Good morning. Good afternoon. My name is Antje Witte. I'm heading Investor Relations at UCB. Dear ladies, dear gentlemen, a very warm welcome to our 2021 earnings call for the capital market. The slide deck and the appendix are available on our website. Before I introduce you to today's speakers, please allow me to remind you that today's presentation and the Q&A session is under the disclaimer and safe harbor statement you see on slide two. Thanks for looking at this. Without any further ado, I'm happy to introduce you to today's speaker on the next slide. Jean-Christophe Tellier, our CEO, will welcome you. He will then hand over to Iris Loew-Friedrich, our Chief Medical Officer, followed by Charl van Zyl, who is looking after neurology solutions in Europe and international markets.
Emmanuel Caeymaex, who is looking after Immunology Solutions and is heading the U.S. markets. Of course, last but not least, Sandrine Dufour, our Chief Financial Officer, who will give you the more financial details of our 2021 performance. With this, I'm handing over to Jean-Christophe. Over to you.
Thank you, Iris. Thank you, Antje, and good morning, good afternoon, everyone. It's really a pleasure to welcome you for our full year results of 2021. There are many different ways I can use to illustrate 2021 performance, but all of them start with our focus on people living with chronic disease and making sure that we are able to help them to live the life that they want to live, as you can see here with Jerome. One of the way I can start with is the fact that 2021 is our eighth consecutive year of growth. Being able to once again deliver double-digit growth, both top and bottom line at constant rate.
Another key highlight of 2021 that I would like to also put up front and want you to keep, because for us it's unprecedented, and I guess it would be unprecedented for a lot of different companies. In fact that in just few months, we have been able to deliver six consecutive positive phase III clinical trial. Iris will come back on that. It's just not meaningful from a statistical standpoint, it's also very much meaningful for people living with chronic disease. We are building momentum, and we are of course very pleased with these results. With this momentum, we think we are in the best possible condition to go through the transition phase that we are having now, and being able to amplify our impact for 2025. Next slide, please.
I was mentioning different type of lenses that we can use to look at our results. The one that is illustrated here is taking the lenses of how do we integrate sustainability in the way we are operating. You have seen the left-hand side of this slide before. It's the slide that summarize what do we mean by patients value ambitions, and how do we build our different pillars of integration of sustainability. I would like to focus now more on the right-hand side of this slide that illustrate on these different pillars what we have achieved in 2021. The first value that we want to create is of course the value for our patient, the people suffering from chronic diseases.
I'm very happy with the fact that we have gained 200,000 more patients this year versus last year, and today, more than 3.7 million patients can benefit from our product. We have also put an access criteria for the first time this year, and we are improving access for our population, either full access or partial access. We will continue in the future to monitor access because it's one of our key component of our patients' value. The second element of integrating sustainability in what we are doing is the value for people. With value for people, we mean first maybe the community we are living in. You know that we have created a community health fund back in 2020 in the middle of the pandemic in order to help more vulnerable population.
I'm pleased to report that today we have 99 projects that have been able to be funded by this initiative. Value for people, it's also value for our all people at UCB. First, it's the way we are growing, and you can see the numbers of jobs created by UCB during the year. It's also how we can try to make sure that people are at their best while working at UCB. You can see here an index of health, safety, and well-being reaching 81.9%, and it's 3.5% more than last year. Value for people is also value for our shareholders.
You see at the bottom of the slide the numbers of this year, EUR 5.8 billion of revenue, 1.64 from adjusted EBITDA. There is an improvement in our ESG ranking you see here, the Sustainalytics rating. Of course, last but not least, it's also value for the planet. We have a commitment to be carbon neutral by 2030. You see here that we have already, since 2015, improved by 62% and reduced by 62% our CO2 consumption. You can see here on the different lenses from sustainability how what we have done and how we have done it in 2021. Next slide, please.
This eighth year of consecutive growth, the strong result of 2021 gives us even more confidence in our ability to reach our guidance that we shared already with you last year of 2025, which is leading in science patients populations, make sure that we will be able to reach EUR 6.6 billion of revenue top line in the low- and mid-30s adjusted EBITDA margin with a continuous improvement of our ESG rating. Next slide, please. How we will get there. Another lens that we can use to look at our results and what we have delivered is to try to go through the different criteria and the different elements of our performance. You see here on the left-hand side of the slide 6 of them.
