Hello. Good afternoon and a very warm welcome to IVA Center here in Stockholm and to Camurus' Capital Markets and Research and Development Day 2022. My name is Lars Frick. I work as a journalist at Tidningen Börsveckan, and I will be moderator today. I had the pleasure of attending Camurus' inaugural Capital Markets Day a few years ago, and back then, there was a lot of focus on R&D for obvious reasons because then Camurus was a very different company than it is today, which provides a clear rationale for this Capital Markets Day. I would like to start off by a brief introduction of today's presenters. We have representatives from Camurus' management. We have Fredrik Tiberg, CEO of Camurus, who together with Jon Garay Alonso, CFO of Camurus, will talk about the current situation, the vision and strategy going forward, and the financials.
We also have Richard Jameson, who's Chief Commercial Officer, who together with Samantha Nickerson, who's GM in U.K. and Ireland, will provide sort of a case study on how to achieve market leadership in a market which in this case obviously is the U.K. We also have Peter Hjelmström, Chief Medical Officer, who together with Dr. Lenka Katila from Akademiska sjukhuset, who will talk about lifecycle management and Buvidal and also give the connection to pain. It's very interesting because Dr. Katila's clinic is unique in the respect that they treat both addictive disorders as well as pain patients in the same clinic. As you will see in the presentations going forward, there is a bit of synergy there from a clinical perspective.
From there on, we move on to Markus Johnsson, Senior Director, Project and Portfolio Management, who together with very distinguished external guests, Dr. Diego Ferone, Professor at the University of Genoa, together with Associate Professor Simron Singh, will give you an in-depth review of CAM2029 and the late-stage pipeline. There are some forward-looking statements in the presentations coming forward, so readers beware. This is today's agenda. As you can see, it's sort of divided into two sections, and the first is more along the business side of things about Fredrik Tiberg's and Jon Garay Alonso's presentations together with the U.K. case. It will be followed with a Q&A. In the second part, we will go and give an in-depth review of the research and the clinical results that really underpin Camurus' business and future strategy.
There are a few practical issues. During the Q&A, please raise your hand, and you will find at the side of your chair there is a microphone. Press the button, and when there is a red light, feel free to state your question. During the coffee break, refreshments will be served upstairs, and of course, for other needs. There is a second Q&A, so perhaps you can sort of focus your questions depending on which presentations you have heard. Of course, in the end, if you remember a question that you would like to pertaining to the first section, you're free to pose the question as well.
The event will be concluded with a little bit of meet and greet refreshments, and management will stay for a few minutes or longer. So if you have any personal questions that you would like to ask face-to-face, please buttonhole management. With that, I would like to thank for me and welcome Fredrik Tiberg to the stage. Welcome.
Thank you so much, Lars, and welcome everybody to this event. I think it's very interesting to see so many of you here today. A special welcome to our external presenters, in this case, our distinguished medical experts, Lenka Katila, Diego Ferone, of course, here on my side, and also Simron Singh, who later in the day will be sharing their insights about our key development programs in Camurus. Before this, I and my colleagues will provide an update on our progress since our last Capital Markets Day in 2018 and the path forward to our updated five-year vision. This introduction I have divided into the present, the past, and most importantly, the future of Camurus. Looking at a present snapshot of the company, we're a rapidly growing pharmaceutical company.
With Buvidal weekly and monthly injections, which we have demonstrated over the last couple of years since launch. We have an advancing late-stage pipeline with blockbuster potential and prospects for several new approvals over the coming years. We have a demonstrated strong financial performance, for the first time in our history, entering into profitability in the second quarter this year. We're also of course having our unique technology, the FluidCrystal technology, which is commercially validated and has a broad range of applications. What we are doing, we're working, our goal is to develop medicines with best-in-class potential, focusing on underserved patient groups with high unmet medical needs.
I think this will become very clear during the day where we are meeting in various ways some of our patients that we have in different indications, and we are also informed about the medical needs that these people have in their lives. In this, we are leveraging our strong development expertise in the company and our leading technologies. We're focusing on two principal areas, the CNS area with addiction and pain being the main indication so far, and rare diseases, going into endocrinology and oncology, which will be discussed later on here. These are areas that are growing. In a growth phase, CNS is growing due to aging populations, growing addiction and mental health issues, as you will see as we go along here.
We're expecting to see almost 90% market growth here to 2028, reaching $167 billion in annual sales. Rare diseases are also expected to grow, mainly due to a large treatment gap between available treatments and need, and also due to the growing unmet need in some areas and availability of new products. With this very brief introduction, I will go over here and talk a little bit about our track record and what has happened in the company since our last Capital Markets Day. That has been quite a lot I would say. We have had a strong corporate development.
We have transformed Camurus from a pure R&D setup in our last meeting in 2018 to a fully integrated pharmaceutical company with infrastructure across Europe and in Australia. This, of course, does not only include commercial sales and so forth, but the whole supply chain, of course, we have made available. That's, I think, quite an achievement. Note that we were a completely academic setting in 2018, which I think you can see that our employees have grown over the years. Actually, tomorrow, we're all heading, the whole company, to Helsingborg to host our first global meeting since the launch preparations for Buvidal in 2019. That will be a very nice experience for us all and inspiring.
Commercially, we have been strong in execution, successfully launched Buvidal in opioid dependence. We have secured access, reimbursement in key markets, and we have emerged as a leader in opioid dependence treatment in our markets as well. We've had 12 quarters of double-digit growth. On the pipeline side, we have reached nine market approvals, centralized and national. We've had successful life cycle management approvals, so we'll come back to that in Peter Hjelmström's presentation later on, and advanced four pipeline programs to phase III or registration phase. We have completed 11 clinical trials in this period and invested more than SEK 1.3 billion into the pipeline. On the corporate side, we have strong revenue growth, as you have seen, and you can see in this graph here as well. Profitability entered into 2022.
In these quite uncertain times, as I'm sure you are all feeling, at least I am, it feels good that we have a solid cash position and at this point, no debt. Our market cap has grown from around SEK 5 billion to now over SEK 12 billion. If we take a historical perspective, I remember in 2005, we had actually a valuation going. Then we were at around exactly SEK 40 million. It's been a nice journey over the years. Bumpy, though, sometimes. Okay. With that, going from the past to the present, it feels good then that we have delivered during these years, and that gives us confidence in our vision going forward. We have set up some clear goals in terms of our commercial development, increasing our revenues 5x over the next five years.
We will have more about that from Jon Garay, our CFO, later on here. Establishing a commercial infrastructure in the U.S. is something that we are right now planning for a potential launch of CAM2029 in the U.S. late 2024, early 2025. Also, we are expecting to see new approvals from the R&D pipeline, as you can see here. From a corporate side, we're working and will be working to increasing our operating margin as top line grows. Sustainability is, of course, another important focus. How are we going to get there? We have identified a number of strategic levers for realizing our vision. This includes a commitment here to sustainable value creation to all involved. Buvidal market penetration, that is, our present markets, increasing our market shares.
Expand to new geographies and indications, and then importantly, advance our in-house pipeline to new approvals and launches. Finally, we are also increasingly focusing on our business development efforts and potentials there. Starting out with the sustainability side, we have worked with that very focused since middle of 2021, where we conducted a new materiality assessment in the company, which lays behind our updated strategy, which we now and where we have a reporting aligned with the UN directives. We are focusing on four different areas. Of course, patients, safety ethics, people is employees and collaborators, environment and being a responsible business. Just to take this away from just being talk, just give some aspects of concrete things that we're working with right now.
This May, we got a call, I should say, or a proposal, a request from the Ukraine Ministry of Health and the WHO. They had a request for humanitarian aid donation of Buvidal for treatment of opioid dependence in Ukraine. Since that came in, we have been working hard to manufacture for the Ukraine and make sure that this could be shipped. Now we're working together with the stakeholders to implement this into the system. That's just a more concrete approach. We're also working with global campaigns towards patient stigma and reducing that for patients with opioid dependence and rare diseases. We just recently finished a campaign around overdosing together with our partner there. Then, of course, it's employee wellbeing and strengthening our compliance framework where we have appointed a new head of compliance.
From that side over to our growth engines and starting with opioid dependence, this crisis continues, unfortunately, year -by -year. As you can see here on the right-hand side, overdose deaths are following. In the U.S., there was more than 100,000 deaths in 2021 in drug overdoses, of which 80% were opioid overdoses. This is, of course, an area where we definitely need to do more. We're seeing similar trends in Scotland, and Samantha Nickerson, she will be telling us a little bit about the trends and what we are doing together with other stakeholders to impact this issue in Scotland. There's a high need for access to better treatments and treatment alternatives, and long-acting injections have been identified as a new paradigm in this treatment setting.
There are significant limitations with daily medications, and that's, of course, something I will come back to also later in the presentation. What is going to drive growth for us over the coming years? This will also be something that Richard Jameson is talking about. As you can see, one of the important thing is, of course, the high unmet medical need, but also the fact that we have been able to, through our development, demonstrate significant benefits with Buvidal as a treatment for these patients, including showing superior treatment outcomes versus daily medication, higher patient satisfaction, and improved quality of life.
We are continuing this work together with our partners, both physicians and key opinion leaders, policy makers, and user groups to build and extend the scientific evidence base, not only for the particular indication, but in the broader use and the broader context clinically. Life cycle management is another important issue. The outcome of this is, of course, also the ultimate outcome is having patients getting an improved treatment and an improved life, which feels really satisfactory from a business perspective. Aside from the market penetration and increase in shares, we're also working with expanding into new markets, especially then, I should mention from our own sake here together with our partners, we have done some significant advances in the Middle East and North Africa recently.
Over the past few months, we've got two new approvals for Buvidal, one in Saudi Arabia, where we actually had a priority review, and we had a recent audit by Saudi Arabian officials and in Egypt. These are large markets. Overall, the Middle East and North Africa have maybe 3 million opioid users or so. It's quite unclear in terms of statistics. And of these, the numbers say that there's approximately 300,000- 1 million injection users. There is a very significant unmet need. Due to these approvals, Buvidal may or will be the first treatment available for opioid dependence in these markets with a significant untreated population. Another market which, it's not everything that goes according to plans, especially when you are not in control of the situation.
One market that we haven't been able to impact as we have wanted is the U.S., which really represents a huge opportunity for Buvidal, of course, and also a major issue in America with 10 million Americans misusing opioids and only 1.4 million receiving treatment. Clearly a big opportunity for Buvidal, which has the name Brixadi in the U.S., licensed to our U.S. licensee, Braeburn Pharmaceuticals. There is a very large treatment need. Long-acting injections are, despite us not being on the market, approaching SEK 800 million in sales this year with only 3% patient share. We believe that there is still a very big opportunity for Brixadi, provided, of course, that it comes to market as soon as possible.
The path to approval here is that, FDA, as you know, have issued a tentative approval. That means that the product is approved from a clinical safety and also at that time point, chemistry and manufacturing and controls perspective. However, as you know, there was a hiccup last year, and this was due to quality issues at Braeburn's third-party manufacturer. I was hoping to have some very concrete information about the resubmission for this meeting, but sometimes you don't get what you want. But we are still hopeful, and I'm expecting to hear more at our next meeting towards mid to end of September. Hopefully then things will be clear. We'll come back to that in Q&A, I'm sure.
Post-approval or potential post-submission, there's a two-month review time or maximum six-month review time, depending on how the agency defines the indication. On the good side, I think we have a very strong product in terms of the product profile, both in terms of its availability in both weekly and monthly dosing forms, multiple dose options, much smaller injection volumes, needles, room temperature storage, et cetera, including clinical data versus standard treatment with superiority outcomes, which is unique for Buvidal. We are spread a little bit over markets. Vivitrol, which is Alkermes naltrexone product, is only approved in the U.S., and it's relatively stagnant in sales.
Our main competitor is then Sublocade, and the only market we have coexistence as of yet in terms of is Australia, where Buvidal currently has around 80% of market share. Indication expansion is the next step, and we'll have more from that from Peter Hjelmström and then also put in perspective by Lenka . We believe and we are working based on the phase III trial results that were positive, and the phase III study was completed in 2020. We have registration processes ongoing both in the EU and Australia and are expecting CHMP opinion in Q4. In Australia we just received questions, and we are expecting that to go towards the approval decision is expected somewhere around mid next H1, mid-H1.
In the meantime, we're also preparing, our commercial teams are preparing for extended launch into this, potential new indication expansion. There is a high unmet medical need, which Lenka will come back to. We have estimated the market to about half of the current expectations for opioid dependence. Leaving Buvidal aside and going into the rest of our late-stage pipeline, that is phase II and onwards, most of the day today will be focused on CAM2029, and that's why we have our eminent guest speakers here. Acromegaly, neuroendocrine tumors, where we have phase III studies ongoing, and then recently started the phase II- B study in polycystic liver disease.
We also have a phase III development ongoing, or it's actually our partner, Rhythm Pharmaceuticals, who have licensed our technology for development of a weekly setmelanotide treatment for genetic obesity disease, where there is currently a phase III study running nicely, and the second study planned for the second half of this year. Potential to start during the autumn here. We have a quite per se stable prostate cancer program that we are currently having discussions with partners around. More importantly, later on here, we have this summer talked about our results from a phase II-A study in Raynaud's phenomenon, CAM2043. This was, as I said, quite mixed results, or the only mixed results we had was the primary endpoint, which was not met at the primary time point of six hours.
I think there is a clear indication of efficacy, unique, especially in the most important outcome, which is the Raynaud's Condition Score, where we had statistically significant reduction in the condition score up to 15 days after dosing. We are right now in a decision phase evaluating the data, and we'll come to a decision later on, probably in Q4, and inform you more about that. In the meantime, and I will leave the early phase programs ahead, but in the meantime, I'll leave the focus on CAM2029, which is our largest opportunity. Here you can see there is an established treatment in terms of somatostatin analogs.
It's a market that have been growing year- by- year for 20 years and now reached $3 billion, and where somatostatin analogs represent first-line treatment of both acromegaly and neuroendocrine disorders, neuroendocrine tumors. However, despite their strong success on the market, these treatments have significant limitations, and we'll hear more about them later, in terms of plasma exposure, limited disease control, and most importantly, perhaps directly is the patient inconvenience of these treatments. Therefore, we developed octreotide subcutaneous depot, and this product is designed to address key limitations of current treatments. If we're looking at this, we are having three target indications, and in each indication, we have different value offerings. In acromegaly, we're targeting improved patient experience and using our enhanced exposure to potentially also achieve improved disease control.
That's not the formal superiority readout in the phase III program. In neuroendocrine tumors, we have designed our program for superiority in progression-free survival. As a secondary point, we also have overall survival. In symptomatic polycystic liver disease, where there is currently no treatment available, we're targeting potential first approval in the indication. I believe we have a risk mitigated registration program, and we certainly have a very attractive product profile. Here is the current ongoing phase III program, and this will be discussed in detail by our next couple of or after the break. We have two phase III studies, where recruitment is just being finalized in acromegaly. ACROINNOVA 1 and ACROINNOVA 2 here. That's a randomized controlled trial and a long-term safety study.
Our big study in gastroenteropancreatic neuroendocrine tumor, SORENTO, the newly started phase III study, and then a bridging study over to our prefilled device. We are predicting that NDA and MAA approvals could come somewhere, and that's why we are talking about commercialization also. In acromegaly, earliest somewhere in the end of 2024. We're estimating an interval here, depending on the market, up to mid-2025. For neuroendocrine tumors from end of 2025, mid-2026. We believe this is a very significant opportunity for Camurus based on the attractive properties and also that the market is very concentrated. There are very few physicians. It's easy to, from our perspective, to penetrate the market. We have a very differentiated product candidate, and we also have a switch opportunity.
There is a lot of patients currently in treatment with the 1st -generation long-acting depots that could be quickly switched over to CAM2029. We've done a lot of market research, both own, third party, and also bought existing reports. Consistently, this market research points to quite high potential, peak patient shares for CAM2029 in the range of between 20%-40% for acromegaly. You can see here for neuroendocrine tumors. This depends a little bit how the data comes out, of course, and that's responsible for the range. PLD in the bottom here. Financially, that represents a very significant opportunity. The idea for us is now to, in Europe, use our existing infrastructure and prepare for launch. It's a focused audience, as I said. Significant market potential of over SEK 4 billion across these three indications.
We also have the opportunity of using our existing commercial infrastructure, which is scalable, to address this target audience. In the U.S., which is the single largest market, we are estimating the market potential to more than $15 billion across indications. We've had very positive payer response from the initial interviews, recognizing the benefits of the profile and the likelihood to be on formularies. Here, we are planning to start initiating the building of the commercial organization, which would mean then implementing medical science and market access functions next year and have a full commercial team in 2024 ready for launch. These are our late-stage developments. Another thing that we are working with now quite intensively is diversifying the business through business development efforts.
