in our radar to deeply understand the patient insight, the patient journey when thinking about how we translate the needs and the challenges there to a pharmacokinetic solution in the form of medicines, which is exactly what we've done both in the case of SUBLOCADE and PERSERIS. This schizophrenia, the life of a patient with schizophrenia is tough. Starting at age between 18 and 23 when the initial diagnosis is made, there is characterized by periods of stability and instability that go on throughout their life. As they age and they get into later part of the life, some of these symptoms abate. But during the majority of the life they are faced with periods of futility and instability. Instability, I'll refer to you, [indiscernible] refer to it as a psychotode or as a decompensation episode until you hear those terms throughout the presentation. But when they decompensate and those are the red dots on the screen there. When they do compensate what does that mean? Well, they usually end up in an emergency room, or they'll let end up being picked up by the police, someone that's ranting and raving down in the street corner, threatening people. That is when they're in a decompensated state where they're actively psychotic. At that moment in time, when they're actively psychotic, the needs of that patient are to achieve stability quickly, achieve stability quickly, get them stabilized, usually in a hospital stay of 5 to 7 days, get them stabilized and then send them back out the door into their living arrangements, which many times are a residential situation supervised or they may be the adult child who's disabled, living with their parents. But that gaining stability quickly is super important. And one of the characteristics of the disease that really mitigates against their stability is actually part of the disease, which about 80% of patients with schizophrenia have, and that's what's known as an anosognosia. Anosognosia, simply means a lack of insight. So as an example, for those of you in the audience who have -- you have a medication that you're on, maybe you're on with the tour, maybe take something for blood pressure. Well, we have garden variety here. And so you forget to take it, you've gone on vacation forgot them sitting on you, that's garden variety not adhere. We all suffer from that. But patients with schizophrenia, because of this lack of insight, they'll believe that they're cured when they're on their medication, so they stop taking it. Or they believe they're being poised perhaps by their clinicians, so they'll stop taking it. They'll not show up for appointments. And that characteristic of the disease makes nonadherence in this category for these patients far worse of an issue than it is for many other categories. Because when they don't take their medicine, they end up where one of those red dots are. They decompensate at some point and they're back usually hospitalized or in some type of a highly supervised setting. So the objective for treatment in this category is to maintain stability, maintain stability -- achieve it quickly and maintain stability. PERSERIS, as you'll learn, is really well suited for this opportunity. Because of the nature of its pharmacokinetic profile, as we'll get into in a moment, it's really well suited for the opportunity. But it's important to keep in mind the objective of treatment here, which are number one, maintain -- gain stability quickly and then maintain it over the longest period of time possible for these patients. The antipsychotic market is highly dynamic. It's highly dynamic because these patients have real challenges with adherence. So when the patient re-presents to a clinician, they're in need of treatment change, right? They've gone off their medication or the medication potentially wasn't working for them. But in either case, they're in need of a treatment change. And this is some market research that we conducted. And you can see that when clinicians are surveyed, they say that within the next 6 months, the vast majority of their patients are likely to need a treatment change. See, the slightly likely, it's 24%; somewhat likely, 21%; and very likely, 17%. So there's a high level of understanding within the clinicians that treat in this space that patients are going to have challenges and they're going to need to consider a treatment change. Whether that means they've gone off their meds or the medication they have is not sufficiently working to manage the symptoms. So keeping on the theme of the dynamism in this market. Let's just take a look at what that means in terms of how it translates to prescriptions. The new prescription portion of the overall market represents almost 1 million patients a year, 1 million patient year. It's 42% of the total market, 1 million prescriptions a year, rather. So that means that every single one of those times that the patient -- the new prescriptions written is an opportunity for treatment change. And the clinicians are considering those treatment changes based upon the attributes of the products that they see, matching it up to the concerns that they have with their patients, keeping in mind here that many of these patients have been decompensated because of the lack of insight and the fact that what's presenting then are the positive symptoms of schizophrenia, the hallucinations, the delusions and the paranoia. In fact, if you talk to a parent of an adult child who lives with them, they'll tell them they know when their son is decompensating because they disappear. They stop bathing, they stop having any kind of contact because they're super paranoid and they'll be in a closet in their room or they'll disappear out the door and be living under a bridge. That's what happens with these patients, and therefore, they really have to be sensitive and clinicians are sensitive to seeing the signs of when a patient is in need of treatment change. So the new prescription part of the market is large. We also know that when it comes to PERSERIS, where we're sourcing our patients from, we're sourcing a patient 65% from orals, so that's no surprise, right? 65% from orals because the oral patients -- the patients that are on just oral medications are many times nonadherent. So many of the patients that are coming to PERSERIS are coming from orals and that's characteristic in the market as well. But there's also a fair amount that are coming from other long-acting injectables and again, for various reasons. All products in this category work, right? I think at the end of the day, we're not casting aspersions on the competition. What we're saying is that there's limitations in some of these other products. And when the patient comes in and they're in need of treatment change because they're getting breakthrough symptoms or they've decompensated, it's time to do that, and that's when it's time to consider PERSERIS. And it's in that moment that our sales team is out there trying to talk to doctors to help them understand the unique product attributes of PERSERIS that really can help in that specific instance. Lastly, on this slide, what we're starting to see is what you would hope to see is that clinicians that have experience with PERSERIS, use it more, right? So they're starting to see a significant share increase for the clinicians that use PERSERIS. So when you look at the 3 bars that are here, I know it's kind of small type and probably even hard to read, but the left-hand bar, the 1%, that's our new prescription share, NRx share. The 2.5% is the NBRx share, the new-to-brand share. And then the 6.3% is the market share of the new Rx market share within the clinicians that are -- have used PERSERIS. So you're starting to see more of a pickup in the clinicians that have used it because they're gaining experience. So our challenge then becomes how do we gain more clinicians to trial it? We'll talk a little bit about where we are exactly with that in a moment. So once we do get in front of a clinician, it's all about the differentiated product profile. Why would they care, right? They have 5 other products, 6 other products out there. Why do they care about PERSERIS? And that's what our story is. That's what really gives us confidence because what we know about the product profile and how it really can meet the needs of the patients in this category. It's a compelling value proposition and it really aligns well with the challenges that we've talked about so far in this presentation. And we believe that when there's no time to waste, it's time for PERSERIS, that is kind of our core selling message, if you will. It's really about that in that moment, when that patient is decompensated and you need a treatment change, you should choose PERSERIS. Our clinical trial design, our Phase III trial, was designed just like that. We had patients who were recently decompensated and then they were put on PERSERIS in the beginning of the trial. So we have a strong claim as to why our PERSERIS is effective there. It's effective there because it's got the molecule of choice for treating these symptoms and because we know that it's -- there's a number of product attributes that really make it attractive for the clinical to use there. Number one is it's subcutaneous. It's the only subcutaneous long-acting injectable in the space. What does that mean? That means that it can be potentially less painful because you're not sticking off a long needle into the muscle. All of the other products in the category are intramuscular injections. It's got an innovative delivery system where it delivers an initial peak plasma concentration in 4 to 6 hours. So you're getting clinically relevant levels on day one. It's designed to reach and maintain target D2 receptor occupancy, dopamine receptor occupancy levels, on that first -- once it receives the plasma concentrations. And what's important about that? Well, the most important thing here is not the dose that you select. It's the choice of your medicine that achieves the target plasma concentrations of dopamine D2 receptor plasma concentration. In this case, in the case of SUBLOCADE, the objective there is to achieve greater than 2 ng/mL with a 70% to 90% mu receptor occupancy. In the case of PERSERIS, the objective is to achieve a 60% to 80% D2 receptor occupancy, because in the disease of schizophrenia, it's not about agonizing, it's not about creating more dopamine. It's about antagonizing the receptor and creating less because there's too much circulating dopamine. That's the theory. And that's the objective here, is to achieve that target plasma concentration of 60% to 80% D2 receptor occupancy. So we don't talk a lot about the dose so much as we talk about the target plasma concentration we're trying to achieve that result, and our clinical trials bore that out. In our clinical trials, we treated a markedly severe patient population, a markedly severe patient population who were exacerbated and we gave them PERSERIS, and we have substantial efficacy results to show for it. So once it's reached and maintain those target dopamine -- that's what you want to do, make sure that it maintain it for the entire month. And again, that's what PERSERIS does. A unique attribute -- another unique attribute of PERSERIS that there's no loading dose or supplemental -- or oral supplementation required. What does that mean? Well, all of the products in the category require oral supplementation or some sort of loading dose, which you'll see in a moment. And then it's really important that it's a safe product, right? So it's a balance of safety and efficacy, this is a known molecule. This is a known molecule. It -- and it's great to know just like with SUBLOCADE, the systemic safety profile is consistent with the known safety profile of oral buprenorphine -- in this case, systemic safety profile is consistent with the known safety profile of oral risperidone. The only other safety issues that -- or the side effects you may have is, as was already alluded to, basically injection site reaction. You would get that with any long-acting injectable. So just to summarize. It achieves and maintains therapeutic plasma concentrations for the entire month. D2 plasma concentrations of 60% to 80%. Product profile that delivers rapid and sustained target concentrations. Significant efficacy against therapeutic targets of interest. What does that mean? Well, we're trying to effect a positive effect on these symptoms of -- the positive symptoms we've discussed, and this favorable risk-benefit profile. Let's talk a little bit about that differentiation. So -- that I mentioned. The PK profile offers unique benefits. What you see here on the first line at the top there is PERSERIS on a weekly basis, what's required in terms of initiation with the product? And the answer to that is nothing is required. You get the initiation of the product without oral supplementation or loading doses are recommended. Whereas every other product in the category requires some form of oral supplementation or a loading dose. And again, it's not to say those products don't work, right? We're not saying that here. What we are saying that this may present a unique advantage when it comes to choosing PERSERIS because you do not have the burden of having to have the patient who already is nonadherent taking oral supplementation while they're trying to get to the appropriate plasma concentrations with the long-acting injectable that you just gave. So we see this as a distinct advantage of PERSERIS. It's the only product in the category that can make this claim. Sorry, the buttons are hard to see. So it meets key LAI initiation needs. I think that's what we've already discussed. When we surveyed HCPs about the unique LAI challenges they have, that it's critical to achieve plasma concentrations early, simplifying the LAI initiation regimen could lead to better outcomes for their patients. And the need for oral supplementation for LAIs is significant burden. So there's wide agreement when we survey our target clinicians about this. And these are areas where PERSERIS really has a distinct advantage. So these differentiated messages we put into our materials, and these are the ones that are seen as most motivating. And when we tested these materials with clinicians, we could see that this drove a high likelihood to prescribe, a high likelihood to prescribe. So you can see, 76% likely to prescribe, and you can see the data represented on the right-hand side. So just to summarize here. We have a differentiated product profile. Again, we're a challenger brand, right? We're not the first to market; we're the sixth. We're a challenger brand in the space. And so the way you need to cut through is to deliver a differentiated message and that's what we believe we have here. It is not just because we've made up some marketing messages that sound nice. Because they are absolutely linked to the pharmacokinetic profile and the scientific underpinning of the rationale for the disease to treat the disease with an LAI. So that is just down to execution, right? That is just down to execution. You say, Glenn, if this is true, when you have such a great product, then why aren't you already at 20 share? Well, we'll talk a little bit about that here, like we're making some great progress. And we can see the fruits of our labor coming out in the way that it is translating into our results we are seeing. We'll talk about that now. For those of you that are aware, we did have a targeted launch, or a regional launch, in the beginning of 2019, February or March 2019 with a small sales force. And we launched that, and we can see that we're already starting to get some good uptake and then COVID hit. Now COVID hit disproportionately -- that disproportionately affected this disease space because if you just think about the offices that these patients are being treated in, so just envision this. Let's say all of you are in the waiting room at the office and the office is 1/3 of the size of this room. That's what an office looks like -- a very busy office with treating seriously and persistently mentally ill patients. And so they had to slow the flow of patients coming through that office and move to much more of a telemedicine model. And patient volumes were managed that way. Imagine then you try to launch a new product and get face time with the clinician, who now is in telemedicine or doesn't have time for you because their schedule is so replete with all the patients they have to see in this really -- a considered manner. And COVID restrictions are in place. So if you're trying to launch a product in that environment, it can be challenging. And so we see that reflected in the results that happened during the COVID period. And as we started to come out of the COVID period, we made the decision to expand the team, and that's what we did, more than double the size of the commercial presence to a national footprint with the objective meaning to cover more of the market, and you can see that there, and cover more of the volume. And as a result, we're starting to see the uptick. We still have some COVID restrictions in place -- at the beginning of this year. So we believe now we're starting to gain the traction that we hope we're getting that, but we believe we're getting that back on track to what we expected. And that's why we are confident in achieving the $200 million, $300 million peak net revenue. So understanding that we -- it's one thing to know who the physicians are, who we need to go to. It's another thing to understand and kind of disaggregate the treatment model, understanding exactly where the ecosystem, what it looks like and where to weigh in. So just again, giving us confidence here in achieving our expectations is really around understanding this marketplace. It's a different ecosystem slightly than what you've heard about earlier with SUBLOCADE. It's a different ecosystem. Here, you have a lot more inpatient hospitalization versus, say, residential treatment centers, because these patients as already described, once they decompensate, that's where they end up. So they come in the hospital. They may go to a crisis stabilization unit, which is a lower level of care, but patients can still be admitted there directly. And then they go back to their group home setting, they may be getting outpatient services from a different provider or they're going to an Assertive Community Treatment program. But ACT programs are federally funded programs designed to help patients with serious and persistent mental illness. So many of these patients end up flowing through these types of facilities. So understanding this and then putting the right commercial model in place to address it, is what we've done. We have some of our -- the team that's in place are institutional specialists designed to go to those nonretail the hospital and the crisis stabilization units. And we have the clinical specialists that are calling on the clinicians in all of these locations as well. So that's the commercial model that we have in place and that we've deployed with the expansion at the beginning of this year. So we have the understanding of the market. We have an understanding of our profile. We put those materials into a compelling story. And then is our team actually delivering it? Well, I'm happy to say that when we use IQVIA brand impact to help us understand exactly what's being said within offices, so this is third-party market research that's conducted on a monthly basis. And what we can see is that on average minutes per detail, percentage of calls with compelling close and commitment to action, primary message differentiation and primary message is relevant to the patients that I treat, on all of those vectors, our team is leading the market according to this market research. So a very positive result for us, been giving us, again, faith and confidence in all the hard work that we put into preparing the team, understanding the market, understanding the needs of the patient and that we would then deploy that in a way that would be effective. So as we've already discussed, this market is large and dynamic in terms of the prescriptions that are generated. This just gives you a sense of the patient population. Now this is not a growing market in the sense that we're going to see rapid increases in the number of patients with schizophrenia because over time, it's always about 1% of the market. So as population grows, so too will the patients with schizophrenia, but it's about 2.8 million patients with schizophrenia in the United States. There's about 60% to 80% patients in treatment as reflected here and the number of patients that are on LAIs. But again, it's about market penetration. And I think that there's a huge opportunity that continues to be here as we move forward. So we're confident in delivering the $200 million to $300 million peak net revenue for the reasons as discussed, we are delivering the -- understanding the top 5 drivers of prescribing. We're delivering a compelling message that has a differentiated product attributes that are seen as valuable to the clinicians as well as patients. Once they understand them and hear them with a right level of frequency -- so it's getting to those customers, as we're doing, and we're seeing more and more of that now. And one of the thing I'd like to say is that our retention of HCPs, once they've written, is also very high. So not only once we get to them that they start to prescribe it, then we're retaining clinicians month-over-month, which I think is really important. So what are the building blocks that get us there? We talked about our confidence in why we think we can get there with the product profile and the attractiveness within this growing market. But the building blocks that we're sharing with you today are 4 areas that we're looking at. The number of HCPs writing. This is where we are today, and this is what we believe is required -- will be required at peak. The number of Rx per HCP. It's 15 today and 36 at peak. The TRx market share. So right now, we're at that 1% we talked about, and we need about 7.5% at current market growth rates to achieve the midpoint by the way, of our $200 million to $300 million target. And then the annual number of patients, growing from the 5,400 that we have today to 40,000 at peak. So in summary, PERSERIS represents an attractive long-term growth opportunity, both in terms of being differentiated in the market and providing us with a diversification opportunity within the U.S. It's growing branded market with 15% CAGR year-over-year -- or in the last 5 years, and it's a branded market. As I said, there are no generics in there as of yet. PERSERIS has significant differentiation that is meaningful to our customers and to patients and meeting the real needs of the patients in their understanding of their patient journey. And we're delivering with commercial excellence, as outlined by some of the market research that we shared with you today. We're mapping to the existing dynamics of the market and we put a commercial model together to address them. And the path to achieving sales objective is clear; the expanded team is now in place and settled in this year. So we believe that as we move forward into next year, we'll only continue to have the type of success we've just started to see as we've gotten through this year. And with that, I thank you very much for your time and turn it over to Christian.