If you monitor that, if you look at them for the period 2015-2021, the first focus is our ability to deliver value for patients. I mentioned the numbers of patients who we have been able to treat in 2021. The second criteria is the launches that we are able to deliver, ability to continue to renew our product pipeline and our products on the market to continue to grow despite periods of loss of exclusivity. During the period, we have been able to launch Briviact, to launch NAYZILAM, to launch EVENITY. This year we are launching BIMZELX, and in the near future, rozanolixizumab and zilucoplan. Because that is the point number three, another criteria of performance is, of course, to look at how the pipeline is doing. Strengthening the R&D, maturing the pipeline is a key component.
I mentioned the six phase III readouts that we had this year, but it's also approval that we get. BIMZELX already approved in Europe, the U.K., in Japan, in Canada, and we are confident that we'll be able to launch in the U.S. before the end of the second quarter. Another element to evaluate our performance is to look at our strategic flexibility. How able are we to reduce the debt? What is the level of flexibility that we get there? Here also, performance has been really very positive with the net debt adjusted EBITDA ratio of 0.5 in 2021. The last two points are about how we can leverage the new opportunities and how we can sum it up into the sustainability.
Because of this flexibility, we can and we have been able to move on inorganic growth and ability to do some strategic and key acquisition. You can see here some of them. The last one, of course, is the agreement that we get for the acquisition of Zogenix, which is a potential great addition to our epilepsy portfolio. From a partnership standpoint, last year, and particularly in December, we have been able to sign a strategic partnership with Novartis on our neurodegenerative portfolio. Last but not least, integration of sustainability in whatever we do. You saw different value components. You see here the different criteria that we can use. Next slide, please.
Yes, I think we are in a good shape, and maybe the best way to summarize it from a financial standpoint is to look at our growth since the last eight years and the evolution of the EBITDA. You see an 8% CAGR for annual revenue growth and an adjusted EBITDA that basically was multiplied by three during the period. Next slide. This is what we have achieved in 2021. My colleagues will come back on certain elements of them. You see here in a nutshell the outcome of 2021. In terms of revenue and adjusted EBITDA, I mentioned the evolutions. 10% growth in revenue at CER, more than 20% adjusted EBITDA at CER.
An ability to close and successfully close the clinical trial. The fact that we are moving now into a launch mode, which is great because this is what we needed in the period of transition that we are starting, and the strategic complement that Zogenix may add to what we have. That the reason why with all of that, we can share with you our guidance that you have seen in the press release already this morning for 2025 with a revenue between EUR 5.15 billion and EUR 5.4 billion, and a profitability between 26%-27%. This guidance, of course, do not take into consideration the acquisition of Zogenix, because we will wait until we will be able to close the deal to integrate it into the guidance.
First things first, let me next slide hand it over to Iris . Before, I want to leave you with this simple message: We are entering into a period of transitions from a strong position that has never been better than now, and we are very confident that with this in mind, we can continue to deliver future growth for shareholders and different stakeholders. With that, Iris, I hand over to you. Thank you for your attention.
Yeah. Thank you very much, Jean-Christophe, and hello to all of you. Let's move to the next slide, please. You know why today is a very difficult day for the world. Let's still celebrate what is an unprecedented series of successes. Unprecedented in UCB's history and probably also unprecedented in our industry. Following our four positive phase III results with BIMZELX in psoriasis that demonstrated superiority over three competitors, we have continued, and we have even topped this exceptional success story. Within just 12 weeks, from mid-November last year to early February, we achieved positive results from further six phase III studies, large phase III studies across three assets. BIMZELX delivered two positive phase III studies in patients with psoriatic arthritis and two positive phase III studies across the entire spectrum of axial spondyloarthritis.