Here, key objectives for this, which Jon will talk about much more here is, first of all, that this can be a stepping stone to building our commercial U.S. commercial infrastructure. We'll get back to that a little bit more in Jon's presentation. Diversify our product portfolio in CNS and rare disease indication areas. Then we're also looking at new technology platforms and believe that this is an opportunity for significant additional value creation beyond what we have spoken about earlier here, which have been purely organic growth- driven. Where are we going from here? I think it's very clear that we are going to be hyper-focused on growing Buvidal in our market. Laser-focused, some people say. That is, of course, number one.
Expanding into new markets and indications, absolutely an important priority for us, including the chronic pain opportunity. Advancing our R&D pipeline to new approvals, and here we're talking initially about, the earliest is the acromegaly opportunity. Of course growing and diversifying our business, through inorganic growth opportunities. Finally, of course, fully implementing our sustainability strategy. With that said, I think I have. I do believe it's my telephone. It stopped. With that said, I will leave over to Lars, and thank you everybody for listening.
Thank you very much, Fredrik. Now we're moving forward in the agenda and it's time to have a financial outlook. I would like to welcome Jon Garay Alonso up to the stage. Welcome.
Thanks a lot, Lars. Good afternoon, everyone. Thanks a lot for joining us this afternoon in this important occasion for us, where we are going to share with you our vision and strategy for 2027. A few minutes ago, Fredrik was sharing with us the track record of Camurus, and that Camurus has shown a fast sales growth in recent years since Buvidal was launched a few years ago. You can see behind me how the blue bars show that our revenue has been duplicated year -on -year, delivering a CAGR above 100%. This is done thanks to Buvidal market penetration and geographical expansion. While Buvidal has been clearly focused on accelerating the commercial execution, we cannot forget that Camurus has R&D on its DNA.
Camurus has been investing more than SEK 1.3 billion SEK in the last five years to bring the late-stage product candidates into the market, as Fredrik has been saying. While doing that, you can see in the green bars that we are starting to have a way to profitability. We have had been showing negative operating results in recent years, but you start to see a trend in these green bars. So much that Q2 2022 was our best quarter ever, delivering a positive earnings per share of SEK 0.14 . It can sound a modest amount, but this has been a historical milestone in our company performance. This has been possible thanks to two factors. One is sales growth, and the other one is margin stabilizations. Clearly now, we know which is our path to sustainable profitability.
We will not forget that Camurus, we will continue investing to bring the pipeline Fredrik has shared, which is chronic pain management, which is CAM2029 indications to market. Our commitment this year is to invest around SEK 500 million to make it possible. Third data point we would like to share with you about our track record. We think that today we can issue a firm statement for a company that is listed in the stock exchange nowadays in these conditions. We truly believe we have a strong balance sheet. Our statement is based on four data points. On one side of the balance sheet, at the end of Q2, this is public information, we have finalized with about SEK 0.4 billion in our bank accounts.
Also it was the first quarter that we delivered positive cash flow from operations, another historical milestone with us. If we go to the other side of the balance sheet. Clearly, and it's public information, we don't have debt. Our net debt is equal to zero, and our equity ratio is in the range of 78%. With these three, I would say, facts, a fast sales growth, a way or a path to sustainable profitability and a strong balance sheet. We think that we are very well-positioned to continue creating shareholder value to 2027. How are we going to do it? Well, now we are going to share with you the four aspirations we have in order to achieve it.
First one, we envision Camurus to be a company with a SEK 4.5 billion top line, delivering a 30% CAGR growth over these years. Probably we are going to grow much more than any other economy in the world. The second one is we need to solidify our path to profitability. We envision a company delivering an operating margin of around approximately 50%, that it will mean more than SEK 2 billion year-on-year by that time in 2027. The third one is our equity ratio. We aspire to have a company with an equity ratio above 30%. Now you can think, wow, today Camurus, when we did the Q2 report, we were in 78. The difference is going to allow us to drive our fourth vision.
To drive an agenda in partnership and M&A that it will allow us to create value for our shareholders. Clearly, we are not going to do anything. We will do what we need. This means that we need to find partners or targets that they are synergistic to us, either in the commercial stage, either in the pipeline stage or in our technological platform. This is going to be the four aspirations or the four pillars. Now, even more important, you can be wondering, "How is Camurus going to do it?" Basically we are going to have four drivers. Okay. Driver number one is to continue sales growth. Driver number two is profitable business. It will not be a path to sustainable profitable. We will already be a sustainable profitable company in 2027. Improved cash generation.
The fourth one is continue having a strong balance sheet to support our M&A agenda. Okay. Let's go in a bit more details in each of them so we can follow the conversation. Number one, sales growth. We have shared with you our vision to become a SEK 4.5 billion top line. How we are going to do it? Two drivers we think we have. First one is Buvidal. We have shared with you the track record of Buvidal. We think that with Buvidal, via market penetration and geographical expansion, we can build up a commercial brand delivering SEK 3 billion in 2027. It's only SEK 3 billion out of SEK 4.5 billion. The other SEK 1.5 billion will be driven by innovation.
All the pipeline that today we are talking about, chronic management, acro, GEP-NET, Fredrik has mentioned it, more colleagues of mine will be covering it. We will try to bring into the market ahead of that. There will be SEK 1.5 billion. Short number, SEK 1.5 billion , but it has a huge meaning for us in Camurus. Why? Because if we step back and we reflect on it means that 1/3 of our sales by 2027, it will come from products that we have just launched into the market. Camurus talks about innovation, but 1/3 of our sales will be innovative products. The second data that is important is by that year we will be a full diversified pharmaceutical company.
If we step back, we will be operating in opioid dependent segment, we will be operating in endocrine segment with acro, and we will be operating in oncology segment with GEP-NET. Three business units come to market. Finally, our intention to drive an M&A and partnership agenda will help us to deliver additional growth. This is our vision number one and how we are going to deliver it. Now we go to vision number two, profitable business. On one hand, Buvidal sales growth will allow us to fund the development on CAM2029 and chronic management. In other words, Camurus is ready to self-fund all its investment in R&D. This is important because this implies that when we launch acro, when we launch chronic management, when we launch GEP-NET, all these launches, they will be fully accretive to our earnings per share.
In fact, they will allow us to fund any new structure we need when we have decided to go direct into the U.S. Finally, we will continue being very disciplined in our OpEx management. By that point in time, we will have three businesses and we will need to decide what to invest, how to invest and of course, return on investment and time to execution, it will be key. This is our vision how to achieve an operating margin of approximately 50% in five years. Driver number three, cash generation. I think we are going to do this via two levers. Lever number one, working capital management. We are going to do it in an efficient way as many other companies. We will be working to reduce days to collect, days of inventory and to improve our days of payment.
Today we are in a percentage of our sales of double digits. Our aspiration is to be in the midpoint of single digits, around 5%. Number two, capital expenditure. We expect to be humble in the way we manage our capital expenditure, investing year-over-year below our depreciation. As we grow, as we become a multinational company operating in different sectors, we will need to invest in certain strategic projects. We will do it with a vision of positive return on investment and short- to mid-term execution. We will not be searching and we will not be engaging in long-term projects with uncertainty. We will try to be very sure in what we would achieve in three-year period. Number four, foundation for growth. We have been sharing with you the data points on our balance sheet.
We have been sharing with you that we believe Buvidal growth will self-finance our pipeline. We have been sharing with you that CAM 2029 will be accretive to our earnings per share. Basically, we think we will have a strong balance sheet to go into a partner or into M&A transaction at that point in time or even today to a certain stage. However, it is foundation for growth, and we need to find the right partner. We need to find the right targets that they fit in our strategy as a company. The question is: How can we create value through a transaction? What you see behind me is quite the standard, right? Any company tries to go from a long list to a close on day one transaction. Today is not about the process. Today is
You know, I have been working on this area for the last decade. My previous company, I was doing a certain number of deals, about a handful of them. There are two things I have learned, and I have been sharing with Fredrik and our board when we are discussing it. For me, there are the two things that I have learned that make a huge difference when you succeed or when you fail. The first one is who is going to be the partner you identify? Because there needs to be five requirements. There needs to be a very good strategic fit. Fredrik has been talking about our strategy in M&A. If there is no fit in a strategy, there is no reason to pursue.
The second one, it needs to be a stable company, and the management of that company needs to be solid, so we don't destroy value via the acquisition. The third one, Camurus is coming to a growing phase. It's coming to a stage of becoming a multinational pharmaceutical company. Skills and competencies will be key assets for us, and we can get them via transaction. The number four is very simple. It is without a financial evaluation that is positive, we will not engage. The fifth one is value creation. Okay? I will go into that in a few minutes. With these five metrics, the next one is here. This is the other thing that is different for us. When we close the deal, when day one comes, we will execute the plan to create value.
That means that the value creation plan needs to be done from this stage to this stage. Because in day one, we execute. We cannot plan. For me, I learned this in a hard way in one transaction in the past. These are going to be our differential aspects when we get an approach to a potential partner on M&A agenda. The other area is what is value creation is synergies. We are probably looking in the same way. That's not so differential that other companies are looking. We are looking for synergies either in the revenue, so it can be pipeline, commercial, sales force. We are looking for synergies either in the cost, it can be manufacturing, supply chain, headquarters, and it can also be in the financial area, okay? Because we can have their net working capital, we can have their CapEx, we can have their tax.
Now that I'm coming to the end of my presentation, I would like to leave you with a wrap-up of my presentation and the key points I would like to keep you in mind. By 2027, Camurus ambitions to become a company of SEK 4.5 billion, driven by Buvidal and innovation. Camurus ambitions to be a company with an operating margin of 50%. Camurus ambitions to have a balance sheet delivering an equity ratio above 30%. We in Camurus, we expect to create value for our shareholders year -on -year, organically, but also inorganically. With that, thanks a lot for your attention, and I would like to give the word back to Lars.
Thank you very much, Jon. Now, we've heard about a little bit of the bird's-eye perspective on the commercial side of Camurus, and it's time to move on into a specific market. Thus, I would like to welcome Richard Jameson, who will talk about how to establish market leadership in the U.K. market. Welcome, Richard.
Great. Thank you, Lars. Good afternoon, everybody. In 2019, we launched Buvidal into some markets across Europe. In that time, we've emerged as the market leader in the field of opioid dependence. You've heard from Fredrik and Jon how we've added some significant value in that time. Today, I'd like to talk to you about the fact that Buvidal is a real innovation in the treatment of opioid dependence, and I'll talk about that in a moment. Also, I think I'd like to share with you our successful commercial execution that's created the value that we've achieved so far, and more importantly, how that's a foundation for us to deliver durable and sustained growth going forward in existing markets and as we expand geographically. Let me talk a bit about Buvidal in the treatment of opioid dependence.
You've seen this from Fredrik, just a bit of background on the treatment. Opioid dependence is a very serious disease with serious consequences to families, individuals, and of course, society. It has the biggest burden of all the illicit drug users for governments, et cetera. We know current treatments, daily treatments are effective, but they do have significant limitations for patients and for outcomes. There's a clear high unmet need for innovations in this area and access for patients into treatment. Just to put some granularity on that, in Europe, and I'll come back to this in a moment, there are 1.4 million estimated problem opioid users. About half of those are in treatment.
We also believe there's another group of patients that are in treatment for chronic pain and in pain clinics and primary care, but also have a diagnosis of opioid dependence and not treated for opioid dependence right now. You can see the seriousness of this disease. You know, there's 12,000 people have died in Europe and Australia in 2021. It has a significant impact on individuals. In the MENA region, it's a little less clear. We don't know the overdose deaths, but we do know there's a large number of injecting drug users, somewhere between 300,000 to 1.1 million. It's estimated that less than 100,000 patients are in treatment, and most of those in one country. There's a huge unmet need and a need to create access in those countries.
If we look why Buvidal is such an innovation in this therapy area, if we look at daily treatments, they are effective, but they rely on the patient taking the medication every day as prescribed, and in reality, that does not happen. We often see patients using illicit, med drugs on top of their medication, so the adherence is poor. We see a significant burden for patients. Often, they have to come in every day to the clinic or a pharmacy to have their dose supervised. Doesn't allow them to live a normal life, of course. They're susceptible to misuse, diversion, and abuse. They sell a product or misuse the product, which causes a public health consequence. We also know there's high relapse rates.
If you start 100 people today on daily medication, in six months, you've only got 50 people still in treatment. There's a clear unmet need here. As I said, if you remember the number earlier, of those patients with a problem opioid use disorder in Europe and Australia, only about half are in treatment. Half choose not. One of the reasons is because the rules and regulations about coming into treatment and having to turn up every day puts people off, and they won't. If they're not coming into treatment, of course, that's a high-risk time for them to relapse and potentially overdose. How does Buvidal address all these? Well, I think we can tick everything.
We know that with Buvidal, you have your dose given over a month or a week, and during that time, you have a therapeutic level of buprenorphine. If you take an illicit opioid on top of that, you will not see any benefit. You won't feel the euphoria or anything. It's providing that protection around adherence. Of course, coming into the clinic once a month or once a week is a lot less burdensome than having it. Remember, these are specialist clinics, and people are driving a long way sometimes to have treatment. They get on a bus in the morning and take an hour's bus ride, stop, have their medication, take an hour's bus ride back with a gap in between, and quite often their day is gone just in that treatment system.
We know because Buvidal is administered by a healthcare professional, it negates the risk of any misuse or diversion by the patient, of course, 'cause it's once inside the patient. They have nothing to sell or give away. We know from our clinical studies and also from the real-world experience and the real-world evidence that Peter will talk about later on as well, that we are seeing better retention rates of patients in treatment. We don't see this dropout level, and typically we're somewhere anecdotally at 80% retention after one year, compared with that 50% I said that are dropping out at six months with the daily treatments. This is an interesting one.
Users now seem to want to come into treatment because of the availability of a product that doesn't have all the burden and stigma associated with it, and Australia is a very good example of this. Australian market was growing very slowly, maybe 1% a year. Since the launch of long-acting buprenorphine in Australia, it's grown at 10% in that time. Clearly there's new patients now coming into treatment. What I think is really inspiring for us is that we hear a lot of patient stories about what happens to patients on this product, and all these things are covered, and I've just picked out five. We have hundreds of these now of this feedback, and they're all from different countries across our markets to show that there's relevance in every one of our markets.
You can see they're saying things like, "You don't have to stand in lines, in queues everywhere." If you're trying to move away from the scene, coming every day to the same place where everybody else is in the scene is not particularly helpful till you get away with that. They don't have to. They are not reminded every day. It's revolutionary for them. They can go on holiday. They can meet friends. They can live that normal life. Then we see this very emotional stuff. It really is magic. It's amazing. Almost as everything as before and giving a new look, outlook on life and their desire to help people to have that. We see this consistently from every market numerous times every month, those patient stories. It really is quite profound.
That's undoubtedly helped us when we launched Buvidal because the experience we had, there's a lot of talk, a lot of noise, and people share their experiences, and that's helped us. We've had a very successful launch, I think, with Buvidal, certainly from a regulatory point of view with our regulatory team and all the approvals they've got and our commercial execution. As you saw from Jon and Fredrik, we've delivered significant value. You saw the sales development approaching SEK 1 billion this year. You can see our market leadership as well, led by Finland. Now more than 60% of all the patients in treatment in Finland receive Buvidal, and that creates obviously a higher cash share.
Similarly, in Australia, Norway, and Sweden, we're now above 20% and probably the leading brand in all those markets. Other markets are developing a bit more slowly 'cause we have some hurdles and some challenges to overcome, which we'll talk about in a moment, but making good progress in those markets as well. If we look at our launch, we set out in 2019, we'd started to build our commercial team or a lot of them in place and have achieved an awful lot in that time, I think. You can see now 82% of patients in treatment live in a country where Buvidal is approved. We have more than 30,000 patients in treatment now. We're approaching 1 million doses have been given in that period. I've mentioned the regulatory approvals.
We've been very successful in demonstrating the value it brings, not just to healthcare settings, but to the wider society. You know, reduction in criminal activity, et cetera. It's a high value, and that's enabled us to deliver on some strong pricing compared with the standard of care, up to 10 times. We've got a great team in place, very expert, in terms of both commercial and clinical. And as Fredrik also mentioned, it's not just about launching a product, you've gotta build a distribution network for a narcotic across all these countries, and that's not as straightforward as it sounds. We've achieved that, and now we can deliver Buvidal to every patient within 24 hours of them, even earlier. Okay.
Really, I think that learning and that launch success we have has really given us a strong platform that we can deliver durable growth going forward. Just to go back here, I know I talk about this a bit. This is the 1.4 million, and you've got half people in treatment and half people out of treatment. If you look at those people out of treatment, why not? Why don't they come into treatment? There tends to be, this is a bit general, but there are three reasons. One, they don't want to, but they don't want to today. Tomorrow they may change their mind, of course, 'cause the nature of this disease is people get more sick and they et cetera, and they're more likely to come to treatment. They cannot access treatment.