Good morning. My name is Christian Heidbreder, I'm the Chief Scientific Officer at Indivior. And the objective of my presentation today is fivefold. First, I would like to introduce you to our R&D organization as well as the medical affairs and safety organization, our philosophy and the vision, strategic focus and the current pipeline. Second, I will take you through some of our key projects to actually create and disseminate new evidence in support of SUBLOCADE as a treatment of choice for opioid use disorder. Third, I will remind you of the scientific foundations of PERSERIS. Fourth, I will review our current pipeline, starting with AEF0117, in partnership with Aelis Farma for the treatment of cannabis use disorder. INDV-2000, which is aiming at becoming the first nonopioid medication for the treatment of opioid use disorder, in partnership with C4X Discovery. And INDV-1000, in partnership with Addex Therapeutics, for the treatment of alcohol use disorder. And last, I will share with you how we are currently identifying key receptor systems and potential drug targets in large-scale neural networks to prepare the medications of tomorrow and further grow our pipeline. So let me start with the first part, an introduction to Indivior R&D and medical affairs and safety. As you can see, we currently have 108 employees in the research and development organization split into 4 main functions: Chemistry,Manufacturing & Controls; Global Medicines Development, including all nonclinical and clinical aspects of drug development; Global Project & Portfolio management and the last but not least, Global Regulatory Affairs. We also do have 79 employees in the medical affairs and safety organizations split into 3 main functions: the Global Medical Safety function as well as medical affairs in the United States and medical affairs in most of the world, including Canada, Europe and Australasia. We do have hubs in Richmond, Virginia; Fort Collins, Colorado as well as Hull and Slough in the United Kingdom. We do have long-standing innovation leadership in addiction medicine from the very early discovery and synthesis of buprenorphine at the Reckitt & Colman labs in Kingston upon Hull, leading at the end of the day, to several medications for opioid use disorder. And you can see here SUBUTEX and SUBOXONE Tablets, SUBOXONE Film and more recently, SUBLOCADE. We also have a strong support and experience in label update and extension; geographical expansion in most of the world; pipeline growth in addiction medicine, and I will dedicate a section of this presentation to our current pipeline; life cycle management studies; long-term collaboration studies; externally sponsored studies; real-world evidence work streams and of course, quite a lot of peer-reviewed publications and presentations at international conferences. Our philosophy is very much aligned with all the materials that you have already seen today presented by Mark, Richard, Vishal and Glenn. But also with this, a very interesting publication that was released in 2019 entitled Medications for Opioid Use Disorder Save Lives. And I would like to summarize here 6 important points from that publication. First, FDA-approved medications for the treatment of opioid use disorder are effective and actually save lives. Withholding or failing to have available all FDA-approved medications for opioid use disorder in any care or justice setting is denying appropriate medical treatment. A lack of availability of behavioral interventions is absolutely no justification to withhold these medications. Long-term retention on medications translates into improved health outcomes. Most people who could benefit from these medications, unfortunately, do not receive it and access is inequitable as you have seen from Richard's and our result presentation earlier today. And last, confronting the major barriers to use these medications is absolutely essential to addressing the opioid crisis. So I think that these are very, very important messages that are really at the core of who we are as an organization. Therefore, our vision as an R&D organization is really threefold. First, transform world-class science into life-changing medications for the treatment of substance use disorders and associated comorbidities. Second, innovate evidence generation based on insight collections and analytics, not only to better understand our approved medications, but also to inform the discovery and development of the medications of tomorrow. And last but not least, accelerate access to treatments by articulating not only the clinical value of our medications, but very importantly, their economic value. So this is the realm of health economics and outcomes research, and I will show you a few examples of those later in the presentation. Our strategic focus is very clear. As you have heard earlier today, we mainly focus on opioid use disorder, cannabis use disorder and alcohol use disorder, mainly driven by the gravity of the epidemiology, but of course, we always keep an eye on other opportunities, including psychostimulants. I would say, especially these days, when some authors have referred to as the new twin epidemic that is the co-use of opioids with stimulants such as cocaine and methamphetamine. So we continue to look for additional opportunities in this space as well. This is our current pipeline. You can see in dark blue the currently marketed medications, I will spend a little bit more time in the next section to elaborate on all the life cycle management studies that we are currently performing. And then in light blue, you can see the 3 projects that we currently have in the pipeline, again, 1 for cannabis use disorder, 1 for opioid use disorder and the last 1 for alcohol use disorder. So let me move now to the second section more dedicated to SUBLOCADE. Before I talk about SUBLOCADE, let me remind you of a few pharmacology basics to really understand why buprenorphine is so unique. Actually, if you compare buprenorphine with a broad range of opioid-based compounds, you can see that buprenorphine is very unique for 2 main reasons. First, it has a very high affinity to the mu-opioid receptor. Second, it has a very slow dissociation at that same mu-opioid receptor. And that's a very unique combination. Why is that important? Because it means that once buprenorphine -- once proper concentrations of buprenorphine are on board, there is very little opportunity for illicit opioids to actually sit on that receptor. This is why buprenorphine, at the end of the day, has been very effective in quickly stabilizing patients, but also managing withdrawal symptoms, craving and very importantly, helping to prevent relapse or reinstatement of opioid seeking and taking behaviors. The scientific foundations of SUBLOCADE are really based on this critical relationship between plasma concentrations of buprenorphine and the mu-opioid receptor occupancy in the brain. Let me take a couple of minutes now to take you through why that relationship is so important. If there are no buprenorphine on board or very low plasma concentrations of buprenorphine on board, we are really in that situation. That is, very few brain mu-opioid receptors are occupied, which means that more mu-opioid receptors are actually available for illicit opioids. And this is what you can see on that image there, the colors that you can see, the red, the green, the yellow, these are all receptors, mu-opioid receptors, that are currently available. That is not a good situation. Patients are at risk under that situation. However, if you now increase plasma concentrations of buprenorphine, and we determined that there is a minimal threshold of 2 ng/mL that translates into a minimum threshold of 70%mu-opioid receptor occupancy in the brain, now you can see a very different picture. What does that mean? It means that very few mu-opioid receptors are actually available for illicit opioids. SUBLOCADE is delivering these important plasma concentrations of buprenorphine consistently over the 1-month duration treatment. So remember these pictures. At risk, no buprenorphine or very low buprenorphine on board, SUBLOCADE delivering the most appropriate levels of buprenorphine at a minimal threshold of 2-nanogram/mL and minimum 70% mu-opioid receptor occupancy in the brain. So that is good, but we then have to demonstrate that actually this fairly unique pharmacokinetics profile translates into clinical efficacy, safety, and we went beyond by looking at patient experience, what we call patient-centered outcomes. And here are just a few examples of peer reviewed publications. You can see on the left-hand side there, we demonstrated that actually SUBLOCADE can block not only the subjective effects, that is, the drug liking effects of illicit opioids, but also the objective effects: that is, the actual self-administration of these products. We then demonstrated clinical efficacy and safety after 6 months, 12 months and 18 months of exposure to SUBLOCADE. And then finally, we went beyond the traditional clinical endpoints that are required for regulatory approval. And we started to focus on patient-centered outcomes. Why is that important? Because recovery is not only about abstinence from opioids. It's significantly more complex than that. And we started looking at the impact of SUBLOCADE on physical health, mental health, employment, the way patients reengage in their community. All those are critical factors to recover your life. And so this is what we have done in a series of our studies and to just a few examples here. And then last but not least, we were the first to initiate a study that we call the RECOVER study. And in the RECOVER study, we were really wondering what is actually happening to patients when they stop treatment with SUBLOCADE, and we followed them over extensive periods of time. And what we clearly demonstrated there is that the longer the treatment, the better -- the higher the probability of recovery from this chronic disease. And I will show you now a few examples of these studies that we performed. So we are, in fact, now moving to, I would say, a next wave of studies that are really now looking at the impact of SUBLOCADE on a broad range of treatment settings, but also, for example, adherence and long-term recovery, patients at very high risk of opioid overdose. Nonfatal overdose -- we don't speak enough about nonfatal overdose and the potential dramatic consequences of these nonfatal overdoses. And then I will show you a couple of examples of the potential impact of SUBLOCADE in the criminal justice system and the Veterans Health Administration. At the end of the day, what we have done here is a fairly multidimensional strategy, whereby we are working together on further label updates, long-term collaborations, externally sponsored studies, real-world evidence work streams, lifecycle management studies. And of course, we are publishing all that knowledge. So I'm not afraid to say that we are currently building probably one of the largest evidence-based understanding of medications for opioid use disorder. Last but not least, and you have seen with Dr. Horton earlier today, with Dr. Santoro, we are really focusing on patients' insights and advocacy to really further increase our understanding of the disease space and the available medications. So let me start with a couple of examples on adherence and long-term recovery. This is actually, here on the left-hand side, what we call the recovery long term. So believe it or not, we are now at 4 years after a treatment with SUBLOCADE. So we basically followed a cohort of subjects who actually participated in the original Phase III trial. It has been, on average, now 4.2 years after they received their last SUBLOCADE treatment. And what can we see? Well, I think that the most important message here is that you still see a high level of abstinence from opioids: 74% in the past 7 days, 60% in the past 30 days. That is quite remarkable if you think about it. There are 2 other things that we discovered trying to understand actually what is the algorithm of treatment success. When there is very low odds of opioid misuse, that is associated with improved quality of life and treatment effectiveness. That is exactly what SUBLOCADE is doing. It is improving the life -- the health-related quality of life, and that is measured by improved treatment effectiveness. So it makes a lot of sense. However, we also determined that, unfortunately, you have a higher odds of opioid misuse if you suffer from depression, psychological