In addition, we obtained strong phase III results with zilucoplan and with rozanolixizumab in people living with generalized myasthenia gravis, so that we can deliver an impactful portfolio of two medicines with complementary mechanisms of action to these patients. Let's move to the next slide. If you review the recent literature, the probability of a single phase III study in immunology or in neurology reading out positive is roughly around 50%. The probability of six phase III studies in a row reading out positive is very, very low. In addition, the data were collected before and during two massively challenging pandemic years for patients and for our investigator sites, and we are immensely grateful for the exceptional collaboration that we experienced. Despite these headwinds, our phase III studies are of outstanding robustness, consistency, and quality, and they shine in terms of clinically meaningful efficacy and positive benefit risk.
I think it's fair to say that we have delivered beyond what can be expected, and you can trust us to continue to deliver. Please take this as an indicator of our continuous strong performance in drug development, thanks to our amazing people and teams. Next slide, please. While I cannot tell you more details of our results today, I want to draw your attention to the full depth and breadth of our positive efficacy results. Let's take the example of psoriatic arthritis. This is a complex disease affecting patients' lives in many dimensions. There's the painful and progressive joint disease, the inflammation of the tendons, the stigmatizing skin disease. So when we say positive on primary and secondary endpoints, what's actually behind this statement? Our psoriatic arthritis program covers biologic-naive patients and patients who were inadequate responders to TNF inhibitors.
While the ambitious primary endpoint ACR50 focused on the joints, we also collected data on a series of highly relevant secondary endpoints. We want to know in depth what the efficacy of our medicines actually means for patients. Just one example. Minimal disease activity brings together different, very relevant outcomes. The hurdle to achieve this level of response is very high. Succeeding in minimal disease activity means that patients enjoy an active social and working life, largely free of visible symptoms, largely free of pain and fear of disability. This translates into vastly improved quality of life, and it means that patients are back in control of their lives. We are moving from symptom control into enhanced quality of life. Next slide, please. Generalized myasthenia gravis, gMG, is a severe, debilitating, life-limiting condition with a substantial impact on the lives of patients.
Again, improving quality of life is of pivotal importance. gMG fluctuates over time so that patients are confronted with an unpredictable disease. Fatigue and impairment of mobility and also impairment of speech bring significant limitations to their daily activities. Patients need to constantly adapt to their disease, which takes control of a large number of aspects of their lives. The MycarinG study with rozanolixizumab and the RAISE trial with zilucoplan reported positive results with the patient-reported MG-ADL as the primary endpoint. However, in addition, we have shown across an unprecedented broad range of additional patient-reported outcomes that both our investigational medicines allow patients to regain control of their lives with re-engagement in social activities and enhanced well-being. Our data indicate the promise of a journey back to a normal life in aspects that truly matter for people living with gMG. Next slide, please. Let's have a look at the pipeline.
We have delivered in an impressive way, I hope you agree. We continue to deliver with regulatory approvals for BIMZELX around the world for the treatment of moderate to severe plaque psoriasis. Our new positive and very impactful clinical study results will translate into the next wave of regulatory submissions for BIMZELX, for zilucoplan, and rozanolixizumab as of this summer. While these are very clear priorities, we also have dedicated teams in place for each pipeline asset, and we're working hard to progress our well-filled clinical pipeline according to our plans. Let me share a few examples with you. The phase III study with Staccato alprazolam is very different from any previous clinical study in epilepsy. To be honest, such a study has never been done before, and I am convinced that only the leader in epilepsy can do it.
In a very innovative and demanding design, we measure the rapid termination in less than 90 seconds of single prolonged seizures. We recruit patients with a history of prolonged seizures in an outpatient setting. We train the patients and their caregivers so that they can actuate the Staccato alprazolam device by a regular breath when the next prolonged seizure happens. Simultaneously, caregivers will measure the duration of the seizure. As the leader in epilepsy treatment, we recognize that this is an unmet need, and we make every effort to deliver this tailored treatment approach. We're also progressing our phase II portfolio of disease-modifying agents for Alzheimer's and Parkinson's disease in strong and productive partnerships with Roche and Novartis. We continue to build on our successful track record of alliances, which maximize our opportunities to reach the patients in need while we share the risks.