Some countries have restrictions on the ability to access, and a lot of patients cannot cope with the rules and regulations, so bear that in mind. Then if they are in treatment, you can see the medication treatments, it's generally either buprenorphine or methadone, and that split changes by market. If we turn that into the addressable market, and I showed this slide in this same meeting in 2018 when we were assessing where Buvidal was gonna work, and it still stands good today. We know that those patients on sublingual buprenorphine have a very easy transfer to Buvidal, and lots of patients make that move now. We also know there's patients on low-dose methadone that, again, can be transferred onto Buvidal relatively straightforwardly. It's in our label. We have this group of patients that recycle.
Now, every year, if you look at most markets, about 30% of patients drop out of treatment and 30% come back into treatment. It may not be the same people, but most markets are either growing slowly or relatively flat, so there is this group. Now, of course, if they're coming in to treatment, they're often coming on illicit opioids. We can initiate people. It's in our label, straight onto Buvidal, so that's an option there. Then you've got this group of people outside of treatment who do not come into treatment 'cause the burden of the everyday turning up may well now come into treatment. Total addressable market is somewhere in towards 750,000 patients. I think our learning is that there actually is an opportunity beyond that as well.
We're seeing increasing demand from patients on higher dosing methadone to come onto Buvidal. They would not have come onto sublingual because they still have that same burden around the daily treatment, but they are interested in looking at long-term. There's a number of research programs ongoing with new methods to be able to transfer people from those higher doses. We also have this group I mentioned before who are not in treatment for addiction, but are in treatment for chronic pain, but they would have a diagnosis for opioid dependence. They have a resistance, I think, to attend an addiction clinic 'cause they don't see themselves as that addict, if you like, and so they tend to stay in that group.
There's a group there, and if we have that combined indication with pain as well, we have the luxury of treating their pain and their addiction. Of course, there's those new geographies. I've already mentioned the opportunity in the MENA region. I think what's interesting here is there's a growing recognition of the need to treat. A lot of these countries kind of ignored the issue, but now they're beginning to recognize that more and more. I think it's very important that Buvidal actually is the first product approved for opioid dependence in a number of those markets that Fredrik mentioned, in Egypt and Saudi, for example. That's because they had some concerns about approving daily treatments because they're worried about creating an issue around diversion. That's a significant move for us, I think, on that.
Fredrik's mentioned, Jon mentioned, and I think I mentioned that we're gonna have 100,000 patients in treatment by the end of 2026. How are we going to do that? Well, why are we confident for this? Well, firstly, I think hopefully I've shared with you today, and you've seen it elsewhere from the patient stories, et cetera, that Buvidal really is a game-changing product. It makes a difference to patients. We have robust clinical and real-world evidence that demonstrates how Buvidal works. We have very highly positive patient and healthcare professional experience with the product. There's growing awareness among the treatment community. This is quite a close community of people, and they often talk to each other, and you often hear these stories.
If you ever want to go onto Twitter and put Buvidal in there, you'll see quite a number of patients talking to each other about this. We've done some market research in a number of countries now, and if you ask patients, you've given them profile of Buvidal, more than 40% say they would like to try it. They see the benefit this product will bring to them where they are, and of course, we've got these new patients who are now will enter treatment because of Buvidal.
We're also seeing some wider stakeholder recognition of the value that we bring, and Sam in a moment is gonna talk a bit about that in the U.K., that change at a policy level has really given us an opportunity to expand our use of Buvidal in that market because we're now understanding and addressing the access and funding hurdles that we are faced in some of our, some of our markets. What's interesting, we know that in those markets where we've addressed the access and funding hurdles, we get quite this is within three years, in three years we have market share on average of 23% of the total patients in treatment. We know if we address these challenges, we know patients want to try it, and we know physicians want to prescribe it.
This is based on the countries in Australia, Finland, Sweden, Norway, Scotland, and Wales, where we've seen high level of penetration on average. We now have three key pillars to sustain our growth. One is to continue to build access and penetration in our existing markets across Europe, including some of the big European markets like the U.K. and Germany, et cetera. Expand geographically. We have a big opportunity in the Middle East region, for example, and other countries as we go around. Expand our indication to include those patients that are not in treatment but probably have opioid dependence 'cause of a pain condition. If we look at how that's built, you can see this is where we estimate we're gonna be ending this year with 37,000 or so patients.
Access and penetration in our existing markets will drive the majority of the growth, another 58,000 patients in our five-year plan. We have expansion into new countries, giving us the 100,000 which will be reached by the end of 2026. In that graph, this is the big chunk here. I think to demonstrate how we do this, the U.K. is a superb example, and I'm delighted to invite Sam over today, our U.K. and Ireland general manager, to share her experience because we're seeing that wider stakeholder recognition of policy change and how this will influence how we will penetrate with Buvidal. Sam.
Thank you, Richard, for the introduction. The U.K. market represents a tremendous opportunity for Camurus because the U.K. has the largest number of patients in treatment in Europe and Australia. To address drug-related deaths, and also in response to the pandemic, Scotland and Wales accelerated their uptake of Buvidal. However, the new drug strategy, which was published towards the end of 2021, is actually paving the way for change in England, which I will talk more about in this presentation. We have a high-performing team in place now to really capitalize on this, on this change and to make a profound difference to the lives of the patients and their families. As I mentioned, the U.K. has the most patients in treatment in Europe and Australia, but the U.K. also faces a crisis, okay.
In 2021, over 6,000 people lost their lives due to addiction. Scotland specifically has the highest number of recorded drug deaths for any country in Europe and has the unwanted title of the drug deaths capital of Europe. You will also see from these numbers here, while we have a high number of patients in treatment, we have almost the same number of patients who are not in treatment. This particular crisis has really led to a change. It's led to a high-level government focus on how to address this crisis, a commitment to address the crisis, and to find ways in which lives can be saved. Coupled with the pandemic, this resulted in accelerated uptake in Scotland and Wales of Buvidal.
As you can see from that quote there from Angela Constance, strong government support. During the pandemic, Buvidal was a COVID contingency measure in Scottish prisons, and positive reports really highlighted the benefits of Buvidal in that population. Therefore, the government extended access to Buvidal to include the community in addition to the criminal justice settings. Widening this access to Buvidal in the community has actually led to over 4,000 patients being treated in Scotland and Wales combined. What that equates to is 10% penetration of all patients. We continue to drive growth in Scotland and also in Wales. We have a high-performing team that are delivering on that growth. We have a mixture of strong commercial expertise, sales, marketing, market access, but we also have clinical expertise.
Very recently, we hired two members of the team who have actually had their own experience of managing Buvidal caseloads. We also, with this team, we are engaging with a very broad stakeholder group. We've alluded to this earlier in the presentation, and we certainly have faced challenges in England, but we are now starting to build momentum. Years of austerity led to disinvestment, and without investment in the system, what we saw was a decimated workforce, a lack of innovation and it did not go unrecognized. The government actually recognized the need for an independent review, which was conducted. What that review did was actually make 32 recommendations for change. Now, I'm not going to go through all 32, but the one I wanna draw your attention to in particular is the clear recommendation for significant investment.
What this actually led to is a new strategy. Towards the end of last year, the U.K. government published a new strategy. The ambition of this strategy is to build a world-class treatment and recovery system. In order to do that, the government is investing over SEK 500 million over three years to rebuild the treatment system. I think what is also really important is that this strategy recognizes the need for innovation. The strategy recognizes the need to do something different, and within that, recognizes the role that Buvidal can play in treating patients. Where does that leave us now? We've talked a little bit about the new strategy. We've talked about the accelerated uptake in Scotland and Wales due to the pandemic, and also the high level government support.
What all that means for us today is that in Scotland, Wales, and Northern Ireland, 100% of health boards have access to Buvidal. What that also means in England is that 74% of the local authorities or municipalities also have access to Buvidal, and I wanna draw your attention to the 84% here. Within the drug strategy, 50 regions in the first year are getting enhanced funding, and Buvidal is already prescribed in 84% of those. Our focus now is on how we drive the increase in the number of prescribers and how we drive the depth of prescribing. We've talked a little bit about the new strategy, paving the way for change in England, and we can obviously capitalize on this.
What I wanna do now is just show you some of the focus areas that we will continue to keep our eye on. We will drive that funding and access in those top 50 areas. We have 84% of those. We've got more to go for. We will start to unlock the criminal justice opportunity. Now, I've talked about funding and the funding that has been made available, but within criminal justice specifically, we still face a funding challenge that we need to overcome. In the prisons in England at any one time, you are looking at between 18,000 and 20,000 patients that are being treated with opioid dependence treatments. We still have a challenge there to overcome. Importantly, we need to be building on informed choice for patients.
I talked a bit at the beginning of this presentation about how we can make a difference to the lives of the patients and their families, and what I now want to do is introduce you to Kevin and Jim from Scotland. Kevin developed problems with addiction at the age of 19 after he left prison. He has a history of poly drug use. He has been homeless, and he has actually described himself as leading a very chaotic life. Despite entering treatment for opioid dependence, he has relapsed multiple times. He's actually overdosed on at least nine occasions, and Kevin certainly considers himself to be very lucky to be alive today. I want to introduce you also to Jim, who is his support worker.
Now, Kevin started treatment with Buvidal towards the end of December 2021, and what you're now going to see is a video where Kevin talks about how his life has changed since being treated with Buvidal.
Oh, it's 180 degrees. I've got my house. I'm engaging with all my family. I'm in here volunteering. I engage in here with people like yourself. With me, it was alcohol on top of the methadone. I always felt I needed something on top of it just to make my life, get through life in general. Whereas with the Buvidal, it's just opened my eyes. You know what I mean? It's just, everything's just cleared up, and I want to have a life again. I bumped into my wee sister on the town, and she phoned my son and says to him, "I don't think your dad's got a way back this time." Thankfully, with all the support and the help that I got, I have managed to get it back.
She says to me last week, just last week, she's like, "I'm amazed at you. I did not think you were going to survive that, Kevin." I've never been very confident that I'm going to get off it and stay off it at all. I've never had that confidence. But this time, with the Buvidal and the psychosocial stuff, I'm very confident. I believe we need to start making ORT attractive, and I believe Buvidal is the drug that would do that. It'll be a pioneer. You know what I mean? No, I don't care that anybody says no, but we need to let people know what's possible. As I says, he was at death's door most days that I seen him. For him to get through it's just, it's a miracle.
Right. A very touching case. Now it's time for the Q&A session. A friendly reminder, there is a microphone on the side of your chair. Raise your hand if you want to ask a question, and then press until there is red light. I would welcome the former presenters up, Fredrik, Jon, Richard, and Samantha, please. A lot of the potential lies in increased penetration or access, as we saw in the previous presentations. It's a large part, so can you tell us about what you can do as a company? Because it's rules and regulations. What can you do, like, working with patient advocacy groups or working with the regulatory agencies to improve the situation for people who are outside treatment, like 66%, if I'm correct?
Yes. I mean.
Which is due to rules, regulations, and.
Yes. Yeah
not wanting to go.
There's a number of questions there. Last year, I mean, I think firstly, taking those people outside of treatment, I think one of the things is we are able to support the places where they congregate to give them some informed choice, build awareness, let them know there's new treatment options available. Many patients will go to places like needle exchange centers to get clean needles, et cetera. That's the time to engage those then and give them a balanced choice of what the treatment options are. They probably already know about methadone. They probably already know about something called buprenorphine, but they may not know about long-acting injectable buprenorphine.
Right.
That's the time to catch that group.
Mm.
In terms of wider access and penetration, I think the stuff that Sam demonstrated today, you know, in the U.K., getting a government. 'Cause if you think about it from a government perspective, this is a very positive thing 'cause people with opioid dependence are usually a burden on society as well, because they're not working often, and obviously, because the nature of the disease, there's some criminality associated with that disease. So if you can engage more people into treatment, there's a much lot of va-
Mm
larger value beyond just the healthcare setting, and it's important that we engage those wider policy makers so they understand that and they can support creating access.
Right
for those groups.
Can I add one extra point?
Mm-hmm.
I think the other thing is you cannot underestimate the power of word of mouth. When you see patients who really have turned their lives around and other patients see them, I've seen examples where patients have said, "My goodness, I cannot believe what Jim looks like, and I want to look like Jim." I think you cannot underestimate also the patients themselves and the word of mouth plays a key role.
Right. 'Cause I'm thinking the rules and regulations for current treatment guidelines a re probably construed at the time of methadone being the dominant treatment, for instance. With the successes of Buvidal, do you think that will help sort of a feed-forward mechanism, like when regulatory agencies see the results, that they would be more inclined to sort of change the rules to accommodate?
I mean, I think.
a new treatment landscape?
I think that the rules will remain for daily treatments because there's a balance between risk and benefit there. They have to try and manage that these products aren't diverted too widely, so they keep that control and those rules and regulations. I don't think it applies to Buvidal because you don't need to come in every day for your treatment to pick up.
Mm
'Cause you know there's no risk of diversion. I don't think those rules and regulations will get in the way of that. I think people will see that very quickly.
Right.
I think the most and also important is just if you're just looking at the trajectory of all markets. I think a lot of this growth potential is already in that trajectory. I mean, if you just take it fundamentally and I think one of the things that Richard alluded to is, of course, the large group of patients that are on methadone that are increasingly seeing the long-acting treatment as a treatment alternative. Albeit, it's not easy to switch a patient on high methadone doses to Buvidal, but that is being addressed quite significantly now by clinicians inventing new methods for transfer and so forth. It's not available at this stage, but from a labeling standpoint and so forth.
Mm.
I think that over time, this development will be driven also very significantly.
Mm.
In Australia already, I think there is quite a lot of activities in that space.
The U.K. has obviously been a very successful market and one of the first where Buvidal was launched. Do you have any learning experience that you can bring with you, penetrating new regions?
Yeah, yeah. We're learning from all our markets actually as we go along. I mean, there's different things we learn from different times, you know. Clearly, I think the U.K. is particularly ahead on that policy change. You know, we could not fix it working at a local market level. I think Sam was probably fair. We knew the austerity. There was a lack of funding, and nothing was gonna change that. We had to get the government, not just us alone. There were lots of people talking about the independent review.
Mm.
They needed more investment. Now that's come, that frees up that. Would you say, Sam?
I think that's very fair to say, yeah.
Yeah. It's fair.
The uptake in Australia is driven very much by, I think, also by physicians who recognize the value of the product. That in turn is driven by the fact that we interacted very early with physicians and allowed them access through clinical studies and so forth to the treatment, and also had collaborations with the New South Wales government already in 2017. I think for a new launch, you know, new indications, say acromegaly and so forth, we also have a lot of learning from that. That, I think, is to interact and collaborate with the users, and that's both doctors and other people, stakeholders around the system.
Right. You mentioned that Australia is the only market where Buvidal is sort of head-to-head with Sublocade. Perhaps could you tell us more about that dynamic where?
Well-
where it was actually a competitive situation.
I think it's indicative of the strength of Buvidal as a product overall and capturing markets. I think that's self-evident, so to speak. We'll see. I mean, the reason for this is of course that we have a strong sales team, but also that we have strong data, clinical data with superiority, and we also had the collaboration around the DEBUT study, which showed the improved patient satisfaction. I think it's driven by users and physicians.
Mm.
It's the result of that is the current market share.
Jon, you have a 50%-ish operating margin as a target, five-year target. Could you tell us something about the journey there? I suppose it won't be a linear development from current levels up to 50, but is it sort of back-end loaded with a rapid increase?
Somewhere in the middle. Yeah, I mean, in the first two years, we don't expect to have a big acceleration. We expect to consolidate our profitability. The acceleration of the operating margin will come when, mainly CAM2029, it comes to the market. This is the point in time in which, if you remember, Buvidal finances our pipeline. When our pipeline comes to market, it's fully accretive to earnings per share. We expect, I would say the year one and year two, which is 2023, 2024, is basically to become profitable, solidly profitable. Acceleration of profitability, it starts in, I would say 2026, 2027, midyear 2025.
Great. Do we have any questions from the audience? Could we start here, please, and then we will.
You have touched upon it, but when we were here last time, several years ago, we discussed the U.S. market and the rather annoying or even outright stupid regulations where long-acting drugs were at a disadvantage.
Mm-hmm.
As I remember it, we didn't discuss other markets in that respect. Are there generally a scarcity from within when it is about the regulations for long-standing?
Mm-hmm
... as compared to daily use of, these drugs? Or has there been an easement on the regulations?
I think generally speaking, there has been a lot of initiatives taken to make in favor of long-acting injectables. However, I think the structure of the U.S. market with a big private market was perhaps not ideal from an introduction standpoint of a new treatment paradigm. Indivior, who was, you can say, is the market leader in the U.S., they have gone over more to the organized health system and focusing their strategy on that because it's more able to take on this kind of challenge. There is still a lot of hurdles left in the U.S. system, and some are being addressed time by time.
I think if something is positive with the fact that we are not still on the market, is that once Buvidal is on the market, I think it will come in at a better condition than it was in 2018 when Indivior first launched. There is a clear positive movement in terms of regulation and also understanding the dynamics in the system. You can see that in the sales approaching almost $1 billion total for long-acting products. If you look at it from a market share perspective, it's a big disappointment. I think there is a huge opportunity, but it still it requires. Hopefully we'll see that coming over the next few years.