distress, opioid craving and withdrawal and opioid use disorder symptoms according to the DSM-5. And of course, that is unfortunate for all those patients who do not have access to treatment. Second example is coming from Australia. This is what we call the collab study. It's a real-world evidence study where we looked at patients who were actually treated with SUBLOCADE for 12 months. And the main message here is the time retained in SUBLOCADE treatment was associated with number one, high retention rate. You can see 86% after 6 months, 75% after a year; improved quality of life and employment and decreased odds not only of opioids, but a broad range of other illicit substance uses. This is a very important study that we launched a few years ago, aiming to really understanding the pharmacodynamic interaction of buprenorphine with fentanyl in opioid-tolerant subjects. Why is that important? Because we have seen the epidemiology earlier today from both Mark and Richard. This is becoming one of the main drivers of opioid overdoses in this country. So what we did is to run this lab experiment in opioid-tolerant subjects to really understand the relationship between plasma concentrations of buprenorphine, the probability of apnea that is cessation of breathing, potentially leading to death -- that's unfortunately the drama with the opioid overdose -- and all that in relationship with increasing levels of exposure to fentanyl. Now I do have a laser point that, unfortunately, is not working on this screen. So I will leave the microphone for 2 seconds just to show you the exposure to fentanyl. This is the exposure to fentanyl from the very low levels to very high levels. And so what do you see on this graph? You can see that unfortunately, when there is no buprenorphine on board or very low concentrations of buprenorphine on board. But for whatever reason, you have been exposed to high levels of fentanyl, you have an 85% probability of apnea. This is absolutely dreadful. And this is what is driving right now the opioid overdose crisis. There is some good news, however. If you increase plasma concentrations of buprenorphine, especially to levels similar to those that are currently delivered by SUBLOCADE -- and again, look at the threshold of 2 nanograms per mL and above, you can see that your probability of apnea decreases to 12% with 2-nanograms per mL; 5% with 5-nanogram per mL. And by the way, 5-nanograms per mL is happening when SUBLOCADE is at steady state. 85% down to 5%. And this is why we believe that SUBLOCADE is a treatment of choice for opioid use disorder, among other features. This is another example of what we are currently doing, together with Dr. Ken Lee in Canada, looking this time at nonfatal opioid overdoses. And in that study, we basically looked at 3 different medications for opioid use disorder. You can see SUBLOCADE there on the left-hand side, the BUP-XR, buprenorphine-naloxone sublingual product and then methadone. And we looked at the incidence of nonfatal overdoses. I think that the graph speaks on its own. We saw very, very few nonfatal overdose events with SUBLOCADE compared with sublingual buprenorphine and methadone. This was a retrospective study. We are now validating these very encouraging data with a prospective study that is actually currently ongoing. We talked a lot about the criminal justice system. So let me share with you a few examples of publications. This one has been driven by Dr. Josh Lee. It was published in JAMA Network Open earlier this year, really looking at the impact of SUBLOCADE versus sublingual buprenorphine-naloxone in 52 incarcerated subjects. And there are a few key messages there talking about the importance of transition of care and how we can actually facilitate that transition of care. You could see that 69% of subjects who were actually treated with SUBLOCADE had an opportunity to stay in a buprenorphine community treatment after they were released from the criminal justice system versus only 35% of those who were treated with sublingual buprenorphine. You could also see that SUBLOCADE led to significantly better outcomes in terms of a negative urine drug screen and then significantly less re-incarceration compared with sublingual buprenorphine and naloxone. So some very, very encouraging data. Dr. Josh Lee, actually, as we speak, is now working on a significantly bigger study to further refine and validate these results. This is another very interesting publication, more qualitative in nature, but they were aiming at interviewing subjects in the criminal justice system during the COVID-19 pandemic. And here are a few key messages that they wanted to send in their publication: that SUBLOCADE treatment clearly impacted interactions with peers and the criminal justice staff as well as their quality of life during and after incarceration. The treatment effectively eliminated social pressures to actually divert daily medications in the criminal justice system. It also mitigated quite a lot of COVID-19 potential exposures by eliminating daily contacts with the criminal justice system staff. And then it decreased the need to commute to either an inpatient clinic or to pharmacies. So some very, very encouraging results here. The last couple of examples I took here relates to the Veterans Health Administration, a very important publication here by Dr. Cotton earlier this year, really looking at 26 very clinically complex patients in the Veterans Health Administration system. And you can see here a few key data. First, the retention was really high for that patient population. 81% actually received more than 6 injections of SUBLOCADE. Our maintenance was very high as well, 77% were actually maintained on the highest dose of SUBLOCADE of 300 milligrams. And then you can see the impact of treatment on a series of parameters such as a significant decrease in emergency department visits, hospitalizations, days of hospitalization -- of course, use of nonprescription opioids and a decrease in homelessness. You can also see that the mortality rate was unfortunately quite high as we typically see in that patient -- complex patient population: there were 6 patients, but please note that 5 out of them were not related to substance use disorder at all. And all of those were also disengaged from treatment. And then the last one, I wanted to present to you, is actually not a publication of a study, but rather the publication of protocol for a new study that is currently ongoing. This is a pretty big study, as you can see, a 52-week 20-site that is really going to be dedicated at comparing SUBLOCADE to sublingual buprenorphine and naloxone in a population of veterans. The primary endpoints will be retention in the medication as well as opioid abstinence, but the beauty of the study is that it will go far beyond. There will be a constellation of secondary end points. As you can see here, the study will look at other illicit substance uses; psychiatric symptoms; medical outcomes, including prevalence rates of HIV, Hep B and Hep C; as well as social outcomes, housing instability, criminal justice involvement; and then, of course, the healthcare resource utilization and the cost effectiveness of these two medications. Let me now move to the third section of the presentation and talk a little bit about PERSERIS. This section for me will be very brief because Glenn has done an outstanding job presenting to you all the background. But just reminding you of a few very basics on the scientific foundation of PERSERIS. As Glenn mentioned, the product or the formulation was really designed to deliver a very stable and appropriate concentrations of risperidone immediately after the first injection. And you can see that quite clearly here, a very, very stable level of risperidone, again, from the very first injection. As Glenn mentioned as well, the plasma concentrations of risperidone were also engineered to be within that famous 60% to 80% dopamine D2 receptor occupancy in the brain. And why is that important? Because again, after several decades of research, we know that if you do not reach 60% of dopamine D2 receptor occupancy in the brain, you lack clinical efficacy. Unfortunately, if you go beyond 80%, you start running into side effects and typically what we call the extrapyramidal syndrome or pseudoparkinsonism that you absolutely want to avoid. So the key was to engineer the product to deliver these very stable plasma concentrations of risperidone within that bandwidth: 60% to 80% dopamine D2 receptor occupancy in the brain. We also showed then that unique pharmacokinetic profile led to clinical efficacy and safety. Again, as Glenn mentioned, the original Phase III trial was in patients with acute exacerbation of their schizophrenic symptoms. And this is why the study actually lasted only 4 weeks. And this is what you can see there at the beginning of the graph. But then we demonstrated that after 1 year, you stabilize these patients. And these are basically the flat lines that you see there, on the right-hand side. This is exactly what you want to see to stabilize your patients over extensive periods of time. The fourth section now will be dedicated to the future and what we currently have in our pipeline, and I will start with AEF0117 for cannabis use disorder, a partnership with Aelis Farma. And before I talk about this molecule, let me give you a little bit of background. The latest data from the World Health Organization clearly state that we are now dealing with 209 million people worldwide using cannabis. And that number of past-year cannabis users has increased by approximately 23% over the past decade. Now if you look at the situation in the U.S., we are now talking about almost 50 million past-year users of cannabis among people age 12 or older. And unfortunately, we now have a pool of 14.2 million people actually diagnosed with a cannabis use disorder according to DSM-5. So I would say that there are really 4 challenges in that disease area. Who says challenges also says opportunities, and I will try to demonstrate what needs to be done next. So first, it is a normalization of use. The latest data now clearly indicate that 37 states here in the United States plus the District of Columbia legalized cannabis for either medical use or recreational use. But we also see, unfortunately, a new generation of products, very high potency cannabinoid products. Actually, the potency of THC in cannabis was about 4% to 6% 20 years ago. On average now, we are talking about 17% to 20%. The drama is also now access to synthetic cannabinoids. And those products may have a potency of up to 70%, 7-0 percent. So that's a huge and radical change in the cannabis landscape. Second is presentation and diagnosis of the disease. There is still a lack of education and understanding of the symptoms that may actually lead to a cannabis use disorder. The third is the treatment and the management of the disease. Let's be clear: There are no therapeutic options right now for patients suffering from cannabis use disorder. There is no therapeutic option for acute withdrawal, and there is no therapeutic option for acute cannabinoid overdose. So there is a massive gap in the treatment landscape. And then last, the maintenance and the follow-up of these patients, especially those who are not only suffering from cannabis use disorder but from comorbid substance use disorder and psychiatric illnesses. There is absolutely no follow-up at all for those who are in that situation. So I would say that the storm right now has 4 main components that may lead to cannabis use disorder. First, the increasing prevalence of use. Second, the increasing intensity of use in terms of both frequency and quantities. Third, the increasing THC content of cannabis products and last but certainly not least, the age of cannabis use initiation. So a fairly scary situation, what are we going to do about this? And this is when we have met some scientists from Aelis Farma in Bordeaux in France under the leadership of Dr. Pier V. Piazza. And we got really excited about this new mechanism of action. And I will try to explain this to you in relatively simple terms. So actually, what Dr. Piazza and his team discovered is the stimulation of the cannabinoid 1 receptor by THC actually increases brain pregnenolone, what is happening to brain pregnenolone when it is released. When the second big discovery that they made is that pregnenolone will actually bind onto that allosteric modulator site on the cannabinoid 1 receptor. It has a completely