This way, we aim to secure our next wave of impactful medicines, particularly in neurodegenerative diseases. With this exciting prospect, I would like to thank you very much, and I hand over to Charl . Charl, please.
Thank you, Iris. I also want to take a moment to thank everyone for joining the call today. Of course, it's my pleasure to share with you the highlights of 2021, but also share with you a little bit of an outlook of 2022 and where we will focus our efforts in the coming year. There are two important messages I would like to position with you. The first one being that we feel very confident about our leadership position in epilepsy. With what we have in our hands today, we feel that that is secured for the next five to 10 years.
The second important message I would like to position with you is based on our phase III results, we feel very confident that we have all the ingredients now to be able to lead in the patient population of myasthenia gravis by 2025. If you can go to the next slide, please. What I would like to illustrate a little bit more and expand a bit more on the concept of leadership in epilepsy, and to illustrate it here are a few of the facts that really make us a leader in epilepsy and that we will still continue to make us a leader in the future. It of course starts with a deep investment in evidence generation, a deep understanding of the patient community, understanding the medical community and the unmet needs.
As you can see there, we have a body of evidence, over 250 clinical trials, 25,000 patients over 10 different epileptic conditions that we have generated this evidence that is, in a sense, translated for us today into a compelling in-market portfolio that is consistently outgrowing the market. There are a few highlights in 2021 that I would like to mention. As Jean-Christophe mentioned, our expansion into more patients, over three million patients in epilepsy that have been treated in 2021. Vimpat, as we promised to you, has reached its peak sales of EUR 1.5 billion. Briviact continues to outperform the market by a factor of threefold. We've seen, of course, expansion also of Briviact in other label expansion into children.
As Iris has mentioned, the start of the phase III program in Staccato alprazolam provides us in the future with a very strong option for rescue therapy with a drug device combination. Of course, the proposed acquisition of Zogenix will add additional opportunities for us to expand into new patient populations. The third point I want to mention here is also our leadership and our know-how in the area of science of neurodegeneration. Of course, our two landmark partnerships in Alzheimer's and in the case of Parkinson's has really allowed us to again show a strong validation of the science that is behind our key assets there. When you reflect on all of this, you see a really strong position that we have earned over time in the space of epilepsy as well as in neurodegeneration.
It makes us therefore very confident that with this know-how, with this commercial success as well, that we can translate this also very confidently into the space of myasthenia gravis. If we can go to the next slide, please. I know we have received a couple of questions on the Zogenix, and I want to again emphasize the key rationale behind why we see this as an important addition to our epilepsy portfolio. As you would see in the slide, there's approximately 70% of patients that are reasonably well controlled with current treatments on the market. Of course, UCB has gained that leadership position in this space with gold standards like Keppra, Vimpat, and Briviact. But we also know that 30% of patients are labeled as drug-resistant or patients that are not responding to current treatments.
There are a few patient populations or smaller populations where we are able to address with our current portfolio and the future portfolio, these unmet needs of these patients. In the case of acute seizure therapy, we have NAYZILAM today, of course, but also with the future of Staccato alprazolam, we are able to provide the best in-market portfolio to address rescue therapy with drug device combinations. We are also expanding the indications for rozanolixizumab in autoimmune epilepsy, which is also an important rare form where we will see future results. Coming to the Zogenix acquisition, it really addresses for us populations where we have not been before, Dravet and Lennox-Gastaut.
With the evidence that's there today and what we see from evidence of key opinion leaders, this is truly a breakthrough therapy in this space, a gold standard as it's been referred to, and of course, provides us now with an opportunity through the differentiation that it provides in a high unmet need area, the potential to continue to live our patient value strategy in this particular patient population. Of course, it provides for us as a corporation, synergistic revenue in the short term, but also important earnings contribution in the midterm. If we can go to the next slide, I want to expand a bit on my second important message to you, which is our unique portfolio in myasthenia gravis.