Right. We have a second question, please. Sir, yes.
Do I need the microphone?
Well.
This is on.
By your chair.
It's on your side.
On side of the chair. Should be there somewhere.
Erik Hultgård, Carnegie. Two questions, if I may. One for Fredrik, maybe a bigger strategic question. We've seen you're investing a lot in your late-stage pipeline, but you haven't disclosed much about the early sort of any early development projects that you have based on your current technologies.
Mm-hmm.
My question is basically, do you intend to invest more in the early pipeline or do sort of IP limitations make you more prone to investing in new technologies and new companies?
I think really our focus has been right now on execution in the commercial setting. Of course, the late-stage asset is very attractive, and from a return on investment standpoint, it's natural for us. It's not like we're not working in the early-stage pipeline. There is a lot of activities going on and a lot of interesting developments also on the technology side, which I think will come up maybe more towards the early part of next year. We are investing, but with our priorities being late-stage development, commercial. That's our clear focus right now.
Thank you. The second question for Jon, maybe, on your targets for 2027. You had SEK 1.5 billion from innovative medicines. Could you sort of give some color on the split, I guess CAM2029 versus Brixadi royalties, whatever you assume there? I guess that's important also for the margin development. Thank you.
It's-
Thank you.
Brixadi when it comes is geographical expansion of Buvidal. The innovation aspect of Buvidal is the lifecycle management, which is the chronic pain. Basically, if we are talking very high level, roughly 1/3 of SEK 1.5 is Buvidal lifecycle management. Two-thirds of SEK 1.5 is CAM2029, which is only with two indications, acro and GEP-NET. It's our assumption.
Right. I think we had a question from the gentleman in the burgundy sweater, please.
Yes, that's me. Patrick from DNB. Also a follow-up question really for what Erik asked on the 2027 targets. I mean, this year you're saying that you're gonna spend approximately SEK 500 million on R&D. What are your expectations when you get to 2027? Will it be on a similar level or will it be higher?
I think we align with what we disclose in Q2. We expect our peak investment in 2023, 2024, keeping SEK 500 million , and then we expect to probably go a bit more modest in the range of SEK 400 million, about that.
SEK 400 million is really the level that you feel is sustainable to drive growth and because I suppose that when you get to that point, the money that you will spend at that time is not really related to the things driving your growth at that time, right?
No. It will be new projects we will find, and it will be the early stage that Fredrik Tiberg has referred.
Okay. Last question then from me. When it comes to your forecast for Buvidal, what are your expectations on pricing given that you're now expanding into new geographical markets?
Yeah. I think we are expecting. I mean, of course, there's always pressure on price, so we are expecting a certain pressure on price, but no dramatic impact. Definitely there is a component of you know continuous slow price decrease in our markets. Also, as we are moving into less high-priced markets, so there will be a pressure, but that's compensated by volume.
Correct.
Okay. Great. Thank you.
Well, perhaps a follow-up on that. Well, sir, please go ahead.
A follow-up on the 2027 figures. In the SEK 3 billion for Buvidal, is there any figure on the U.S. in that?
Yes, of course. Yes.
Very modest.
We have the royalties, the mid-tier royalties that is public information that is a signed deal with Braeburn. By 2027, Brixadi is in the market.
Right. We have a question from Miss, and then the gentleman in the gray shirt.
Yes. Thank you. Suzanna Queckbörner at Handelsbanken. I have three questions as well.
Yeah.
The first one to Fredrik, please. I was wondering, you mentioned a new technology platform that you were thinking of developing. How should we think of that beyond the FluidCrystal?
I mean, what we are looking at is from a corporate development standpoint. We are looking at three targets in terms of potential licensing or M&A activities and so forth, and that includes also expanding our, because one of our real expertises in the company is, of course, you know, in the area of drug delivery technologies and platforms. We're looking at that. I wouldn't overemphasize it. We actually have some very interesting developments with regards to our current technology also. We're expecting some things to come on that as well. But definitely it's one of our focuses from potential business development, and we are looking at some technologies right now or technology companies as well that could be interesting too as a synergy.
It's not part of our core strategy, I should say.
For Jon, based on the margin and also how you've been communicating about CAM2029, should we not assume partnerships going forward anymore for the U.S. Launch?
We can never remove this option out of the table because if we receive a very good offer, we are forced to share this with our board. You ask us today, which is our vision. Within today, we can create value by bringing CAM2029 directly with our own resources and setting our own footprint. That's our priority but if anyone comes with an astronomic offer, we are obliged to share this with the board and they will make the best decision.
Thank you. One question for Sam. In terms of the U.K. launch and the payer situation that you explained, how would a patient in England with opioid addiction versus one in Scotland access currently Buvidal?
Sure. The system's different between Scotland and England. In Scotland, well, the health system is run by the NHS, whereas in England you tend to find obviously more third sector or voluntary providers. The actual patient presenting for treatment would not differ, just where they would go would differ. You have more, if you like, of a specialist setting in Scotland, and but the actual journey the patient would take wouldn't actually be any different. It's just there's a slight nuance there that the funding is from the NHS for Scotland, Wales, whereas the funding is via the local government or the municipalities obviously in England. Yeah.
If it is available, would they be able to initiate on it as soon as possible, or do they need to actually start on a daily first?
If they are currently on a sublingual formulation of buprenorphine, they can start, so to say, and.
Yeah. There's no requirement.
No
To start on a daily treatment first. If you're new to treatment, you can start. If it's available and
Yeah
Approved, you can start straight onto Buvidal.
Yeah. If you are a methadone patient, you would have a test dose to make sure obviously you can tolerate the buprenorphine.
Right. I think we have.
Does that answer your question?
Oh, sorry. I think we had a question from the gentleman in the gray shirt as well. Are you still interested in asking a question? No? Right. Time.
Last this time.
All right. Yes, please. Go ahead.
Yeah. Viktor Sundberg, Nordea. Just a question on your revenue guidance here on the 5x revenue growth. Do you assume any kind of probability of approval for CAM2029? Is there a risk adjustment, I guess, is my question in the prognosis?
Yeah. Yes. The answer is yes. We have re-adjusted our prognosis. The data is based on external third parties' research.
Just to clarify, I mean, it's like the press release tomorrow. It's an ambition, not a prognosis.
Sure. Also another question, in the U.S., do you feel confident that your partner here, Braeburn, has the resources to compete against Indivior? Have you had any indication of what kind of sales ramp up they have been undergoing here in anticipation of a launch in the U.S.?
I think you can never be, you know. I do think that they have invested significantly into this product, of course, and product opportunity and so there must be significant efforts making sure that it returns something to the owners. I think that's the best guarantee for success going forward. I cannot comment that now. I mean, obviously they've had a lot of time to fine-tune their launch strategy, et cetera. Time will tell. We are not kind of overloading our hopes, but we are keeping them quite realistic at this point.
Just a very quick final question also on CAM2029. You said before that, maybe if you're looking for M&A, you're looking to build a U.S. sales organization maybe to support CAM2029. Is that the main scenario in your outlook here, or is it more to build your own sales organization in the U.S.?
Our figures are based on building our own sales organization there.
Yeah. Thank you.
Right. Unfortunately, we're out of time. Remember, the good news is there is another Q&A session as well as meet and greet after the event. There will be more opportunities for you to talk to management. Now please, refreshments will be served outside, coffee, conference.
Just one comment from me. Remember, the highlights are after the break, not before the break.
It seems most of you found your way back. Apologies for the bell, but sometimes it's important to keep roughly to the schedule. Anyway, now it's time for the second section of today's Capital Markets Day, and I would like to introduce Peter Hjelmström, CMO here at Camurus, who will talk about life cycle management and chronic pain. Welcome.
Thank you, Lars. Good afternoon. Time passes quickly, actually last time I was standing presenting in this room was six years ago at Camurus Capital Markets Day in December 2016. At that time, we were just finishing our phase III clinical trials with Buvidal. As you know, these trials came out positive, otherwise I would probably not be standing here. At the time of launch, that launch was supported by a very strong evidence base for the product. The results of the trials had also been published at very good scientific journals. However, since the launch of Buvidal, we have continued to work to increase the knowledge about the product and its use in the marketplace.
I am actually very proud of the medical team, and the rest of the team at Camurus, in what we have produced, the last couple of years. Just look at these figures. 69 scientific publications about the product. 141 presentations at scientific conferences. 17 investigator-sponsored studies, supported, including over 2,500 patients. These efforts have not only led to an increased knowledge about the use of the product, but it has also enabled us, to update, the label of the product. In Europe, we have got the high monthly 160 mg dose approved, enabling us to cover a full dose range with the product.
In Australia, in addition to the 160 mg monthly dose approved, we have also corrected some deficiencies that came with the first approval of the product there, including now the ability to directly initiate on the product. However, the life cycle management of the product doesn't end here. Right now we have a number of investigator-sponsored studies ongoing with the product, including the large AREDIA trial on top of this list, which is a trial in Germany, an important market for us, looking at patient-reported outcomes, quality of life. The first interim results of that studies were presented at a conference in Munich in July this year. Also a number of studies ongoing in the United States, including the IDEA Innovation, MAMS, RDD studies.
All of these studies done in collaboration with the National Institute on Drug Abuse, NIDA, with important readouts. Last on this list is an investigator-sponsored study in Australia with Professor Nicholas Lintzeris as the principal investigator, looking at patients with opioid dependence and chronic pain. At Camurus already several years ago, we saw the medical need for treatment of pain in patients with opioid dependence. Our U.S. partner, Braeburn Pharmaceuticals, performed a randomized controlled placebo-controlled trial in opioid-experienced patients with Buvidal a couple of years ago. We have already announced the top-line results of this study. The study came out positive.
What you want to see here on the left-hand side, is the separation between the green Buvidal curve, CAM2048, and the white placebo curve. What you see here is a decrease in average pain scores, which was the primary outcome of the trial, during the run in on weekly Buvidal. Then a separation that became clinically significant and also statistically significant after a couple of weeks when the weekly depot effect was worn off in the placebo group. Also, this was a placebo-controlled trial, and rescue medication was used. If you look on the right-hand side, you see here that the Buvidal CAM2048 treated patients used less rescue medication as well.
As I mentioned, these differences are believed by external community, clinicians that were talked to to be clinically relevant. Based on these results, we have now submitted regulatory applications in Europe and in Australia. We can come back to this in the question-and-answer session, but these regulatory submissions are now being reviewed by the authorities. With this short introduction, I would like to summarize that we see that there is a medical need for Buvidal, not only in treatment of opioid dependence, but also in treatment of chronic pain. There is currently no medication approved for treatment of both opioid dependence and chronic pain. As you will hear from our next speaker, Dr. Lenka Katila, we believe that buprenorphine, and in particular, depot buprenorphine product like Buvidal, might have an important role in the treatment of both these diseases.
Thank you very much, Peter. Now, it's a pleasure to introduce Dr. Lenka Katila from Akademiska sjukhuset, Uppsala University Hospital. Welcome.
Thank you very much. Good afternoon, ladies and gentlemen. As you heard, I'm anesthesiologist, but pain specialist, and most of my time I treat patients with pain and addiction because we have a specialized program at Akademiska sjukhuset in Uppsala, where we treat those kind of patients almost 30 years. Speaking about these topics, we have to start about the pain. All of you have probably experienced pain at least once, right? If not, you are unlucky one because you have a genetic defect, and it makes your life very serious. Well, if you don't feel pain, you don't have very important information from the body that something is wrong. That's very important thing in acute pain. Pain is always very unique.
It's not only the damage itself which is defining the pain, it's all the story around you, your background, how you are raised up, your education, your psychosocial situation, your employment status, et cetera.
As it's very unique for each of us, you all need very unique treatment. There is no universal medicine which treats it all. It's always the complex of treatments which we need to use for that. To do a good job, we need to make something what is called pain analysis as doctors. Okay, I should change the slide sometimes also. Well, the pain analysis consists of finding what kind of pains do we have. The three main kinds of pain, what we describe as doctors are nociceptive pain, which is the usual pain at the muscles, bones, and your viscera. Neuropathic pain, it's when some kind of nerve is damaged, and then nociplastic pain. Nociplastic pain is actually the disease of the pain system itself.
It's an imbalance between the downstream regulating signals, which are actually usually lowering your pain and upcoming signals, which will be extensive and very difficult to manage. Next thing, what is very important to understand that acute pain and chronic pain are two very different entities. While in the acute pain, the damage is very often corresponding to the intensity of the pain, in chronic pain doesn't have to be the truth. In chronic pain, actually, the scars are already healed. We don't see anything on X-rays. We don't see anything wrong with the patients as doctors, but still patients perceive very strong pain. In this point, the pain is losing this warning meaning. Actually, other way around, the pain is giving anxiety, which very often is perceived by the patient as a warning and making it more difficult to handle it.
Well, now let's look what happened with opioids. In acute pain, opioids are very strong weapon, which we have against the pain, and we wouldn't be able to do the surgeries. We wouldn't be able to treat acute pain without them. Let's look what happens if we use them for a long time. This third picture is showing something what has happened in nucleus accumbens in brain. When the morphine binds there to morphine receptors, it's starting the cascade of reactions which leading to the release of dopamine. Dopamine, it's our feel-good substance. We are happy of it. It's relieving anxiety, but of course it's relieving the pain as well. If this continues, if the drug is coming to the brain once and once more, the release of dopamine decreases until we empty the depot of dopamine, and instead the total anxiety is coming.
We are suffering of addiction at that point. Chronic pain or chronification of pain is something what we don't understand completely actually. We know from fMRI pictures when we do the pictures about the function of brain during the chronic pain, that there are several centers in brain which are activated when the patients got chronic pain. Those centers are like thalamus, amygdala, prefrontal cortex, and we call them circle of fear. Why? Because we see it as a sign of stress. It can be concomitant disease, it can be psychiatric disorder, it can be isolation, which is provoking it can be a difficult childhood. We see that this circle of fear activation, the stress is leading to chronification of the pain because there is development of neurochemical inflammation, which is affecting nerves in those brain centers.
This second picture is actually a very classic model of development of addiction. Addictive people usually start with addiction, with taking overdose. At some point it's experiment, but many time, it's also somehow self-treatment of anxiety or problems. The process is in the brain when you take the fMRI of the people with these problems, you will see basal ganglia, which are with the blue picture here. The next stage would be withdrawal stage, and there will be amygdala and thalamus, which will be seen. The third stage, it's a preoccupation stage where you have the state of cravings, and it's prefrontal cortex, first of all, which is activated. Probably you can see the parallel to the chronic system, right? The activation of the addiction centers is producing fear, stress, and it's leading to worsening of the pain situation.
Actually, even though acute phase opioids helps the pain, chronically use, they worsen the pain. It's very, very important part of it, an explanation why we cannot treat chronic pain without treating the addiction if it happens. Well, what happens, those patients who comes to me usually says, "I don't take those drugs because I want to be high, I want to have fun. I struggle with pain, and if I don't treat it, I will be nervous. I'm screaming to my children. I have a very bad mood, and it's impossible to live with it." They are talking about something what we call hyperkatifeia, a situation where you are affected by opioids, and you cannot leave them, and also you don't feel good. Usually, the patients in pain don't take medicine to experiment or to take overdose in the first day.
They treat their pain. I usually say to them, "Well, the real heroin addict doesn't use heroin to feel high. They use it to feel normal again. They use it not to have pain, actually, and they use it not to have anxiety." Knowing that, World Health Organization, International Association for the Study of Pain, came out with a very important statement on opioids 2018. It says that while in acute pain and cancer pain, the use of opioids is evidence-based, in chronic pain, it's other way around, it's very questionable. It's not that we shouldn't use opioid at all, but we should use it in very well defined group of patients during limited time and with limited doses. Even though they still are in the risk of mood disorders, tolerance, dependence, addiction development, and other neuropsychological disorders.
The next question is, are all the opioids same? Are there good guys and bad guys? Well, I am nobody's perfect, as I usually say. I know there are those who can help, those who can harm, and there are those who can kill. What is the difference between them? What is defining why they are so? Well, it's rather complicated process to explain, but the main answer is on their effect on opioid receptor. Opioid receptor is a protein sitting in the membrane, and you should imagine a structure where are coming different things, other substances activate it. Sometimes they fit very well, sometimes they fit little bit bad, and it's defining how the receptor is reacting and activating the other side of receptors.
The subunits of opioid receptors alpha, beta, and gamma, and β-arrestin are central in defining what action it will give. While alpha, beta, and gamma are expressing analgesia, respiratory depression, and constipation, β-arrestin is presenting tolerance development. The different opioids are acting different on those receptors. How do we choose opioids? Well, there are different international guidelines. As you know, in Sweden, we have regional organization of healthcare, and thus we have regional guidelines. Those are Uppsala guidelines, actually. They don't differ so much between the regions and between the international guidelines. You can see that we recommend different opioids according to the type of pain, but also who is introducing the therapy, if it's a general practitioner or if it's a specialist in pain.