new discovery that nobody even talked about in the past. What is happening when pregnenolone actually sits nicely on that little allosteric site on the CB1 receptor. Well, it is going to block very specifically what we call the downstream pathways that are responsible for the intoxicating effects of cannabis, but not other downstream pathways. That's very important compared to what we call cannabinoid 1 receptor antagonist that basically sit on top of the CB1 receptor. But by doing so, they block everything. They block the pathway I was just referring to, but other downstream pathways. And unfortunately, by blocking these other downstream pathways, you start seeing a lot of side effects. And this is really what we wanted to avoid. So now you may tell me, well, so that's very simple. If it's just pregnenolone released, why don't you just inject pregnanolone that should do the trick. You are right theoretically, but things are always more complicated than you think. And here, we are gaining that situation. Pregnanolone, is not a druggable compound. What does that mean? There are 3 main reasons why you cannot do that. Number 1 is a very short half-life. Number two, it is metabolized in downstream active steroids, such as testosterone, progesterone, estrogen so you can only imagine the potential side effects here. And third, it has very poor oral bioavailability. So this is the antithesis of a new molecule that you can develop for this indication. So what do we do? This is where the team made a big difference. Aelis Farma actually created and discovered a synthetic compound that will bind on that allosteric site on the CB1 receptor. And that is AEF0117. So let me give you a little bit more information about this compound and why we actually started to be quite excited about it. Why did we get excited for several reasons. First of all, very clean Phase I trial, single ascending dose, multiple ascending dose, very good toxicological profile as well. And then this Phase IIa study run by Dr. Meg Haney at Columbia University, where she actually demonstrated that the compound first of all, decreases the cannabis subjective effect. And you can see here a few examples where you observe a very nice dose-dependent increase in -- decrease in this subjective effect. But Dr. Haney also demonstrated that this compound significantly reduced its cannabis self-administration. So altogether, this was an indication to us that there was a pathway forward and so where are we today? When we took an option on this compound, and now we have an opportunity to potentially exercise our option upon positive results from what we call a Phase IIb or clinical proof of concept. And you can see that this is a pretty big clinical proof of concept with 330 patients. And we are going to assess to what extent the compound can actually significantly inducing a greater proportion of subjects with a response of less or equal than once a week use of cannabis. That's pretty stringent. Most of these subjects are suffering from moderate to severe cannabis use disorder and use 5 or more times per week. Time lines we're estimating the last subject last visit in that trial in the first quarter of 2024 and a final clinical study report in the third quarter of 2024. Let me now talk a little bit about INDV2000 as a nonopioid medication for opioid use disorder. And why is that important? You have heard today that the great majority of patients will probably have to stay in treatment for many years. And so some patients do not want to stay in treatment on an opioid-based medication. So for all those who do not wish to stay on an opioid-based medication, we want to offer a nonopioid medication option. And this is what we are trying to achieve with INDV2000. So let me talk to you a little bit about the mechanism of action. INDV2000 is what we call a selective orexin-1 receptor antagonist. So in the brain, you basically have 2 main orexin receptors, the orexin-1 and the orexin-2. We are not really interested in the orexin-2. Why is that? Because that receptor is mainly localized in brain regions that are involved in arousal and wakefulness. Actually, there are some medications right now that have been approved by regulatory agencies that are what we call DORAs, Dual Orexin Antagonists and they are used actually for sleep disorders. But there is compelling evidence in addiction science that the orexin-1 receptor is really the 1 that is localized in brain circuits that are heavily involved in reward, including drug rewards. And there is clear evidence from the nonclinical literature that you could make a difference if you were to develop a selective orexin-1 receptor antagonist, and this is exactly what we have done with INDV2000 in partnership with C4X Discovery. So we are a little bit back in time in 2019. We actually received a EUR 10.6 million grant from the NIH, through the NIH field initiative to really enable us to start the nonclinical and clinical development of this compound. So that was a very, very good news for us to receive that grant from the NIH, very nice recognition. In '20 and '21, we mostly dedicated our time to focus on the Phase I single ascending dose of this product. We actually tested 8 doses characterize the full pharmacokinetic profile, the toxicology profile and the safety profile and the profile looks really good so far. This year and next year, we will move to the second part of the Phase I trial, really dedicated through what we call a multiple ascending dose, but we are also going to perform additional clinical studies and very importantly, additional nonclinical toxicology studies. So that is the plan with this product. And then the last 1 I would like to share with you is INDV1000 for alcohol use disorder in partnership with Addex Therapeutics. This is actually GABAB positive allosteric modulator. You may ask me, can you please repeat this because it's a little bit complicated. So I will try to make it as easy as possible. But first, let me give you a little bit of background why the GABAB receptor. Prototypical GABAB agonist is baclofen and baclofen is a very old drug that was originally approved in the early 80s for spasticity. But equally, I seem to remember that the first paper, one of the first papers in the literature about the using baclofen for substantial disorder was in around 1985. Actually, it was a paper on cocaine. But then over the years, people really started looking at a potential for a GABAB agonist such as baclofen in a broad range of substance use disorder, including alcohol. There was then this book in the year 2000. It was between -- around 2005 from Dr. Olivier Mason. Olivier Mason was a very successful French physician who unfortunately suffered from alcohol use disorder. And reading the literature, key discovered baclofen and decided to self-treat with baclofen. And the book is all about his journey through alcohol use disorder, but also his own treatment with baclofen. And in his case, the treatment was very successful. It has been a major patient-driven effort in France under the leadership of Dr. Mason as well. Again, things that are always more complicated than we think there are unfortunately a lot of limitations of baclofen for this particular therapeutic indication. And here are a few examples. Number one, because of its pharmacokinetics, you need to use the drug at least 3x per day which for an indication like alcohol use disorder, let's be honest, it's already a no go. It's extremely difficult to keep patients in treatment retention if you have to take at least 3 times a day. Second, there is a very careful dose escalation to prevent some of the side effects early on in treatment. And unfortunately, for alcohol use disorder, you probably need to go far beyond the currently approved doses of 80 milligrams per day. There is a potential for side effect, especially sedations. There have been multiple attempts to actually create new formulations, but all these attempts have failed. And then it was approved in France, a very restricted approval. And unfortunately, what we have seen also with a broad range of off-label use of the drug is an increase in reports of mortality. So again, there is always a solution. What is the solution, in this case, GABAB positive allosteric modulator. So a little bit similar to what I explained for AEF0117. The GABAB receptor has another allosteric modulator side. And so the idea is in order to keep the clinical efficacy that we see but significantly improve the safety profile is to develop an allosteric modulator at that allosteric side. Now this is complicated. We had to go back to the drawing table, so to speak, of what we call a lead identification and then lead optimization program. And there are typically 3 main components of this, major medicinal chemistry efforts, then you characterize your new lead molecules into biology, both in vitro and in vivo. And then last but not least, you start characterizing in the drug metabolism and the pharmacokinetics. So we currently have a few lead compounds, and we are aiming at selecting one of these lead molecules for candidate selection in the first quarter of next year. Last section of the presentation is to talk briefly about the future. And so to us, it is really critical to develop over many, many years now a very deep understanding of the brain circuits that play a key role in substance use disorder. But very importantly then, the next step is to try to identify key receptors within these circuits and to keep things relatively simple. There are currently 3 main brain circuits that play a key role in substance use disorder in general. The first 1 that you can see there in blue is what we call the Basal Ganglia. And this is a series of circuits that are heavily involved in what we call incentive salience. What is incentive salience? It is the increased motivation to seek a drug, and that motivation is actually triggered by environmental cues that have been previously associated with drug-taking behavior. So for example, if you use to take the drug with very specific people or in a very specific place, even if you are abstinent but you meet some of these people out of chance or you're just to walk by that place, just that cue might be enough to trigger relapse or reinstatement of drug-seeking and drug-taking behavior. And that is the power of what we call these conditioned cues. And this is a core problem in substance use disorder in general. That circuit is also unfortunately involved in pathological habits and perseveration. Even if you know that there will be very negative consequences by seeking the drug and taking the drug, you feel compelled to go for the drug, seek the drug and take the drug. This is related to major dysfunctions in that brain circuit basal ganglia. Second big circuit is the Extended Amygdala. This is a series of networks that are involved in the negative emotional state that you may feel under a drug withdrawal. So when the drug is no longer there, this activates this extended amygdala system. And in the last one, and certainly not the least because it plays a critical role is what we call the Prefrontal Cortex and that brain circuit is really driving the executive function and the decision-making. So again, it's -- this is very complex interaction between pathological habits and persevering in that habit. You know that the consequences are negative you still make the decision to go for the drug. That's the prefrontal cortex, alternations in that prefrontal cortex circuit. And then last but not least, this is also a circuit that drives craving for the drug. So needless to say, you understand the complexity of the task at hand. But over many decades now, we improved our understanding of some of these major alterations in some of these circuits. So for us, as a company, the goal is to really try to understand what are these key receptors. What are, for example, the receptors that are present in nodes interacting with these 3 systems. And then the next step, once we have identified the these key receptor systems, it is to assess whether or not there is a molecular target that actually fits that receptor system. And then last but not least, we do a lot of due diligence. That's the business development part of the deal, whereby we look for potential partners who may have already developed a drug that is targeting these key receptor systems. So on that note, I thank you very much for your attention, and it's my pleasure to introduce you to my colleague, Nina DeLorenzo, because how we deliver really matters.