What you will see in this slide, really on the left-hand side, is where the current treatments are clearly not providing the right control and the appropriate control for patients. As Iris had mentioned, this is a highly individualistic disease with many different stressors that may occur. We see today with treatments available like steroids, immunosuppressants, or plasma exchange, that they are nonspecific to the treatment, but it essentially provides some relief for patients. When we look at what we have today in our hands, based also on the very strong phase III results, we have two important mechanisms of action in our hands that are essentially the drivers of the pathophysiology of this disease. Complement inhibition and of course FcRn inhibitor in the case of rozanolixizumab.
We see both of these play an important role to address the individual needs of these patients. Individual needs can be many different factors, their environment, their ability to be able to be mobile, their independence. The ability to be able to essentially address those individual needs of these patients will be important in the future. With these two treatment options, we are able to provide that very consistently to these patients. Of course, we are building very much our know-how in this space. We're working deeply with the medical community and patient advocacy as well. Our important goal that we set together with the community is that we want to have fewer patients experience exacerbations and more symptom-free days in the future. This is an important ambition that we believe we can achieve with the portfolio that we have today.
With that, again, I want to thank you for your time today, and I would like to hand over to Emmanuel.
Charl, thank you very much, and greetings, everyone. 2021 has been a really exciting year as we have been expanding our portfolio in immunology. My goal today is to provide you with some insights into the strong underlying performance with CIMZIA, give you a sense of where BIMZELX is at in terms of its launch momentum in the markets where we have launched, and also give you a sense of how it is perceived, how it is used. Then finally, EVENITY, which we market with our partner Amgen, is a drug that has been growing very significantly last year despite the pandemic, and I'd like to give you a sense of where we are and where we will be going next. We have three growth assets that are differentiated in our immunology portfolio.
On the next slide, we will start with CIMZIA. CIMZIA has grown by 5% at constant rates. You saw that. The story is really that we've had very solid volume growth that has outweighed the negative pricing impacts that we've seen following the inclusion of CIMZIA in the jumbo group in Germany and the change in the reimbursement price, the ASP price in the U.S., for the lyophilized formulation mostly. With that 12% growth, CIMZIA is now touching a full 170,000 patients worldwide, and you will note that the growth of the asset in international markets has been remarkable. Behind the growth here that you're seeing at constant currency, there really is significant volume growth in every region of the world.
That is based on the differentiation of CIMZIA, which is recognized universally for women of childbearing age, but also in spondyloarthropathies, where it's affecting psoriatic arthritis is driving business in dermatology, in fact, in the U.S., and where the non-radiographic axSpA indication is unique in the United States and enjoys very widespread first-line access. With that differentiation and also our use of data, of advanced analytics and the use of multi-channels and remote engagements of our customers, we have been able to essentially grow volumes and offset any pricing impact. As I look forward to 2022, some of those price impacts that hit us in April and July will start abating on a year-on-year basis. Therefore, I would foresee a good growth in the second half of the year at constant rates.
Now let me move to BIMZELX, bimekizumab. In fact, 2021 was the year when bimekizumab became BIMZELX, with the approval in Europe, with the approval in Great Britain. You know how differentiated the asset is, with the three superiority studies in psoriasis against standard of care. Iris has just mentioned that late last year, we were able to de-risk bimekizumab in psoriatic arthritis and in axial spondyloarthritis, and we're gonna be glad to share results at EULAR and at ACR this year. You know, early June EULAR is going to be the time where you will have access to a lot of that data and what it means. Now, the reason that is important, even for psoriasis, is that there's a lot of evolution in terms of comorbidities between psoriasis and psoriatic arthritis.
There are inflammatory back pain in psoriatic arthritis patients, and increasingly we understand that a lot of HS patients actually also suffer from inflammatory back pain and from axSpA. Having an asset that deals with these IL-17-mediated diseases and raises the expectations and the standard of care is what we're after. Together I think you know that, but together these disorders touch about 5% of the population in Western markets, so it is significant. Mark in England agreed for us to show a few pictures and his name because he was a patient who joined our BE RADIANT study, the head-to-head study versus Cosentyx about three years ago. He's been completely clear of plaque psoriasis for a full three years now. His life has changed.