For example, those most dangerous opioids, or the most potent opioids, those are fentanyl, methadone, and actually high-dose buprenorphine. That should be started by the pain specialist. Let's look to the comparison of most commonly used opioids in Sweden. In the first column, codeine. It's a weak opioid. It's actually a natural alkaloid, which you can see. And it's slightly moderate effect on pain, but also quite low amount of side effects. You develop tolerance on it very, very long time. Of course, you can be addicted to codeine as well, but it takes very long time. When we look at the stronger morphine, it's more potent against the pain, but also has more side effects. Oxycodone is also very potent, and actually, compared to morphine, has a lot, a rather better use for patients in renal failure because it's not dependent on the renal excretion.
What is very important is very high addiction potential. I guess nobody here keeps it as a secret that excessive use of oxycodone is one of the considered reason of opioid crisis in U.S.A. The last three opioids, fentanyl, methadone, or buprenorphine, are the strongest one. They're really superior according to their effect. Very low doses of them are treating the pain very effectively. What is different here is their side effect profiles, as you can see. While fentanyl and methadone in overdose will kill you because you will stop breathing, probably buprenorphine will not do the same thing, unless it is combined with benzodiazepines, alcohol, or other sedating drugs.
Also, the effect of endocrine system, constipation, is much lower. You can get addicted on it as well, but probably you will not get dysphoria, the mood disorders which are very difficult to treat, the pain. Why is the buprenorphine good guy? First of all, superior analgesic effect thanks to the binding characteristics on the opioid receptor. Secondly, slow dissociation and long effect. Third, very high binding capacity on the morphine receptor and affinity to that, which is leading to the when there are other opioids present in the system, they will not come to the receptor because buprenorphine will not let them come, and that is the genius idea behind the addiction treatment in this case. Of course, the drugs itself are not the only solution.
We need a complete team to treat the addiction, not only with the medicine, but also we need occupational therapist, we need physiotherapists to start those people move again. We have nurses, addiction psychiatrists, and so on. Our program in Uppsala was started in 1994 by Annika Rhodin, Leif Grönbladh or Klas-Åke Nilsson, and thus we will have soon more than 30 years experience treating pain patients with addiction. Our average patient is 52 years old and suffered of pain 20 years, 15 years on opioids. 80% of them has got psychiatric disorders, and most of them are addicted on oxycodone or fentanyl when they come to us. 13% of them has injection treatment when they come to us. What the patient says about the treatment, how they are satisfied.
Well, 75% of them perceive very good effect of treatment against the pain, and 25% quite good. I mean, nobody is not satisfied, and I think it's great. Of course, in pain, it's not the only the pain, the thing what we are measuring. We are measuring very often quality of life. Before those patients enter our program, they have lower quality of life than homeless people or average pain patients in the Swedish Rehabilitation Register. After the program, the quality of life is higher than those people who went through general rehabilitation in the Swedish Pain Register. I will be very happy to show you more numbers when we finish our ongoing study, SALSA, where we recruit patients who were in the program since the beginning.
Right now, I can give you only the testimony from our qualitative study, which was done by my colleague Hanna Ljungvall. She was the previous director of the program. This patient said in her interview, "Well, of course, it would have been wonderful to be completely medicine-free. I've eaten tons of medicines of all kinds, but at the same time, and then I had no choice. So to survive, and then I choose it because I didn't want to just lie in bed and being in a lot of pain." You understand those people don't want to take pills to have fun. They want to live. They want to move. They want to go to school with children. Pills are very often a symbol or also ritual.
One of my very first patient on Buvidal told me, "It's wonderful to skip thinking about taking the pills all day and still be pain-free." Imagine this, after 20 years of pain and 15 years on opioids, where probably you have to take pills every two hours. You wake up in the night every two hours to get the pills to be pain-free. My belief is that if we continue with this job and we treat patients with the smart drugs which treat both their addiction and pain at the same time, we can save their lives. Thank you.
Thank you very much, Lenka, for a very compelling presentation. I'm sure there will be questions for her later on in the Q&A, but now it's time to move into the late-stage pipeline. As Fredrik mentioned earlier, we've saved the best for last, not least our eminent external presenters. Right now it's time for Markus Johnsson to take the stage. Welcome, Markus.
Thank you, Lars. It's a pleasure to be here to present CAM2029 and how we intend to take this important product through registration and to the market. I should say that in this session, I will provide an overview of CAM2029, including key product features and the status of the clinical program. This will then be followed by our expert guest speakers, Dr. Diego Ferone and Dr. Simron Singh, who will provide further details into the acromegaly and NET indications respectively, and also put CAM2029 into a clinical and medical perspective. CAM2029 or octreotide subcutaneous depot is in phase III development. It's an investigational treatment of three serious rare diseases with high unmet medical needs. Acromegaly, gastroenteropancreatic neuroendocrine tumors, GEP-NET, and polycystic liver disease, PLD.
The product is designed for enhanced efficacy and patient convenience, which we will elaborate on further in the presentation. Octreotide belongs to a class of drug substances called somatostatin analogs, in short, SSAs. These substances have found wide use in different therapeutic areas. They are anti-secretory and anti-proliferative, and importantly, of course, they're used as first-line treatments in acromegaly and neuroendocrine tumors. SSAs have also found use in other fields of endocrinology and oncology, as well as in gastrointestinal, kidney, and liver diseases. The SSA market is dominated by long-acting injectables, with the key products being Sandostatin LAR based on octreotide, and Somatuline Autogel based on lanreotide. Now, Fredrik mentioned earlier that the market size, the global sales 2021 for these key products, was close to $3 billion. Despite the tremendous success of these products, they do have limitations.
These limitations relate firstly to the respective product design. So they both products are injected with very large needles, which may cause, of course, injection site pain and of course, patient inconvenience. Both products also need to be dosed by trained healthcare professionals, so typically no option for patient self-administration, which is not very flexible, you could say. Both products are stored under refrigerated conditions, meaning that every time you have to administer these products, they need to be conditioned at room temperature for at least 30 minutes before they can be administered. Secondly, the both products actually have limited ability to control symptoms and impart biochemical control to patients. Here we have to mention also the latest approved SSA product, which is on the market, which is Mycapssa.
It was approved in 2020 for the treatment of acromegaly, but it's not approved for neuroendocrine tumors. It's an oral octreotide product for twice daily dosing, but also this product has limitations. For example, it has significant food effects, requiring dosing under fasting conditions twice a day. That's difficult for compliance. Also, it has shown modest efficacy in the pivotal trials, so 42% of patients in the U.S. pivotal trial for the U.S. registration actually lost control when switching from injectable SSAs to the Mycapssa product. CAM2029 is targeted to address these limitations with differentiating features such as ready-to-use formulation based on our leading FluidCrystal injection depot technology, rapid onset and long-acting octreotide release, 500% increased plasma exposure versus Sandostatin LAR at constant dose with the potential for improved efficacy.
As you can see in this picture, the product design comprises state-of-the-art prefilled syringes and prefilled pens, enabling convenient patient self-administration. Seeing the device on a picture like this is one thing. It's another thing to actually see it in reality. It's a very simple device, and it's very intuitive to use. The patient only needs to carry out a few simple steps for the injection. Basically selecting the subcutaneous injection site area, for instance, in the abdominal area, removing the needle cap, pressing the device against the skin, and inject. The injection takes about six to seven seconds for the highest dose of CAM2029. I should also say that there is another nice feature of this device, and that is that the injection needle is actually hidden for the patient, so they never see the needle.
Besides that, of course, the needle in our device is much thinner compared to the competitor products. We have a 22-gauge needle, and it's also much shorter than compared to the competitor products. To put this into perspective, a 22-gauge needle for CAM2029 means about 40% thinner needle compared to Somatuline Autogel. Importantly also, we have room temperature stability, so that means that our product is truly ready to use. You can pick it off the shelf, and you can use it directly. Now with these features, we believe that CAM2029 has potential improvements over the current SSA treatments. For patients, of course, as we discussed, self-administration should mean reduced treatment burden of dosing visits and increased patient autonomy. The enhanced octreotide exposure may lead to improved symptom control. Overall, these product features may lead to improved quality of life.
For the healthcare system and for, of course, for healthcare professionals, there is no need for complex reconstitution and temperature conditioning, time saving. There is no risk for incomplete dosing or product waste due to needle clogging, which is a drawback of the Sandostatin LAR product, which I forgot to mention, but that is a reconstitution product with risks of product waste and incomplete dosing. There is no risk on that side with CAM2029. This is potentially resource saving. Of course, the potential for improved efficacy and overall treatment outcomes is of high priority. In terms of enhanced octreotide exposure, we have shown in both phase I studies and phase II studies that we have about 500% increase in bioavailability with CAM2029 compared to Sandostatin LAR.
This is more clearly illustrated in this graph showing octreotide plasma concentrations following multiple injections of CAM2029 and octreotide LAR or Sandostatin LAR at the same dose. Clearly, you see that the octreotide plasma concentrations are much higher for CAM2029 compared to Sandostatin LAR over the complete dosing period. Another noteworthy feature is that we have an immediate onset of release, octreotide release when after injection compared to the Sandostatin LAR pharmacokinetic profile, where you actually have a lag phase after the injection of one to two weeks before you actually attain therapeutic plasma levels. This study was performed in healthy volunteers, and the pharmacokinetic profiles were mirrored by the pharmacodynamic profiles in terms of IGF-1 or insulin-like growth factor 1 concentrations. It's an important biomarker.
For CAM2029, we saw an immediate and significant suppression of this biomarker, which was sustained throughout the dosing period. For Sandostatin LAR, we saw a slower suppression of IGF-1, and the overall suppression was not that extensive with Sandostatin LAR. I know this will be discussed later on also in the talks by Doctors Ferone and Singh. So far, we have completed five clinical trials with CAM2029, showing dose proportional long-acting octreotide release, enhanced octreotide exposure with about 500% increase in octreotide bioavailability, rapid and sustained suppression of IGF-1 in healthy volunteers, biochemical control indicated in acromegaly patients. Dr. Ferone will mention that further in his talk. Symptom control indicated in NET patients, which will be further discussed by Dr. Singh.
We also completed a bridging PK study from the prefilled syringe format to the prefilled pen device, and this is to support our regulatory filings. Finally, and importantly, of course, we have a safety and local tolerability profile supporting the confirmatory phase III trials. Currently, we have two phase III trials ongoing in acromegaly within the ACROINNOVA program, as Fredrik mentioned earlier. The first study is the efficacy study, a placebo-controlled study with the primary endpoint being based on biochemical response in terms of IGF-1. Importantly here, this study is fulfilling the regulatory requirement for efficacy. The second study is a long-term safety trial, a 52-week trial, which is fulfilling the regulatory requirement for safety exposure. I will not go into further details of these trials, but that will be discussed by Dr. Ferone later on.
In the NET indication, we have the SORENTO phase III trial ongoing, assessing superiority versus standard of care of CAM2029 versus octreotide LAR and lanreotide Autogel in terms of progression-free survival or PFS. The primary endpoint will be assessed after 194 progression events, so it's an event-driven trial. This single large trial of about 300 patients fulfills the regulatory requirements for safety and efficacy. Dr. Simron Singh will provide additional details on the SORENTO trial later on. For polycystic liver disease, we have just recently started the phase II-B trial, POSITANO. Before discussing the details of that trial, I would just say a few words on the polycystic liver disease. It's a rare genetic chronic disorder characterized by progressive growth of cysts in the liver. These cysts can cause severe symptoms and a significantly impaired quality of life.
Currently, I think Fredrik mentioned that, there are no approved pharmacological treatments for polycystic liver disease, but there is an increased body of evidence showing that SSAs can be very useful in this indication. It is estimated that roughly 30,000 patients with symptomatic PLD can be amenable to SSA treatments, and in this, in relation to this number it's based on U.S., EU, and Australia. As I said, the POSITANO trial, phase II-B trial, has just started. It's an efficacy trial, placebo-controlled, 3-arm trial where we are assessing two different dose groups of CAM2029 versus placebo. The primary endpoint is liver volume change, and the key secondary endpoint is based on assessing a Camurus-developed patient-reported outcomes tool, PLDS or PLD symptoms.
I would like to finish off with some recent and upcoming milestones in the different programs that we have. Starting with acromegaly, we target completion of enrollment in this study very soon, actually beginning of Q4 this year, so in both phase III studies. Top-line phase III efficacy results expected first half of next year, and we target NDA and then MAA submissions by the end of next year, beginning of 2024. In the neuroendocrine tumor indication, we have started the SORENTO trial. It's proceeding well. We estimate enrollment completion by first half of next year, and the completion of the efficacy part will be after 194 progression events. We estimate that the NDA MAA submissions will be in 2025. For polycystic liver disease, we have received orphan drug designation in the U.S.
We have developed new patient-reported outcomes and aligned these with the FDA. The phase II-B trial is ongoing. It started in June 2022. We target enrollment completion by first half next year, and top-line results expected one year thereafter. With that, I would like to hand over the floor to Lars and our guest speakers of course.
Thank you very much, Markus, and I will quickly hand over the floor again to Dr. Diego Ferone. Please welcome.
Can you keep this slide on, please? Thank you very much for inviting me for Camurus. I hope that I can fulfill the task because what I heard from the previous speaker is a little bit different from what we are used to do in our series. This slide is very important for me because they called two studies, one POSITANO and one SORENTO. I want the third study will be named Capri because I was born there. They remember that. I will never forget this. I didn't realize this one. You should know that neither SORENTO nor POSITANO was my idea because especially for SORENTO, I was involved and I proposed so many different complex names, and that guy came up with Sorrento, where my mother was born.
Since I've been perfectly, I want a Capri study. This is mandatory before we start. Okay. Anyway, let's go more serious. I'm fortunate I don't work anymore in Capri, but I work in another lovely city, which is Genoa. It is on the seaside, a little bit more north, close to the French border. It is not Capri, but it is enough lovely place. The Cinque Terre, Camogli, Portofino, I think you know something. A lot of Swedish people are there, then it is quite popular. Since 20 year I'm working there, and I'm dealing majority with patients with pituitary tumor, including the acromegaly, you have already heard this name, and also neuroendocrine tumor, but we have another big expert on neuroendocrine tumor from Canada. He will talk about that.
I will try to address why it's very important, although Markus already gave you some information, the medical treatment of this chronic disorder, which is acromegaly. Acromegaly is a very complex disease. I will try to illustrate the disorder. This disease, it's due to a pituitary tumor, we will see this later, but is a systemic disorder. It is a disorder which is known since many years. Actually, this was the first patients described by Pierre Marie in 1891, but this was the first patients in which there was the description of the connection between the systemic disorder and the presence of a tumor in the brain, in the pituitary, in the head, in the skull. The disease was much well-known since the ancient.
I don't know if you have heard about the giants, the myth of giants in the Greek tradition. The giants were acromegalic. Acromegaly from Greek is an enlargement of the hand, of the feet, of the head, which describes the main feature of the disease but is a much more complex disease. I will show you why. Is well-known since the past. This is one of the most famous giant, is Robert Pershing Wadlow, which was one of the tallest, 2.71 m. And 450 lbs. This is the comparison with a normal person and with the kids. Another famous acromegalic person was Maurice Tillet who was a French actor. He was always play the role of a bad guy. These poor acromegalic people that are very sweet person, they have to be represented like a monster.
Another one is an actor which was playing the role of the shark in 007 movies. Goldfinger, do you remember? Maurice Tillet is also the guy which inspired the figure of Shrek recently. He's the guy. Is the only moment in which acromegaly has been represented like really these people are. They are sweet person although this horrible feature induced by the disorder. Unfortunately, as I anticipated you earlier, majority of these people with this disorder, here you see some statistical data about incidence, prevalence, the mean age of diagnosis and the fact that can affect either male than female.
Here you see that the majority of these patients, unfortunately, are diagnosed as delayed and for this reason, in the majority of case, they have a large tumor in the pituitary, in this important gland that we have in the head. As you see, when it's possible to remove this tumor, and unfortunately this is possible only when the tumor is small, when is a microadenoma. We intend for microadenoma when the tumor is smaller than 1 cm. Every tumor larger than 1 cm is considered the macroadenoma. Unfortunately, due to delayed diagnosis of this disorder, you see that the majority of these patients do not have remission after neurosurgery when you try to remove this tumor. I want also to tell you that the tumor is, in 99% of the case, benign in terms of tumor itself.
The problem of that this tumor produce a large amount of hormone, and I will show you later. The problem then which is associated to this disease and the fact that, not only they are not cured, but they also have some rate of recurrences of the disease. They are benign, this tumor, but they recur quite often. Is quite high the rate of recurrence even in the hand of the best center with the best neurosurgeon. Here is the recurrence rate within five years after surgery. Then you have patients don't have remission. You only remove part of the tumor, which is good because in the brain it's dangerous, but you have still some tumor activity in these patients. You have those patients which are apparently cured and they relapse.