Thanks, Christian. Good morning, everyone. My name is Nina DeLorenzo, and I'm our Chief Global Impact Officer. You've heard this morning about our exciting plans to deliver growth in the coming years. but how we deliver this growth really matters to us. As Mark noted earlier, we believe our long-term success is directly linked to operating responsibly and in a way that both minimizes our impact on the environment and maximizes our positive social impact. So today, I'm going to introduce you to Indivior's ESG and Sustainability Strategy. And I'm going to talk about our activities and outline some of our early progress. We're a relatively young company, and we're at the beginning of our ESG journey, but it's a top priority, it has the attention and ownership of the Board and management has been charged with operationalizing it. We are building it into everything we do. We've worked in the past few years to formalize our internal structure around ESG, and now we're looking ahead to expanding our efforts. Our ESG framework links directly to our vision as a company. We used a patient lens to frame our strategy to maximize Indivior's positive global impact and shareholder value through our mission of making innovative treatments for substance use disorders and serious mental illnesses and to change lives for the better. The pillars of our strategy are to transform patient lives prioritize our people, conduct our business with integrity, meet our environmental responsibilities and provide our products. Importantly, these pillars are aligned with several of the UN sustainable development goals. We've also aligned our work to other leading disclosure frameworks. Our strategy is to reduce our environmental impact in line with good practice, lead on social impact and establish Indivior as a company committed to an effective sustainable global integrity and compliance program. So on the environment. We recognize the importance of climate change, and we support the activities of groups such as the intergovernmental panel on climate change and the UN Framework Convention on climate change as well as the various initiatives that aim to achieve greater transparency and to enable stakeholders to monitor the related areas of climate change and environmental performance. In 2021, we established the foundations of our approach. Specifically, we enhanced our Scope 1 and 2 emissions reporting and began to explore appropriate reduction targets. For 2022, we enhanced our reporting of activities related to climate change as our strategy is maturing and developing. We will begin target setting once we have fully established our baseline. We also look forward to minimizing our emissions by installing solar panels and a geothermal heat pump at our Hull U.K. facility, and exploring a more sustainable fleet for our U.S. sales team to include switching it over to hybrids in the near future. And we're pleased to say that earlier this year, as Mark mentioned, we became a member of the UN Global Compact. On social aspects, at Indivior, we see our social purpose as a major strength. So we seek to make this an area of leadership for the company. In addition to the inherent positive social impact of the products we provide and the patients we help, we're setting out to develop a comprehensive impact strategy that amplifies our work supporting underserved and stigmatized patients. A strategy that creates shared value for our business and for our stakeholders, something that can help transform the disease space. We're excited about the possibilities ahead. Earlier this year, we were pleased to be certified as a great place to work with an 88% employee approval rating. We value our engaged culture at Indivior and believe it's a key advantage for us as we drive our business strategy. Also on social issues, we seek to bolster training and engagement on diversity and inclusion. Indivior benefits from having a diverse set of perspectives. We know it helps us grow our business and meet our commitments. On governance, we know that we have a special responsibility to the patients we serve to conduct ourselves with a high level of integrity as well as to investors to ensure they have confidence in our company. Our commitment to excellence in meeting our government agreements is a testament to Indivior's strong culture and engagement. And we have worked to put in place an effective and sustainable global integrity and compliance program. This aspect of our business remains a significant management priority. Additionally, on governance, Board diversity continues to be an important area of focus. Since 2021, there have been 5 new appointments to the board, 3 of whom are female. While we've made significant strides, we recognize there's more to be done to advance diversity and inclusion at Indivior. And finally, on governance, we plan to incorporate ESG metrics into management compensation in the near future. So as you can see, we are actively developing our initiatives in line with industry best practice. And you'll see this outlined in our inaugural sustainability report, which I'm very happy to say will be released in the coming weeks. So some of the information contained in it can be found in our annual reports over the years, but we felt it was important to highlight the key ESG information in a distinct publication to make it easier for investors to access. We hope you'll take a look at it when it's published. It will be housed on our Indivior website. So thank you for your time, and I'm pleased to hand it over to Ryan Preblick, our CFO.