His ability to work, his ability to do sports and engage in running, his confidence, his self-esteem, have completely been transformed. Now he really leads a different life. He recently got married, and he's a typical patient that we're seeing and hearing a lot of feedback about, in the market as we're launching. The one word that is sticking with me since we've launched in Europe is overjoyed. This is what we're hearing in the U.K. This is what we're hearing in Germany, überglücklich. This is how patients come back within weeks to the practices. I'm convinced that the buzz that this is creating will be a very important factor to drive the adoption of BIMZELX as the pandemic conditions start abating. Now let's look at a few numbers, and let's look at Germany and U.K., who are our first two large markets.
First of all, it's a bit of an art rather than a science to compare launches across time periods, especially with the pandemic impact and the Omicron impact, which really hit the markets as we were launching in those two markets. Nevertheless, there's a way to do this, and we've standardized data across the last IL-23 launches, the three of them, as well as the last IL-17A launch, ixekizumab. What you're seeing here is that in the U.K., thanks to the very rapid access that we were able to gain with NICE, BIMZELX is off to the fastest start. In Germany, for now, we're still middle of the pack. Of course, IQVIA has documented that the pandemic is causing a 30%-70% slowdown in the launches.
We think we'll soon get out of this based on the feedback we're getting. We see an increasing patient pool. We see the face-to-face meetings starting to become possible again, physicians to reinstate their capacity to meet with patients. We also see that, over the last few weeks, the ability to pull through to put pharmacists together with physicians is starting to improve. The lead indicators are very positive. We have 90% awareness in both markets with medical dermatologists. The efficacy perceptions of BIMZELX are really at the top.
In addition, there's a very clear understanding in the European markets about the differentiation based on the mode of action. On the next slide, we can look at another type of benchmark, which is what is the dynamic share for BIMZELX in the IL-17 segment, which is where the asset is being positioned as we start. You can see between September and November that that share increased to about 11%. Just as a reminder, the IL-17 segment, in terms of new patient starts, is about 1/3 of the psoriasis market, including the orals. We see this continuing to grow at quite a rapid pace. Again, with the reopening, we will be able to also invest more in a meaningful manner.
I'm very confident that we will see this curve edge higher month after month over the rest of the year. Now on the next slide, you can discover how U.S. medical dermatologists look at the relevance of the IL-17A and IL-17F dual inhibition. And you see that there's a very clear understanding for the value that this can bring based on the studies that reported in the New England Journal of Medicine, in The Lancet, and at the various congresses. I think that that is understood, and of course, we're very eagerly awaiting for the FDA approval for BIMZELX, which, as Jean-Christophe mentioned, we're expecting in the first half of this year. With the inspections completed, I think we've taken out the main piece that's on the critical path.
Of course, all of this needs to be wrapped up now, but we're confident about a launch in the near term. We are ready in the U.S. We're ready with our bridge programs, with our access. Of course, we have a sales force that is already deployed with CIMZIA. We have our data analytics stack that are working well and that we're applying on our existing business. We have our patient activation plan ready, so it really is a matter of gaining that approval. I'm very confident about the fate of BIMZELX in psoriasis based on what we are hearing and based on, most importantly, the feedback that patients are bringing back to the clinic. Now let me briefly touch on our third immunology asset, which we share with Amgen, and that is EVENITY.
We're in the process of establishing bone builder leadership with EVENITY. In fact, we're getting ready to expand beyond that. More than 200,000 patients have benefited from EVENITY, so there's substantial experience with the asset right now in the field of postmenopausal osteoporosis at a high risk of fracture. Last year, if you were to add up the in-market sales of Amgen, of Astellas, and of UCB, you would reach just short of $600 million. It's become a sizable asset for which we have about half of the profit share, a little bit less than half of the profit share. You can see that in Europe, we started contributing with EUR 10 million last year. This is mostly driven from Germany.
In the meantime, we've gained access in Scandinavia and Benelux in pieces of the U.K., which we intend to expand, as well as the south of Europe for the latter part of this year, hopefully. You can see in the market shares of the bone builder segment, which includes Forteo, its generics, as well as Tymlos, that we're already close to achieving half of that market share. That even in Germany, which launched a year later than the U.S. and Japan, we're tracking to get there. Those rates are exit rates for last year. Our attention is also moving to expanding beyond that. The first way to do this is to continue to push to build bone first in patients that have had a recent fracture before using an anti-resorptive. The second leg is really partnering.