This is the major challenge that we have with this disease. Just go back few slides on what is the reason of this disease. We have this important gland in the head which is named pituitary gland, which is connected with the brain, with the hypothalamus. This gland produce a large number of hormones which are very important for every our physiological activity. There, you should consider that the pituitary, with its own hormone, it control the thyroid, the adrenal, the gonads, the some function in the pancreas, the growth, the body, many, many. Indeed, one of the most important activity is the production of this hormone which is named, you have already heard from Markus, growth hormone, IGF-1. What happen?
Growth hormone is produced in the, this gland, and you can have a tumor that originated though from this cells that produce growth hormone. This tumor will just simple produce a large amount of growth hormone without any control. Okay? When this growth hormone, which is the hormone that make you growing, but not only that, a part of the growing during the childhood and the pubertal phase, this hormone during our life is very important for the maintenance of the body homeostasis, and indeed is one of the hormone mostly used in the doping. Have you heard about doping with growth hormone? It's very common in the sport, unfortunately. This hormone will not only work alone in its own activity.
It will stimulate a production of another important hormone, which is called IGF-1, insulin-like growth factor 1, the one that Markus was mentioning, which is the best biomarker of this disease. We are lucky in this setting because having a biomarker is something extremely important to control the disease itself and also the efficiency of therapy, whatever therapy you're using. Because if the hormone goes down, it means that you are efficient in controlling the disease. Okay? These both are markers, biomarkers of acromegaly due to this pituitary tumor. When we are talking about this, you now know what, why we refer so much with this hormone, because they represent the problem, the disorder. This is the picture.
Once you have this excess of growth hormone from the pituitary, from a benign tumor as you see, you will have all the body involved. Apart from the features of the name I told you, acromegaly, large feet and large hands, disfigurements, look at this. You have a problem at the cardiovascular level because the heart became bigger and is not functional properly anymore. At a pulmonary level, all these morphological changes in the body, in the organs, they determine a lot of problems which are related to the overgrowth of organs, tissue in the body. Apart from some very important metabolic disorders, these patients became diabetics with hypertension and with many other alterations due to the imbalance of hormones which may occur also for other diseases, but this is really systemic. All the body is basically affected.
Therefore, there was many effort in the past to try to address and to target this disease, trying to cure these patients. Of course, we have still nowadays the transsphenoidal surgery, which is through the nose, which is very modern technique that allow how to remove the tumor when it's possible. Is the first approach. As I told you before, majority of patients unfortunately do not recover from surgery also because you cannot be too aggressive with surgery because otherwise there is the risk of damage of the other function of this gland. Removal of the tumor, it's okay, but with a lot of attention to the remaining pituitary function because many other hormones are produced in this gland. Therefore, in the last 40 years, many attempts to develop pharmacological medical treatment.
I remember my mentor in Holland his question 40 years ago when he published the ad to recruit scientists to work on this. He say, "I want to find a way to cure acromegaly without surgery because of the risk of surgery." Therefore, somatostatin analogs, the medication that Markus has described to you, were developed which still today represent the main, the first line treatment in this disorder. Either he's relapsing, he's a nice patient, doesn't matter. Somatostatin analogs, the current available analogs, which are already mentioned to you, octreotide and lanreotide, they are completely superimposable in terms of just two brand from two different company, but the activity of the two medication are very similar, superimposable because the molecule are similar. Second-line treatment will include other approach, which are pegvisomant, pasireotide.
There are other second-generation somatostatin analogs and anti-hormonal activity in terms of pegvisomant. You see summarized in this cartoon here what we do in these patients. We use first-generation somatostatin analog, octreotide LAR, the formulation that Markus described, and lanreotide Autogel, which are very effective drugs. As Markus described very well earlier, there are some limitations due to the way of administration, acceptance from the patient, and unfortunately, also some limitations due to the dose we have available of this compound. Indeed, what we normally do today when we have a partial control, not 100% efficacy, we can increase the dose above the labeled dose or we can modulate the interval restricting to two months, but this means to two weeks.
This means two injections with the characteristic that Markus described per month. Even in some situations, maybe Simron will explain better to you in the other indication, even one injection per week, which is a lot with that kind of device. We can sometimes combine the therapy with the other medication, do a sort of cocktail treatment. This increases the burden of pharmacological treatment for the patients. Apart from the side effects, but also the fact that these patients to take many medications is something that is not well accepted from the patient. A second-line treatment, as I already described you, we have mainly combination of treatment or new class of drugs with the. We cannot be prescribed as first-line treatment, at least in Europe for pegvisomant.
Pegvisomant in the U.S. can be prescribed, but is a medication that do not work on the tumor, but only on a sort of anti-hormonal activity. Here you see what we normally achieve with this medication, with somatostatin analogs. What you see here that the advantage of this, class of drug is that we can address either the hormone imbalance and the tumor itself because they have a very significant, Simron will address this in another indication, anti-tumoral activity. Normally what we want to obtain in acromegaly, normalize hormone imbalance, you see growth hormone and IGF-1, control the tumor size, and improve of course all the clinical situation, the bad clinical situation of these patients. Here you see what I mean, reducing tumor, hormone levels and parallel this with the reduction of the tumor mass.
Sometimes the shrinkage on tumor are so efficient that the tumor virtually disappear on MRI, although it can still be presented with a small tumor that we cannot visualize. But the effect, the efficiency is quite good. It depend strongly from the exposure of the tumor, the receptor on the tumor cells on the drug. This is clear. This fact that we modulate the dose is extremely important because those depending effect in this system are extremely well known in endocrinology. Which are the current limitation? Markus already addressed some point also showing you some picture, and indeed, the intramuscular or deep subcutaneous with large needle, think that these patients. I have patients that I have been treating since 40 years. Okay?
Because one of the advantages in this setting, if a patient is responsive to this drug, he will be responding forever. Different from what Simron will explain to you, this is a sort of abnormality that we are studying for many years, but we don't understand still why. When a patient responds to treatment with this class of medication, he will respond forever. There is no tachyphylaxis, no escape from the response, either for the tumor control or for the hormone control. I have patients that are treated, for example, successfully for more than 40 years. But you can imagine 40 years of injection or a combination of.
Patients are complaining about this, also complain about frequent visits to our center because not only for the treatment, they have to come to us for controlling the hormone, the tumor, the MRI. It's a lot. Unfortunately, although the very specificity of this drug, unfortunately only 50% of patients are completely controlled. We have half of this population that is not fully controlled, then you reduce the activity of the disease, but you are not able to abolish this hormones imbalance completely. This is another important point that we take into consideration.
For the oral treatment, which is the new in 2020 that we started, the fact that we have to give the dose twice per day, the fact that it's food dependent, is still in the real world, in the clinical practice seems to represent a very big limitation. I don't have much experience with this drug, but when I spoke with my colleagues, they had explained to us which are the major limitations. That some I would have expected because the oral route seems to be favored by the patient, but it's not always like this. There are too many other factors which might change the efficiency of the drug, and that is something that unfortunately is a major limitation. Another point where I would like to draw your attention is the quality of life of these patients.
I described you the disease. It's a very disabling situation for our patients. The quality of life of our patients can be monitored with dedicated questionnaire. We have a special questionnaire which we can analyze the quality of life in this patient, in not only from the physical point of view, also from the psychological point of view. There are specific questionnaire which can address this. Majority of patients are complaining for the disease itself, but many patients complain also from the treatment, for the treatment, for the burden of the treatment. You have different scale of patients perspectives, perception about the treatment and the disease itself. The point is that we can measure this.
Indeed, this is one of the most interesting study which was published many years ago, but is still very modern, and it describe the quality of life in patients with this disease when the disease is controlled and not controlled. Not only, these patients are compared with other two population, general population, normal people, or one of the group of people that has the worst quality of life, which are obese people. Obese people, severely obese, morbidly obese, are patients with a very poor quality of life. They are considered worldwide patients with a very bad life. Look what happened. These are the different items, mobility, personal care, daily living, pain, anxiety, whatever.
Whatever you measure quality of life, what you see that untreated active disease, patients with acromegaly which is not controlled, they have the worst quality of life whatever you want to evaluate in every item. Patients with treated, stable disease, they improve significantly the quality of life. Okay. When we look at the comparison of patients treated or untreated with the normal population, general population, of course, it's much worse. The incredible things that the life of these people, especially untreated people, is even worse than obese patient. This makes clear how is the problem of these patients, and for us it's a very critical problem. That's why we are strongly looking forward for something that can help us. Maybe this can also explain what in part emerged from this recent, more recent study.
This was a German study published in 2012, which shocked the endocrinology community. As you know, if this study would have been published in Italy, I would have accepted more this result. But in Germany, German system where everything works precise, where everything works well, you know what have come out? It come out from a registry, then is something extremely important. The result from the German Acromegaly Registry, which include more than 1,000 patients. Look what they find out, that unfortunately, the number of uncontrolled patients still very high, although we have many possibility of treatment. There is another thing that for me it's shocking. Many of these patients do not receive therapy. Why? Maybe one of the reason why is economic problems could be, maybe, but I don't think in Germany.
Maybe it's because some of the acceptance, compliance of these patients is not good enough. That's why maybe we have this picture today and also describing something which we already know, that 50% of patients are not receiving this therapy or are not controlled adequately for this therapy. If this occur in Germany, I would not even think what occurs in other countries where we don't have a precise measurement of this problem. Anyway, it is an important issue. That's why already in the past we tried to improve the performance of this drug. How? Increasing the dose or reducing the interval, giving more than the normal dose, unconventional dose of octreotide.
For example, this was a study we performed in Italy a few years ago, in which we gave to our patients, which were not controlled with the standard dose, standard treatment, the double of the dose, 60 mg every four weeks, or we reduced the interval of the regular dose, 30 mg, but we gave them every three weeks. This practically means that in this arm, 60 mg you can reach with the two injections of 30 mg. This, the patients, they were referring, "You are killing my bottom," because, you know, twice with the big needle. You reduce the interval to three weeks, then they have to perform, in any case, more injections per year.
The results are interesting because increasing the dose in any schedule you want to consider, both systemic, both schedule, both this approach, they induce a reduction of either IGF-1 and growth hormone in these patients. Both were effective, which means that changing the dose, going above the normal range without changing the safety profile, there was an improvement. Some of these patients became controlled, some of these patients became more controlled than the standard treatment. This could be related then to the increased octreotide plasma exposure. Maybe. This study were not performed also with pharmacokinetic study, unfortunately. But we have a clinical evidence and a biochemical evidence that something happen in this patient. This is the graph that Markus showed you earlier from the phase II trial in which we tested the CAM, finally.
The CAM which has been described properly better from Markus, the characteristic, a part of the route of administration and the way, probably, at least we interpreted this data in this way. When we went to perform the study to check about CAM in acromegaly, in patients which were already treated with the normal formulation of octreotide, what we did, we went to measure either IGF-1 and growth hormone, because are the markers. We would have expected most of patients like this remain on the stable, because was a sort of equimolar. It's not equimolar, but was a equal treatment. Same molecule, octreotide. Okay? What happened? That in some patient, we have seen that IGF-1 or even growth hormone were dropped down, which is strange. Patients stable for many years, certain point, you there.
We interpreted that potentially a major exposure has been better described by Markus, or is it possible that is also a major patient's acceptance? We don't know yet this. We are looking to the phase III trial to understand. In any case, we, in a study in which we would have seen a similar efficacy, we have seen a better efficacy of CAM2029, which was a surprise, but was a welcome surprise for clinician. Here you see the study that are now currently ongoing. Markus already addressed. I will be more quick on this because Markus already addressed it. One study is going, has been designed in a setting of double-blind placebo-controlled trial intended to assess the efficacy and safety as well, but mainly the efficacy due to the data we have seen in the previous study.
Indeed, the primary endpoint in these patients is represented by, in this study, by IGF-1, to see if these, what we have seen in phase II occur more often than expected. Indeed, patients will be randomized in CAM once monthly, and the other arm is placebo this time, because we are going to see the efficacy of the drug. This study is clearly also connected with the other study, which is the study designed for the safety. For the safety, we are very happy to welcome this device because you cannot imagine how much big change this can have from the patient's perspective. We have experience with device similar to this one in other treatment in endocrinology. I'll just mention for you diabetes, and insulin therapy, growth hormone deficiencies, growth hormone treatment.
The acceptance of treatment from patients, the patient's perspectives with similar devices, it's much higher. You can imagine how it change life when you make the patients independent from you, then can easily administer its own therapy, makes a big difference, and it change also the adherence of the patients to the treatment. I'm quite sure due to some study we have performed that the drug and depot of the drug that Markus showed you, the major exposure plays a key role in the control of hormone imbalance. I'm also confident that something can be improved also to the fact that we have a different way of delivery of the drug to the patients in terms of patients' compliance. Well, we'll see.
This study is designed basically for the safety, but maybe will give us also some information in these terms. This is the phase III program progress which was going on. Here you see the enrollment by different countries, and here you see the phase in which we are. As you see, quality of life is one of the items that we are going to investigate quite well, especially if we will be able to reach the self-administration moment, which is the topic, and to see if these two aspect combined might give us a potential more efficiency of, I would say, very old-fashioned drug, because octreotide is more than 40 years now, but probably not explored enough in their potential. You will see also we hear also from Simron what that means in other setting.
Unfortunately, we have an underestimated disease because the epidemiological data that I showed you, it's only because this disorder is definitely underestimated. It's slow-developing manner makes that sometimes these patients are not recognized in acromegaly, then they are in active disease for very long term. This slow development made a high disease burden. We have unmet medical needs, clearly. Reduce the treatment burden, increase compliance and disease control. How we can improve, we probably have a drug with a drug delivery system which is more efficient. We will see better after the phase II trial. We have the way to improve the patient's compliance.
We hope that the combination of these two new aspect might probably give us some extra clue, and probably can, at least what you have on the market today, represent one of the best candidate. Unfortunately, the other attempt was the oral, the Mycapssa that Markus showed you. Other limitation emerged in that study, that some of my colleagues in endocrine field, we saw this limitation already early on the development stage. I mean, the real world data are confirming, and you have seen that 40% of patients, they lost the control, which is something that we don't want when you have a therapy that is able to maintain the control long life. Losing the control is a big problem.
With this approach, it seems that we can improve the control, and that's why CAM2029 is a good candidate for acromegaly control. Thank you very much.
Thank you very much, Dr. Ferone. Now, we're nearing the end, but we're not really there yet because we still have the pleasure to welcome Dr. Simron Singh, who will talk about neuroendocrine tumors. Welcome, Dr. Singh.
Thank you. Thanks very much. I know everybody's tired, so I'll try to get to the key points. I should advocate for a trial from Toronto, but I think Capri is probably a better option. My name is Simron Singh. I'm a medical oncologist. I'm at the University of Toronto, and I'm the head of a specialized clinic for neuroendocrine cancers, one of a unique set in North America. Neuroendocrine cancers are probably underestimated, not as uncommon as we think it is. Steve Jobs, unfortunately, had a neuroendocrine cancer, passed away. Aretha Franklin. We're hearing more and more about it. This looks at the SEER database, which is the largest cancer database we have in the United States. It looked at all types of cancers. You could see some are rising, some are decreasing.
If you look at this pink line here, these are neuroendocrine cancers over this period, this 30+ year period, clearly rising. We weren't sure if this was a phenomenon just in the database of the United States or if this was a global phenomenon, and we did a very similar study in my province in Canada. This is Ontario, which is about 14 million people. We looked at a 15-year period to look at neuroendocrine cancers through the Ontario Cancer Registry. The Ontario Cancer Registry captures 99.9% of all cancers in Canada, given the public healthcare system. What we found, and you're looking at the slope here, this is taking the scale.
This was all cancers in Ontario during that period, and this was neuroendocrine cancers, about a 2.5x i ncrease. From 2.48 to 5.86 cases per 100,000. These are new cases, incidence. The key point here, this is happening globally. We're seeing a lot more neuroendocrine cancers than were originally thought. You're probably gonna wonder why. We don't have a great explanation. What we do think it is probably better pathological classification, so they're being classified a bit better, probably better capture, and perhaps there is an element of increased incidence actually going on due to environmental factors, et cetera. This looks at prevalence. Incidence is the number of new cases. Prevalence is the number of people living with the disease at any given time.
The vast majority of patients with neuroendocrine cancer do live a long period of time and are on treatment for significant amounts of time. When we actually look at all the GI cancers, I think most people would probably be surprised to know that after colon cancer, gastroenteropancreatic, or GEP-NETs, the population of our trial, is in fact the second most prevalent GI cancer, okay? More than double the amount of times of pancreas cancer. There are a lot of people globally that are living with this disease, and what we do is we really try to think of this like a chronic cancer, much different than some of the other acute cancers that people may have experienced, unfortunately.
Given that people, many people are living with this disease and many people are living with a long period of time, you can imagine, there's a lot of effort placed to try to improve the quality of life. This was a global study looking at neuroendocrine patients around the world and what the impact of the disease had on their life. You can see here, their big areas were not areas such as pain or some other things we might think of in cancer, but really things about emotional health, ability to participate in my leisure activities, being able to continue with my social life, my daily life. Again, the goal of this cancer is really to control it and to turn it into a chronic disease.