Thanks, Nina, and good morning to everyone. I'm Ryan Preblick, the CFO. I've been with the company now for 10 years. It's a pleasure to be here today to share more details on our medium-term financial outlook and our capital allocation priorities. In my session, I want to leave you with 4 key takeaways. First, we have an attractive growth profile based on our currently marketed portfolio and we expect to add to this over the longer term with our pipeline and potentially through business development. As Mark noted, our growth projections today do not include the Opiant acquisition, since it has not closed yet. The key is, of course, SUBLOCADE on which we now expect to deliver a peak net revenue of over $1.5 billion. Second, we have a scalable business model with a unique commercial platform. We will leverage this model, both through traditional field sales and more importantly, our dedicated efforts across organized health systems and that includes the criminal justice system as well. This will be supported by patient-focused systems, including our hub and by a G&A platform that provides value-added support services, including the continuous upgrade of our compliance capabilities. Third, the strategic priorities Mark spoke to, growing SUBLOCADE diversifying our business, progressing our pipeline, delivering operational excellence are all well funded through our growing EBITDA and healthy cash balance. Our balance sheet gives us significant flexibility to invest in growth to meet our obligations and to generate shareholder value. Lastly, we expect to generate strengthened free cash flow in the coming years which we will deploy according to our capital allocation priorities. Consistent with our strategic priorities, this framework is focused on reinvesting in our growth drivers, derisking the business including through diversification and potential business development and returning excess cash to shareholders. Let me start with our growth profile. Since 2020, we have delivered double-digit net revenue growth, powered primarily by SUBLOCADE. And our adjusted operating profits have more than doubled. Over that period, based on strong commercial execution, SUBLOCADE has become our biggest product by net revenue, and we are now starting to see PERSERIS make a meaningful contribution as well. In fact, our full year guidance of $405 million to $420 million put SUBLOCADE on track to become the #1 selling global brand for opioid use disorder in 2022. And as you heard today, we are confident we can deliver peak net revenue of more than $1.5 billion. For PERSERIS, as Glenn explained, we remain committed and confident in delivering its potential peak net revenue in the range of $200 million to $300 million. Having touched on net revenue. Let me now discuss margins. We are confident that we can generate margin expansion in the coming years based on our scalable business model. This slide shows our path forward by expense category. Over 2021 and 2022, we have made significant structural growth investments to support SUBLOCADE and organized health systems and to expand the national sales coverage for PERSERIS. Going forward, we will continue to fuel the commercial business in a tactical fashion when appropriate. As a consequence, you should expect to see our sales and marketing spend grow at a more modest pace versus the last 2 years. R&D, on the other hand, is expected to increase as a percentage of net revenue as we move closer to benchmarks in our industry. This will reflect our strategic focus on building a strong and balanced pipeline. In addition, we will conduct the necessary life cycle management studies to support our long-term ambitions for SUBLOCADE and generating the real-world evidence is for SUBLOCADE is a critical part of the value proposition for our commercial teams, especially as we drive deeper penetration into the OHS. Lastly, on G&A spend. we underwent a significant cost reduction program in 2020. And going forward, we plan on maintaining a disciplined and efficient approach in this category. Taken together, these 3 vectors plus improved gross margin tends to support sustained margin expansion. I now want to touch on how we will reinvest our profits for growth, meet our obligations and return value to shareholders. Over the period since 2020, consistent with our adjusted operating profits, we have more than doubled our EBITDA even with the step-up in growth investments we made in the past year. This, in turn, has helped us to grow our gross cash and investments position to more than $1 billion. This position of balance sheet strength when set against the context of our relatively constrained capital expenditure requirements gives us tremendous flexibility. It means we can fund our strategic priorities, while at the same time meeting our obligations. It also means we can pursue organic and inorganic growth opportunities to strengthen our leadership position in addiction treatment and science. And lastly, it gives us the opportunity to return excess cash to shareholders as evidenced by our 2 $100 million share buyback programs. This slide sets out our capital allocation priorities in detail. As I mentioned, we expect to maintain the financial flexibility to prioritize growth and shareholder returns, while also meeting our obligations and derisking the business. We will also place a great emphasis on operating in a responsible and sustainable manner. Our growth investments will be focused on commercial execution, patient access and progressing our pipeline. We will also see business development opportunities as supported by our Opiant announcement that will extend our global leadership position in addiction treatment. Lastly, we will seek to return excess cash to shareholders when appropriate. We believe this balanced approach to capital allocation will drive substantial shareholder value in the short medium and long term to help us deliver our vision and mission. As Mark touched on earlier, here is more detail on our medium-term profitable growth framework. As already noted, this is built on our current business only. Based on the outstanding prospects for SUBLOCADE and PERSERIS. We expect to deliver double-digit compounded net revenue growth over the medium term. Let me walk you through some of the considered assumptions. First, we expect underlying BMAT growth to be in the mid-to-high single digits. We assumed a new entry into the LAI market here in the U.S. Third, we assume SUBOXONE Film share will ultimately trend towards analogs with the fourth generic coming into the market soon, although the timing on this is unclear, and we remind you that we do not promote the product in the U.S. Lastly, I want to specifically call out that we expect SUBLOCADE and to meet our previous $1 billion net revenue target in terms of run rate by the end of 2025. Now we expect to generate positive operating leverage, as I discussed earlier. Within this, we expect the improving product mix to lift our gross margin to the mid-80% range despite the current backdrop of inflationary pressures. We will focus our growth investments on U.S. commercial and R&D as we scale our business model. Lastly, we expect to generate strengthened free cash flow, our CapEx needs are relatively modest despite our ongoing investment in additional manufacturing capacity and IT. Our strong free cash flow will allow us to take the balanced approach to capital allocation, I said out earlier, focused on delivering sustainable growth and shareholder returns. Next, I want to update you on our plans for an additional listing here in the U.S. As a reminder, we received strong shareholder support at our EGM in September. The news today is that we have chosen NASDAQ to view our trading venue with a target listing of our shares in the spring of 2023. We have a lot of work to do before then to ensure that we meet SEC financial reporting and Sarbanes-Oxley requirements, but this is well underway, and we are confident we will deliver this important initiative to elevate Indivior's profile in its largest market, and attract a broader group of biopharma focused investors. In summary, I would like to thank you for your attention and remind you of the 4 key takeaways that I started with. We have an attractive growth profile and a scalable business model, which are reflected in our medium-term outlook. Our strategic priorities are well funded through our strong balance sheet, and we will deploy our strength in free cash flow in the coming years to deliver sustainable growth and shareholder returns. With that, I'll hand it back to Mark for closing comments. Thank you.