I often tell my patients, people live with diabetes, people live with rheumatoid arthritis, we wanna do the same, and we wanna make significant improvements to what you're seeing here, where people still feel that this disease has a big impact on their daily lives. So how do we do this? You've heard a little bit about these compounds today, obviously, octreotide and lanreotide. These remain the mainstay, the bedrock of treatment. Almost all neuroendocrine patients will start treatment with a somatostatin analog, one of the two. The reason for this is, to some degree, we're fortunate in treating this cancer. We have a very nice target, SSTR2. These target somatostatin receptors are on a vast majority of neuroendocrine cancers. Because of that target, we have the ability to be able to utilize it and take advantage by using a somatostatin analog.
This isn't the case in many cancers. For example, breast cancer, we don't have a uniform target. Colon cancer, we don't have a uniform target. This is a huge advantage in treating this disease, is we have a fairly uniform target that we can try to attack. As I mentioned, somatostatin analogs remain the mainstay of treatment. This upper corner here shows you the CLARINET trial. The CLARINET trial was the groundbreaking trial that first proved the efficacy of somatostatin analogs. It was testing lanreotide versus placebo. A big, as you can see from the graphs, clearly there was an advantage to being on a somatostatin analog in arresting disease.
This article was published in the New England Journal of Medicine, pretty much the highest tier you can get for medical journals, and became very quickly established somatostatin analogs as the mainstay first-line treatment. Now, the dosing of these drugs has been sort of usurped from acromegaly. As you can probably understand, these are two very different diseases. We've never really understood, are we maximizing that receptor? This receptor that I showed you here, you know, what we wanna do is we wanna saturate this receptor as much as possible, and we don't know if we're doing that with the current doses that we're using. Now, what I haven't shown you here is that these drugs are very well-tolerated. There's many patients in their 80s or 90s.
I wouldn't hesitate to say, out of all the oncological treatments that we use that are antiproliferative or trying to stop cancer, these drugs have very few side effects in comparison. The next step of therapy, for example, when patients progress on somatostatin analogs, would be things like chemotherapy, tyrosine kinase inhibitors, drugs that have a lot more toxicity, that require people to spend a lot more time in a hospital, inpatient and outpatient, and require a lot more healthcare resources. The strategy in the neuroendocrine community is to maximize the use of this receptor. What we wanna do is I describe to my patients, it's like a sponge. I wanna squeeze everything out of this sponge before I move to the next level, and we talk about treatments that are gonna have a more impaired effect on your quality of life.
Below here is another trial that was also published in New England Journal. It's a NETTER-1 trial, and this looked at a slightly different treatment, radioligand therapy, a topic for another day. This targets the same receptor, but these were all patients who had progressed on standard dose of somatostatin analogs, our current first-line treatment. What people were randomized to was radioligand therapy, which clearly works, but this is what's interesting here. These were people who progressed on standard dose somatostatin analogs, and they were given a double dose of somatostatin analogs. The median time to progression was about nine months. When people whose cancer was previously growing, by increasing the dose of somatostatin analogs, we were able to stop, on average, the cancer for another nine months.
Now, as Diego described, this could be a strategy, but currently, this also means getting two needles. Octreotide is almost a 4 cm needle, 18 gauge, thick, has to go into each butt every four weeks. I can tell you from my patients, the number one problem they have is the pain. They spend a couple days afterwards in pain, they're uncomfortable, and if you're doubling that up, certainly that is not a good experience for patients. This started to increase our interest in knowing that escalated somatostatin analogs, more penetration of that receptor I described, is probably a good thing for these patients. The research question that we've been interested in is, does long-acting somatostatin analogs above the standard dose or exposure, so either by giving more or decreasing the dosing frequency, does that improve progression-free survival as compared to standard dose SSA?
As Markus described, when we talk about CAM2029, what we are talking about is getting more exposure of the somatostatin analog to that receptor. So far, all the data that we have is retrospective. It's data that was established for other reasons, or it was treatment that's already happened. People have gone back. As you can imagine, there's a lot of flaws with that. The gold standard is prospective data. The retrospective data does look promising. There is some variability, but it does look promising to say that if in fact we increase somatostatin analogs, we increase exposure of that receptor, we can probably have better effects, we can delay progression of the cancer, and we can do this in a way that is patient or person-friendly.
The only prospective trial that we've seen on this so far is the CLARINET FORTE trial. Now, this is an extension of that previous CLARINET trial I showed you, where people who progressed on the standard dose of lanreotide were then dosed in a slightly different way. They got an injection instead of every four weeks, they got it every two weeks. Okay? This was not randomized, i.e., there wasn't a comparison arm. This was just an observational extension arm. Okay? Better evidence in the retrospective study, but not prospective evidence that could be enough for the regulatory environment. There is two groups. GEP-NET is primarily made of two groups, small bowel neuroendocrine and pancreas, and they were both included in this trial. What do we see here? We see some modest improvements on these people.
Again, these are people who have already progressed on standard dose somatostatin analogs, and then we're having dose escalation to see. You can see here that in some of the patients here, those with what we call a Ki-67 less than 10%, they were able to induce very similar from what I showed you before, eight to nine months of stability of disease in disease that had already progressed. Okay. When you look at here, you see that in some patients at week 48, so almost a year out, from the pancreatic patients up to the midgut patients, somewhere between a quarter to a third still had stability of disease. Now, if we didn't do this, if these patients weren't having escalated somatostatin analogs, what would have happened?
They would have gone on for a further line of therapy, probably would have been a tyrosine kinase inhibitor, chemotherapy, a lot more toxicity, a lot more impact on the patient's life, a lot more admissions into a hospital, a lot more use of healthcare resources. As you see, and so our idea here is to really increase exposure of those receptors from the get-go. What I've shown you so far has been two examples of people who've had standard dose somatostatin analogs and then had it escalated. Our idea is to start the high dose right from the beginning to achieve superior responses.
As you can see here, and I think Markus did a better job at this, has really shown you that there is good data that does show that CAM2029 does offer a better exposure to the receptor than what we have on market today, which is octreotide and lanreotide. That leads us to the SORENTO trial. Okay? The SORENTO trial is a randomized, multicenter, active phase III trial to assess the efficacy of CAM2029 versus the standard therapies octreotide LAR and lanreotide in patients with GEP-NET tumors. Okay? This is the first trial that is gonna be looking at this concept. It is randomized phase III, and is the gold standard of evidence, really.
Again, what we talked about here is that we know that higher doses, as I showed you first or shorter intervals, seem to have a benefit in those patients who've been pretreated. What we do wanna do is start off with potentially a more exposed drug that will help saturate that receptor. We know that dose intensity is very helpful for these patients in terms of stopping the tumor, but also potentially improving their quality of life. We know that generally toxicity is favorable in this class of agents, and the data so far with CAM2029 is that that is also the case. The toxicity is a very favorable toxicity profile as compared to some of the other anti-cancer treatments.
A prospective trial is really what's needed to be able to establish a new standard of care for neuroendocrine tumors. The SORENTO trial is a superiority trial. What we're trying to show here is that CAM2029, 20 mg every two weeks, is superior to octreotide or the current standards. It's a 302-patient trial. Patients are being randomized to one of the two arms. When I'm talking to my patients about this trial, one of the things that excites them is this idea that we've designed within it crossover. For those patients who end up on standard therapy, if their cancer starts to grow, they can still cross over and get onto the exciting new experimental arm.
That usually is an enticing factor for patients when I'm talking to them about a clinical trial and participating about a clinical trial. Patients are hesitant sometimes if they feel they're gonna get less treatment on a trial. When we talk to them about this, they know that either you end up on the experimental arm or you have a crossover ability to get the drug. That obviously is an exciting aspect for patients. The two comparators, as we mentioned, CAM2029, you've heard about this. This is a subcutaneous injection. Patients can do it themselves. This is a really big theme, self-empowerment, patients taking control of their own disease. In oncology, this is huge right now. We wanna keep people out of hospital. We want people to actively participate in their care.
We want caregivers to be participants in their care. This is basically a hidden resource that we often don't talk about in the healthcare system is the potential power of patients and family and caregivers in being able to improve healthcare without really adding cost to the system. This can be delivered at home. The comparison is where we are today. These are octreotide and lanreotide, both much longer and bigger needles that have to be given by a healthcare provider. We're hoping that this will be a large advantage in terms of CAM2029. Who could be included in this trial? Just very quickly, what we're basically ensuring this is a wide variety of neuroendocrine patients, but all gastrointestinal. We're ensuring that they have that target that I talked to you about.
Of course, we're gonna do what's called a somatostatin receptor expression scan, and then we're gonna make sure that there's scans that we can measure, that we can actually measure the progress so that we know if the tumor is growing or not. Who's not eligible for this trial? This is fairly standard trial procedures, but what we really wanted to make sure is people who are new to treatment. These are people who are starting treatment, right? The vision for this is that this potentially will be the first treatment patients get. This isn't patients who have previously received somatostatin analogs. This is people primarily who are starting treatment from anew. This is our trial study steering committee. As you can see, it's an international trial.
It's made up of different doctors from both sides of the Atlantic from centers such as MD Anderson, Dana-Farber, Erasmus, and Vall d'Hebron in Spain. We have certainly got a large group of doctors together who are world experts on neuroendocrine cancers. All these doctors here primarily see neuroendocrine cancers as their practice. The one thing I really wanted to emphasize, though, is what's really interesting and I'd say exciting about this is we have a global patient leader for neuroendocrine cancers, himself a neuroendocrine cancer patient, as part of this trial steering committee. This is where oncology trials are headed.
As I mentioned, patient engagement and patient empowerment is a big part of oncology moving forward, and this is gonna become the standard now where you include patients in research very early, and this helps us understand the framework, the viewpoint of patients, what patient wants are, how we can do the research accordingly to make sure we're meeting patient needs, as well as when we think about things like trial recruitment, what are patients thinking? How do we get the word out to patients? How do we build excitement among the patient community for these type of treatments? This is where we are right now. We have 10 of 11 countries open for recruitment.
We are over half our sites, in fact, I think it's a bit higher now, are activated, and so we're getting quite to the point where we have a number of sites around the world that are gonna be recruiting to this trial. We're at about 20% of patients randomized already, so quite happy with that. Our uptick has been very good. We also have engagement with the INCA, which is the International Neuroendocrine Cancer Alliance. It's an international patient group that are active participants, and as you can see, we have a worldwide participation. Where do we think this is gonna go, or where do I sort of envision this?
For neuroendocrine patients, to them, this is a continuous journey, and I think, as an oncologist, our cancer system has been guilty of this sometimes, is that we think of cancer as episodic care. A patient comes into clinic, gets treatment, we deal with some of their issues, and then they go home, and we sort of pretend to ourselves that things stop in between there and that their next visit is when the disease starts again. Well, the disease doesn't stop then. Maybe my involvement or my input into them stops, but really what we're understanding now is all cancers, but especially neuroendocrine cancer, is a continuous journey. We want treatments that patients are part of.
We want treatments that are continuous and that continue to manage the cancer as a continuous experience rather than an episodic care where you come get chemotherapy, go home, deal with the side effects, and then come back for another dose. As I mentioned, you know, we like to think of this as a chronic cancer. The survival times for neuroendocrine cancer are long, and people live with this disease, and so we wanna think of it in that sort of a way. What really is becoming more and more important is determining what's important to our patients, okay? You know, obviously, survival is important, but cancer care is much more complex.
You know, the idea that people are just gonna you know, cancer outcomes have improved in all cancers greatly, and this idea that all we wanna do is keep people alive is no longer good enough. We wanna keep them alive, and we wanna keep them alive well. We wanna improve their quality of life as we treat their cancer. To do that, you really have to think about what are patients trying to achieve, and what sort of tools do we have to achieve that? Decision-making has become a lot more complex. When we're thinking about any cancer treatment and what decision making we're gonna do, of course, the biggest factor is going to be we want it to be effective, and that's evidence-based medicine right here.
The decision isn't like it was, you know, 20, 30, 40 years ago where the doctor made the decision, told the patient, "This is what the treatment you're gonna take," the patient said, "Thank you, doctor," and left the office, right? That doesn't happen anymore. It's really shared decision-making now. It's a discussion about what's the evidence, but also what is the patient's preferences? What do they want? What kind of autonomy do they want in their cancer care in this continuous journey? What are their important outcomes? What's important to them, in terms of their cancer treatment? It's really shared decision-making now. Then the third part is the reality of resources. The institution, the resources, the healthcare system, whether it be Canada, whether it be Sweden, public, private, there are still constraints of resources of what we're gonna be able to do.
We want to be able to use quality treatments that potentially are resource-friendly and improve the patient's outcomes in ways that patients think. I think when we think about this, we wanna think of new treatments. We wanna think, do they meet these criteria? Hopefully this is what we're doing now. As I mentioned, this is gonna be the largest trial of somatostatin analogs to date. There's been a very high level of interest in both healthcare practitioners as well as patients, as I mentioned to you in the last slide. CAM2029 offers a lot of these potential options including good quality care, patient autonomy, as well as a resource-friendly treatment. What we have is a potential for this to be the standard of care.
If the SORENTO trial is positive, this will be the first-line therapy for all neuroendocrine cancer patients and potentially for many patients who are already on somatostatin analogs might get switched over to this. From a systems perspective, this is a resource-friendly treatment.
I have a role as a healthcare administrator as well, and this is why I sort of harp on this, but I will tell you, if I have to think about resources, this type of treatment where a patient at home is able to give themselves an injection, manage their care at home, receive a small needle, which doesn't have a large amount of complications versus a patient who's receiving chemotherapy has to come in, take a day off work, arrange for childcare, have two days to recover from the treatment, it requires nursing time, requires a chair time, requires me to potentially have more beds in the ER so that if patient is vomiting or is sick, they can come into the ER. That's a big difference, right?
These are the type of treatments we wanna see moving forward, a win-win-win situation. It really comes down to trying to understand what kind of treatments in cancer are gonna move forward. What are the treatments that are really gonna allow patients to live their life with cancer? These are all stories. These aren't the actual patients. These are stories about three patients of mine. One patient, he came to me with this cancer, neuroendocrine cancer, and what all his goal was, he wanted to live to his daughter's wedding. He wanted to make sure that he would live to his daughter's wedding, and he wanted to be there, and he wanted to be a participant in the wedding. He didn't want to be someone in the side on a wheelchair feeling sick. He wanted to participate.
Another patient of mine said, "Dr. Singh, I've worked really hard all my life. Me and my wife are planning to travel, as many people have done. We've delayed this till our age, and now, this surprise has been sprung upon me. I wanna go through our bucket list. There's places we wanna visit. That's my goal. Put me on a treatment where I can see I can do that traveling with my wife. If I had told him, for example, that "I need to put you on chemotherapy, and you need to come into the cancer center every two weeks, and you're gonna have to be in a hospital," it wasn't what he wanted. He wanted to have whatever time he had to be able to travel. This last patient, it was a particularly sort of heart-wrenching story.
A lot of patients in neuroendocrine cancer can be symptomatic. They can have a lot of frequent bowel movements. This patient unfortunately suffered from that, and he would have accidents. In Canada, I think like some parts of Sweden, not as good as Canada, but hockey is everything, right? Hockey is everything that we have. He grew up playing hockey. His son is playing in minor league hockey games on Saturday morning at the rink, and he couldn't take his son to the games because he was always afraid of having an accident, and the bathroom wasn't close to the stadium portion. It was a bit out. He either had to wear a diaper, which he was scared of, or he potentially had to not go to the games, and he wanted to take his son to hockey games.
That was so important to him. It was something he shared with his father. He wanted to share it with his son, knew that he was living with this cancer. You know, through somatostatin analogs, we were able to control his disease, control his symptoms, and he was able to do that, and that was, for him, a success. The idea would be when we think about cancer treatment, what we really want is we really want effective treatment. We want treatment that is going to be patient-friendly, and it's going to be resource-friendly. What we're hoping is that this use of somatostatin analog receptor, the SSTR2 and CAM2029, will sort of be the way in the future for neuroendocrine patients. Thank you very much.
Thank you very much, Dr. Singh. Since we promised to save the best for last, Fredrik will not appear right now, but we will have the Q&A session instead. Please, Dr. Singh, Diego, could you join us here with Markus, Peter Hjelmström, and please, Dr. Lenka Katila. Now, this is the final Q&A, and maybe there is a question that you would wanted to say or pose in the previous session, so we could take this as well, and then perhaps, Fredrik, you can join as well. I feel a bit intimidated with this big group of brains. Maybe we can start off with some questions from the audience, so I can settle down. Does anyone want to ask our eminent panelists here? Yes, please. Nordea.
Yeah. Viktor from Nordea again. So on acromegaly, I just had a question for Dr. Diego . I'm very curious on your view on the efficacy so far. In terms of clinical data, what would you like to see in order to, you know, switch patients that you have in your clinic at the moment? What would you be looking for in the phase III trial, in order to feel that this is successful enough to maybe switch some patients? Maybe also if you could give some color of what kind of patients that you would first consider to switch and what kind of patients you would maybe keep on the standard of treatment, as you have it right now.