So just a few comments before we get to Q&A. I hope you came away today just seeing the passion that the leadership team brings to both the disease space as well as the ownership, it certainly is representative of the 900-plus employees that we have in Indivior across the 39 countries we operate in. I also hope that you've come across with the same confidence that we have in the future for Indivior. We have a strong growth profile in the years ahead. We will deliver sustainable shareholder value in the years to come, all based on the following 4 factors. We are the global leaders in addiction we take the unique, the passionate insights that we have from both the patients and the disease space and merge those with breakthrough science to create great treatments. Second, SUBLOCADE is a transformational asset for the treatment of moderate to severe opioid use disorder and will deliver in excess of $1.5 billion of net revenue. Third, we continue to seek diversification opportunities in both addiction and comorbidities, both organically and through business development. And then lastly, we will generate significant cash through continued operational excellence moving forward and to support delivery on our strategic priorities. So with that, we'll go ahead and transition to Q&A section across the entire presentation. If there's more questions on SUBLOCADE, we can go to those, but we can also have some on the operating model. And I'll invite the management team to join me up here and hopefully grab a mic.

My name is Isaac, I'm with Piper Sandler. On PERSERIS, can you give us some details on how many reps you have in the field targeting physicians? And how large the call audience is? Secondly, can you share with us, I guess, your thoughts on -- I mean -- I think we know that the category is growing -- the LAI category is growing, but can you share with us your thoughts on kind of why the category isn't growing faster. Is it on the patient side? Is it on the payer prescriber side? And then lastly, on PERSERIS, can you talk about your thoughts on peak sales in the context of a potential new entrant in the LAI risperidone category next year. I know Teva has their FDA action date scheduled sometime for the first half of 2023 and that's an LAI risperidone chronic, but also a ready-to-use product and subcu, of course. So that would be helpful. Thanks.