What I would really like to see, I will answer first to this, because I would like to see less my patients. Because, you know, for these patients, they had to come once a month to the hospital. Basically, if would not be for the route of therapy, I wouldn't see the patients every month. Or, you know, we see normally these patients in a diagnosis, and once we have to arrange the treatment, we see the patients in probably in the first year. Normally, we could see the patients two, three times, okay? Independent from the treatment. With this situation and sometime also for some logistical questions, very, very. It's not a very good things also for doctors, for the involvement. These patients are coming too often to the hospital. That is the main point.
For example, as I already anticipated before, in other settings, in other disorder in endocrinology, we have achieved the possibility to make the patients more independent from the doctor. I can tell you something more. Recently, during the first wave of COVID, as you remember, north of Italy was quite big affected, okay? We were just in that moment exploring, in another study, which was performed, for many other purposes in acromegaly, like other chronic disease. We want to also assess the feeling of the patient, okay? These patients were provided with tablets in which, they could interact with us via tablets, okay? Then at a distance.
main interesting point that emerged from this experience for us because we discovered from our patients their own feeling in this setting, that these patients not only suffer to come to the hospital for the injection, but they also come to the hospital, and they remember what they are dealing with. It's a sort of very complex psychological situation which affect and this impact negatively to patients' adherence to treatment. When you see, as I told you before, in acromegaly, we have one advantage compared with neuroendocrine tumor. Once you have established the treatment and you have assessed the response, that response will be the same, even for 30, 40 years, which is the experience we have so far. If you see a certain point of the story of this patient that something is going wrong, you don't have any possibility.
All this is due to a very rare, three cases reported in 40 years, a formation of antibody against the drug, or the patients is not performing the treatment properly. You have a lower adherence to treatment. This happens in this chronic disorder when you have a such complicated disease. What I'm looking for is to have a medication of this class, somatostatin analog, as Simron said, less harmful of any other treatment, even compared with the chemotherapy in that other setting of patients. I'm also treating that kind of patient. I want to have a medication that give to the patients less thinking to the problem, but also more efficiency.
That's why the combination of a better route of administration or whatever you want to call that, but something that improve patients' compliance, in the meantime, probably, might give you also major efficiency. It's the best. We will see less the patients, we will save a lot of money in terms of health system, and we will, the most important thing, simplify the life of this patient. I hope I have answered your question.
Yeah. Thank you. Just a quick follow-up. In terms of oral treatments, there are also an oral treatment in clinical trials at the moment called paltusotine, I think, that presented data at the Endocrine Society Congress this summer.
Yes.
What is your level of excitement for that treatment, and how do you think that will fit in the landscape going forward?
Yes. I didn't participate to the trial, but because I didn't want. I have to be honest in this, I never trusted this drug for this formulation, for main reasons. Some are emerging now. You are losing 40% of control, and you cannot have this. In patients in which you are having such good control, if you lose the control, especially for acromegaly, you will impair all those complications. Second, I would have expected a very high dependence from food. I also had the opportunity to talk with some gastroenterologists. They had some concern also about the mechanism via this capsule at work in terms of opening some structure in the gut to make the drug available.
Another point that I didn't know at that time, but I know today, to the study I mentioned you, every day taking pills twice a day, maybe more than one pill, this will remind every day to the patients what he's going through, okay? This point emerged quite clearly from the questionnaire we submitted, administered to these patients during the COVID period in which we were not able to follow the patient. Those patients in the beginning were very happy of every kind of treatment and every kind of monitoring. A certain point, they became also fed up with the monitoring. Because the major point raised by the patients was, "I don't like that something remind me every day, every week what I have. I'm trying to forget what I have.
That is another important. For me the overall formulation, although you would think about the best, but that does not guarantee you something that has to be balanced constantly as you have seen. If you reach that level of control, that level is to be maintained. If you have something that does like this, from the hormonal point of view is even worse, okay? Because this hormonal imbalance may create even other problem to the patient.
Dr. Ferone, since you're already speaking, I have a question. It's probably me, but you said that more than roughly half of the patients in acromegaly aren't biochemically controlled with the current treatments. Obviously from the graphs we've seen, superiority with CAM2029, but still there are therapeutic levels of the drugs with the alternative treatments, and it seemed to be fairly stable IGF and GH levels. What is it that makes CAM2029 superior? Is it the simpler treatment or is it the higher plasma exposure or maybe a combination?
I think it's a combination because, well, when I first saw the data about in the phase II trial about the control, I didn't know about the pharmacokinetic data. I didn't know that. My first thought was, better adherence of patients to treatment. But then when we went to look in, with Fredrik, with Markus and, other people about this kinetics, we were quite impressed because as Simron showed you, another achievement we are trying to get is the optimization of the drug delivery and the drug dose. And that I think, the inspired the different trial design. I think that finally a combination of event. I'm sure that the drug, dose, the drug, schedule is important. Is important. But if you can combine a better adherence with a better exposure to the drug is, bingo.
You know, that's what you want. I have to be honest.
Yeah.
I didn't know in the beginning. When I first saw the data, I said, "What is going on here? Something is wrong in measurement of IGF-1.
Mm.
Since we have a laboratory in which we can assess. My former boss, he was an expert of IGF-1 measurement. IGF-1 measurement is not so easy as it can appear, but he was an expert. What we did, we had the scores of the patients enrolled, and we went to check if IGF-1 was correct. If it was correct. You clearly see this.
Yeah
Reduction of IGF-1. My first impression basically was related dosage problem. As scientists we should be skeptical, you know. Dose, dosage, assay problem. No problem assay. Compliance, probably, but pharmacokinetic open another view and why that's the study design of SORENTO is also to address the dose problem.
Right.
The dose point.
Dr. Singh, this might be a difficult question to answer or maybe it's a stupid question, but you have the retrospective data indicating a positive effect of increasing the dose of SSA, and now you're doing the SORENTO trial. Do you feel that this maybe it's not as robust a foundation of data that's usual in a clinical phase III trial? Do you think there's a sort of adverse effect on success rate? Or I don't know if it's even possible to answer that, but perhaps you get the gist of my question.
Yeah. Yeah. Retrospective data, you know, using good scientific practice is always hypothesis generating. You would never make conclusions from retrospective data, partially because there's huge amounts of bias within it. If you are collecting data on a registry, you're gonna collect only those patients who continue to show up, for example. Those patients who don't show up are gonna be lost. You may not treat somebody accordingly based on age or based on the geographical distance, et cetera. Those sort of biases are inherently within retrospective data. As well, you're not designing the research question before you collect the data. You're asking research question using data that preexists for other reasons. That's just general by nature. Any regulatory authority, but also it's good scientific principle.
At most, you can generate a hypothesis, which you need to then confirm with prospective data. That would be the case for any drug development. The other thing is that retrospective data, if you go through it, is very heterogeneous. You know, these neuroendocrine patients, we've defined here what we call a cohort, a group of patients, like I'd mentioned in that slide with inclusion criteria, they need to have the receptor. We looked at their grade, we need their anatomical sites. We wanna make sure that what would the patient group that we're testing is who actually would be using it if the drug gets approved and goes to market. You want to have similar populations.
Whereas in retrospective data, you know, it's kind of a hodgepodge of people that are coming from different places and also on different doses. I think a big difference would be most of our retrospective data is people who started on standard dose and then got escalated. Often maybe escalated 'cause there was no other option or et cetera. This trial is very different in that it's gonna be looking right away at increasing that receptor saturation so that it's a more effective treatment to start rather than a stepwise process.
Thank you very much. Markus, you have three indications within CAM2029. One of them has an orphan designation, the other are defined as rare. I guess the orphan designation have some regulatory advantages, right. But still, rare disease, do you still have more flexibility in, let's say, pricing? Which has been one reason that many pharmaceuticals, including AstraZeneca, are moving into the sort of rare disease area.
You know, first of all, I don't think I'm the right person to talk about pricing.
Maybe Fredrik.
Maybe Fredrik.
Commercial guy.
Yeah, I think, I mean, first of all, we do have an orphan designation in acromegaly as well, and we are applying for it in other indications. Sorry. We do have orphan designation in acromegaly as well.
Yeah, right.
We're applying for it. We will also apply for orphan designation for polycystic liver disease in Europe, not only in the U.S. Where we have it now. The timing of those applications, they are based on the data you want to have at the time of and based on the authorities' different requests. I think the outset of the question is a little bit out of. Of course, we have looked at pricing implications and we have had pricing interviews with payers. They've been positive so far in the U.S. and Europe. I think we have a good pricing strategy.
Thank you very much.
Yeah.
Mm.
I have a question.
Yes, please. Carnegie.
Thank you so much. I have a few questions on the SORENTO study. First, what hazard ratio in PFS is the study designed to show? Is the study powered to show? Secondly, maybe for Dr. Singh, your level of confidence to hit the primary endpoint given the historical and sort of retrospective data. Finally, any trade-off on higher exposure in terms of safety that you would expect to see in the study?
You're gonna really test me here, or if you remember, I don't know the hazard ratio remember off the top of my head for SORENTO. Maybe Fredrik does. I mean-
Yeah, we have 75% actual.
Yeah.
Yeah.
It is, you know, at 25 it's 0.75. For that hazard ratio, I would say it is not an incredibly ambitious hazard ratio when you consider drugs. When you're looking at a hazard ratio of 0.5, for example, in other trials, that means that you're basically saying that there's a 200% improvement. For that, I think the chance to add to your second question, do I think that this trial is well designed to meet that? Absolutely. Looking at the number of patients as well as the stratification, we've stratified very nicely along the factors that neuroendocrine patients might diversify. Given the retrospective data and given what's being used, I mean, what I didn't describe to you is actually if you look at the data, many patients are getting escalated dose anyway.
Some patients who may decline further toxic therapy or may not have other choices, they're already getting escalated dose anyway. I do feel fairly confident in that. Of course, the randomized trial is a randomized trial. In terms of toxicity, so far in all the phase II studies haven't seen any signal yet of increased toxicity. I don't have any hypothesis at this point that there's gonna be any toxicity differences. That's really good because somatostatin analogs at baseline are already a fairly toxicity favorable way of treating cancer.
Thank you. Do we have any further questions? Yes, please.
I think a question basically for Markus. You spoke briefly about polycystic liver disease with SSAs. There's a growing body of evidence that shows that when you take the patients off this treatment, there's some sort of relapse or sort of the volume of liver starts to increase again. Is this something you're gonna take into account with your clinical trials, or is it something that you are just gonna monitor as you go through?
Well, I mean, the clinical trial, I mean, we are testing two dose groups of CAM 2029 versus placebo, a 12-month study. Then there will be an extension trial, of course, that you know everybody will be allowed to optionally transfer to CAM 2029. We will, you know, we'll see the effect of transferring from placebo to CAM 2029. But I'm not sure I'm answering your question there, but.
I think, well, 'cause I think the clinical trial is for 77 months, which you've done on the board, which is what? Six and a half years. I think it's standard. I was just wondering whether you foresee these patients to be on this treatment for the rest of their life or yeah.
Oh, yeah. I think this is going to be, if successful, it's going to be a chronic treatment, definitely. Yes. Definitely.
This is what happened in acromegaly.
Yeah.
This is what happened in acromegaly. Different from neuroendocrine. In acromegaly, when we started this treatment years ago, we didn't expect this actually. In acromegaly, at least, in pituitary I would say, in pituitary in general, this class of drugs seems to act differently. I mean, the abnormality in this setting is acromegaly so far. Because what you see in neuroendocrine tumor, it's that a certain point, but unless you are not able to modulate, that's why Simron was addressing the point of gain time to spare the time for more aggressive treatment. In acromegaly, it's different. I don't know what will happen in polycystic ovary, but in polycystic liver. In acromegaly, if the patients respond properly or respond of 50%, okay, in terms of reduction of the biochemical parameter, this will be the forever. It's an abnormality.
Aspect of regulation of receptor. I was very impressed by your presentation because she showed the receptor for opioid which interact with the molecule which is called β-arrestin, which is our major target of investigation in this moment. Because probably in pituitary you have an alteration of one of these molecules regulating, which makes your drug working forever. Patients with acromegaly can be controlled with somatostatin analogs forever, unless you don't stop the treatment. When you stop the treatment, what you see? Increase of IGF-1, and this is followed by the increase of the tumor size. If you start the treatment again, you will see IGF-1 going down, tumor shrinking again. It's impressive.
Okay. For all three indications, you see it as a, chronic and-
Yeah
for the rest of your life. Yeah. Okay, great.
The other important point I forgot to mention before, when you treat patients with acromegaly, they have high risk of double the risk of death, untreated patient. They can die from cardiovascular or stroke or cardiac failure or cancer because the growth factor may induce cancer. The mortality of acromegaly is doubled if you don't treat that. When you treat patients with somatostatin analogs, you completely normalize the mortality. There are some data which clearly show in the New Zealand population, there was a beautiful study which showed that as much you normalize the hormonal imbalance, as much you gain the normalization of mortality.
In terms of morbidity, comorbidities, you improve a lot to obtain an improvement on quality of life, except for some aspect, depending from the disease history, the time of exposure to growth factor of the patient. I mean, if a patient is diagnosed earlier, you have a sort of complete restoring of the situation. If a patient is diagnosed late, some aspect cannot be improved. For example, bone abnormalities, disfigurements. You can still gain a normalization of the mortality, which is incredible. It's an important achievement.
Thank you. One more quick question, so if I may. You spoke about the shared decision-making at the end. Is this gonna be the same for the opioid dependent studies as well? Is it just for this particular study that you want to incorporate this?
For the opioid decision-making? For the opioid studies?
Could you repeat the question, please?
It's more that the patients who may be having the injections once a day, they're now having it once monthly. I was just curious whether you were kind of incorporating them in the decision-making of this as well.
Yes. I mean, they are already incorporated into the decision-making. We are really, as Sam and Richard mentioned, I mean, the clinical practice with Buvidal is really that the patients, when they ask for the treatment, this is really when you see take-up in some countries. Why you really don't see the trajectory curve now in the growth coming in some markets a little bit slower. I mean, we saw a rapid increase during the COVID times, but this is important. I expect actually in the pain treatment, this is even going to be more important because these patients are often not actually having proper treatment now because due to the stigma. They don't want to go to an addiction clinic.
They want to be treated at a pain clinic. There's really no good treatment options for the patient. This we envision going to be a dual treatment decision by the healthcare providers and the patients. For us as a company, it creates a little bit of a challenge obviously, because then we need to also work not only with healthcare providers, but also with the patients with regards to the educational efforts and so on. This is what we are working on right now, preparing for the launch of Buvidal in this new indication as well.
Lovely. Thank you.
Right. Do you have any further questions from the audience? Well, I think our time is up for the Q&A session, so it's time for a big hand for our presenters. For some concluding remarks from Fredrik Tiberg.
Yeah. Thank you so much.
Please, Fredrik.
Thank you so much. First of all, thank you for taking the time to listen in to this capital markets and R&D day. I think it's a really good opportunity for us to explain what we are doing and it's great to also have external experts here to comment on the different studies. One thing I think is important and I think we conveyed here is that treatment and medical treatments, they are composed of different dimensions. One dimension is efficacy and having an effective treatment that reduces symptoms or reduces time or actually increases life expectancy. The other one is quality of life and all the associated thing. For some patients, the quality of life aspect can be extremely important, whereas for others, efficacy is the real determinant.
I think this is really an example of our aim to work across the spectrum for our patients and that we have a very patient-centric view in our developments looking at all aspects. If we take acromegaly, for instance, there where our clinical program is not designed to look at superiority. It's designed to show that we are better or that we are an effective treatment and that we provide
Hopefully good quality of life for patients. That's the driving force. Because this population is so small, you cannot dimension a superiority trial there. Whereas in neuroendocrine tumors, of course, we have both dimensions of quality of life and efficacy and with the superiority endpoint. That's just an example. I think when it comes to treatment, we also have to understand that every patient has its preference, and it's good. Our view is in opioid dependence, it's good with different treatment alternatives, and that is what drives the improvement for patients. With that said, I will move over to the concluding side from a investor perspective. I think what we have shown and what we continue to show is that there is a lot of potential in Camurus, both in our existing franchise in opioid dependence treatment.
We are improving the lives of patients with opioid dependence. We are expanding this into new markets and providing improved access for patients. From a financial perspective, short term, we're seeing Buvidal as the main driver of our growth. Midterm, we're hoping that through the collaborations with our eminent clinical experts and investigators, we will also get the late-stage pipeline to turn into new approvals and new drugs for patients and further promote our long-term growth. Of course, I got a question about the early pipeline that is not going to impact our 2027 numbers, but hopefully build the company and credibility for the future. With this image and with those final words, I would just like to say thank you to everybody for attending this Capital Markets Day.
After this, we'll all have time to ask questions to our experts, our group of senior management, which is almost complete here. We are missing one person because of the big event we have tomorrow. Thank you, everybody, and we'll move out to the next, the corridor. Thank you, and thank all the speakers.