Thanks for that, Isaac. I think I'll take the last question and then I'll hand to Glenn with regards to our call platform and the number of reps we have out there. Listen, I think what we've seen is every time a new entrant has come in here, it's accelerated growth in the category, and you spoke to the penetration targets with regards to the market and that it's still only at 18% to 20% penetration. So there's plenty of room for growth with multiple opportunities there, and we see significant differentiation existing with PERSERIS that will continue to enable us to hit that $200 million to $300 million of peak revenue moving forward. So Glenn, would you like to address what our platform is and what we call platform is like.

Yes, sure. Sure, yes. Thanks for the question. So we have 110 sales reps, clinical specialists and institutional specialists. So it's a mix of folks that call specifically on institutions and those that call on HCPs primarily. But in addition, I would just like to say that we leverage all of the other ecosystem partners in the space that exists for both brands. So there's -- that brings in a whole host of other people that are involved in the process. So the call platform, the question about call platform size, I think we're looking at the universe of HCPs in the long-acting injectable space, there's about 8,000 HCPs that make up 80% of all of the prescriptions. -- we call on the vast majority of those. We do have a segmentation profile, though, that we think makes of clinicians that are more likely to prescribe PERSERIS based upon what we've seen in terms of the uptake already. And so we focus the call platform on ensuring that we're covering those with the right level of region frequency. Is there anything else.

That's it. Thanks, Glenn. Thanks, Isaac.

Hello?

There we go.

It's James from Jefferies. A couple of questions maybe for Christian, I guess. Just kind of curious if we're looking over the mid to long term for Indivior. We've obviously seen the move from Subutex just about saying SUBLOCADE. Some years ago, there's a soluble tablet in development, which was on. And we beat the end of the runway, when you say in terms of innovation with that compound. So now it's more about are there is within addiction? Or is there something even kind of perhaps early stage compound detail at the moment that we could maybe see a formulation. And my second question is just in terms of some of the other studies with SUBLOCADE. I'm just kind of curious what the opportunity is on the pricing side to demonstrate the value benefits perhaps lower hospitalizations that introduces other kind of savings into the system or in the criminal justice system sort of studies to show if you're with the patient once a month versus once a day where the other kind of savings are, does that give you essentially potential pricing power, which may not be embedded into expectations at the moment, but it could be a value consideration on the company.

Thanks for those, James. Yes, we'll start with Christian. And then if needed, we'll ask Vishal on the criminal justice side to add his thoughts on those studies.

Yes. So on the formulation side, obviously, we are developing a lot of studies as you have seen to focus on SUBLOCADE right now because we really believe that this is the treatment of choice for opiod use disorder. So that's really our top priority. But of course, we are very open to additional possibilities in terms of foundations, mainly on the long-term maintenance side. So that is definitely a possibility. I will not answer the pricing part, but we -- I could not take you through all the studies that we currently are running, but there are several studies that are specifically looking at the cost effectiveness of SUBLOCADE versus standard of care in a broad range of treatment settings. You have seen the criminal justice system, the veteran health administration, but also in the emergency department.

And I think the key on that, James, is those studies are being done in those subchannels across the organized health system. So you've got the IDNs, you got the government accounts as well as the criminal justice system. Anything else to add on that, Vishal, with regards to.

Yes, just to add on your second question, thanks for the question. And building on Christian's point, I think the studies are really focused on all the relevant drivers. So I think as I presented earlier on, our focus remains in growing the base and the growth opportunity really sits in access to patients with a medication and more number of treat patients on treatment profiles. That remains the focus and all the studies help educate the system why this is a good investment to make in patients.

Thank you. Next is Max.

It's Max Herrmann here from Stifel. Just a few questions on PERSERIS then on your sort of your margin -- longer-term margin guidance. So just on purses, mean gave some great data demonstrating, I think, people, doctors who are prescribing PERSERIS at the moment. I think you said that the new chair of new scripts was 6%. So that's obviously, a significant amount of prescribing is going elsewhere to other LAIs and they're obviously familiar with PERSERIS. So is that share of voice that is the issue here? Or what is driving doctors to prescribe other LAIs in reference to PERSERIS I'd be interested to know in terms of payer coverage. You obviously talked about that being great for SUBLOCADE. I just wondered where you are now with PERSERIS for coverage. So those are the 2 questions on PERSERIS. And then just in terms of margin evolution, maybe for Ryan. Obviously, you talked about moving to industry trends for R&D spend. That's sort of is different between depending on maybe when you're a specialty pharma company or whether you're a cannabis general pharma company, obviously, you guys are more in the specialty markets. I just wanted you talking about up to sort of 10% range when you talk about the peers or are you talking about more like mid-teen range where other pharma companies target? And then on the gross margin side. Clearly, historically, pre-generics coming in for SUBIOXANE, your gross margins were more closer to the 90%. So mid-80s seems to be low, particularly given comments previously that SUBLOCADE was a higher-margin product. So I just wanted to understand what's driving that. Those are the questions.

Thanks for those questions, Max. And maybe I'll start with just a reminder that we're still in the first year of a full-scale launch on PERSERIS. We only went to the national launch starting in January. So that traction that you're seeing coming out of COVID and really getting that full national launch is starting to drive the growth you're seeing. Glenn, do you want to just talk about some of the headwinds that you see out there, but the opportunity is moving forward.

That's a great question. I think, yes, there's a share of voice issue. I mean there's a heck of a lot of other LAIs out there. So part of the whole point going to the larger team was to address the share of voice issue and mature that we're covering a much wider range of practicing clinicians. Coming out of COVID, I think that was certainly an issue it's hard to drive penetration with a challenger brand when you can't see anybody. So I think that's been a challenge that we're now starting to see abate as we have expanded the team and the COVID restrictions are reducing. So that's fair. The question on coverage, it's great. The coverage on PERSERIS is our objective there is parity with the rest of the category, and we achieved that. So we feel very confident in the coverage. There are a couple of areas that we continue to optimize. But generally speaking, it's excellent coverage for PERSERIS.

Thanks, Glenn. Thanks, Max. Ryan, do you want to talk about the R&D spend as well as the gross margin profile.

Thanks, Mark. So on the R&D spend, right now, we're about 7% of net revenue certainly took a step up this year, and that's one of the reasons why we call it out to progress more in this, all of ours to have a strong and balanced pipeline. That's one of the reasons why we spent some time this year trying to explain to all the new products that Christian's team is working on. We are going to continue that ramp as we spoke about because one of the major 3 priorities is to have a strong balanced pipeline for the long term. So when we say double digits, we're looking at low double digits here. That's what the benchmarks would put us that in our current industry. The exact quantum of that could differ based upon the midst of projects that he's working on and also where they are in their time. So that would be on the R&D. And then in regards to gross margin. So the range that we put out there today is 1 that we have confidence in, in regards to what we're looking at. And also keep in mind that we are dealing with some inflation that we're trying to factor in as well. You are right, was SUBLOCADE at the top of that pyramid, certainly does have a nice margin profile. But we do have to consider that PERSERIS will be growing. Film will still have some residual and as we talked about today, the balance of the rest of the world business is doing okay. But that part of the portfolio does not have the high gross margin mix that we have in SUBLOCADE. So when we try to factor in mix of the business, seeing some of the headwinds or what we're doing with inflation, that range was what we felt most comfortable putting out at this point.

Just maybe follow up on the PERSERIS. What is the share of voice that you have in terms of the industry.

Yes, we do have some market research on that just recently. We think we're at about 11% or 12% and growing. So it's about doubled since last year.

And in terms of insurance coverage.

The insurance coverage, okay. If I answered that question, it's excellent. We're at parity with the category. That means that...

I mean that we have a 7% coverage.

No, no, no, 88%, 89%, yes. And it just -- on the point on insurance coverage in this category that you're aware, this is highly disabled group of folks and the coverage really aligns with ensuring that there aren't a lot of barriers to those folks getting medicine. So while there are some small plans that have issues at the end of the day, we feel very comfortable with whatever there is. And it's not -- and the HCPs to treat the space to understand any of the barriers they have to overcome in terms of prior authorization.

Thanks, Glenn. Thanks, Max. I'm sensing people are hungry and wanting food because there's not very many questions. Any other questions before we close? All right. We got one. Oops I didn't see it.

Sorry. Just quickly, in terms of -- you mentioned the no currently only generic versus long-acting in the antipsychotics what are some of the expectations sort of in the market if you look sort of consensus estimates and some -- anything in the near term in terms of generic competition to some of those existing brands.

I -- go ahead, Glenn.

Yes. So we've seen -- there's been some cases that have come forward in the past, I don't know, 2 years on some of the large products, and they unsuccessfully being able to achieve that. So in the near term, we don't see anything meaning certainly not in the next 18 months or so. We don't see anything that would be coming in the generic side of the market. And let's -- I think, just to be clear, it is hard to create generics of long-acting injectables. So it's challenging but not that, that gives you any greater sense of attraction. But at the end of the day, I think you just challenging there. But the ones that have come in the past 18 months or so have been unsuccessful. Don't have absolute certainty for you, but hopefully, that answers your question.

One last call for questions. All right. Then let me thank you for the significant investment you've made in Indivior this morning. We really appreciate it. We look forward a bit of time over lunch and then, of course, continued one-to-ones in conference time together. Thank you very much.