Partnering with clinical centers through the Fracture Liaison Services that we deploy worldwide. Partnering with the Capture the Fracture partnership, which aims to reduce the incidence of fracture and improve the treatment rates of fracture. Partnering with policymakers, with tech companies to deploy artificial intelligence to scans, which may be taken for whatever medical reasons and can help detect silent fractures of the spine. We've done this this year, this partnership. Finally activating the patient base. With all of these, we're very confident that we'll be able to continue to robustly grow EVENITY with our partners over the next many years. With that, I hope I gave you some insights to better understand how we look at our portfolio of three growth assets in immunology.
I will now hand over to Sandrine, our CFO, and thank you for your attention.
Thank you, Emmanuel. Good morning, good afternoon, everyone. I'm really pleased to present our 2021 results, which are supported by the strong growth of our product portfolio and gives us a real position of strength as we enter 2022. If we move to the next page, let me start with the net sales. Charl and Emmanuel have already illustrated the underlying dynamics of our product portfolio. Total net sales reached EUR 5.5 billion, an 8% growth and 11% growth at constant rate. They were supported by strong volume growth. We delivered a higher volume growth in H2 versus H1. On the left, you can see a very robust double-digit growth of the epilepsy portfolio.
If we look on the right by product, starting with FINTEPLA, the net sales growth was achieved despite the adverse pricing with the mandated price decrease in Germany that started in April, and change of ASP of the lyophilized formula of FINTEPLA in the U.S. as of July 1. The net sales growth was achieved thanks to a strong underlying volume growth of + 12%. Moving to Keppra. Keppra reached two million patients, and the net sales growing 23% are lifted by the takeover of the distribution of E-Keppra from Otsuka in Japan. EVENITY increased net sales in Europe despite the pandemic and contributed EUR 10 million to the good worldwide performance of this treatment option. You see appearing the revenues from BIMZELX. Of course, this is a lagging indicator.
As you could see, all relevant leading indicators with the launch dynamics in Europe in the charts that Emmanuel has just presented before. Overall, a very good net sales dynamics. If we move to the next page, now looking at the full P&L, this net sales dynamics converted nicely to the P&L in a substantial profit growth. Revenues increased by 8% and EBITDA by 14%. At constant rate, this was respectively +10% and +21% growth. Revenue achieved EUR 5.8 billion, and the 8% growth was driven by net sales. We landed above the top of the guidance range, which was EUR 5.65 billion. You can see an improvement of the gross margin of 60 basis points to 75.1%, thanks to favorable mix of our portfolio.
OpEx increased by 4% only, below top line growth, and they reflect a 10% higher marketing and selling expenses as the company both invests in and prepares for launches. R&D grew by 4%, reaching 28% of revenues and reflected the progressing pipeline with five late-stage assets as well as ongoing earlier stage research. We also had significant higher other operating income corresponding to the net contribution from Amgen in the commercialization of EVENITY. For better transparency, you will see in the appendix of the deck that will be online, a slide that explains how EVENITY flows through our P&L as we consolidate 100% of the net sales from Europe. We do not consolidate the U.S., Japan sales, and we capture half of the worldwide net profits.
Group adjusted EBITDA ended up at EUR 1,641 million, corresponding to a 28% margin. Actually, it's 28.4% to be precise, and there again, above guidance. Profit amounted to EUR 1,058 million and grew substantially post-2020. As a reminder, we had higher one-off expenses in 2020 linked to the acquisitions. That takes me to the core EPS, which was EUR 6.49, a 21% growth, and which benefited from lower financial expenses and a tax rate of 14%.
All in all, we are very satisfied with this financial year. Now, if I move to the next page, we want to complement this view by non-financial performance as well, where you can see meaningful achievements as well in the ESG ratings as we progressed on four of the five ESG ratings we chose to engage with. They include in their evaluation our priority areas for societal impact, and they are important and relevant to our different stakeholders. We were recognized this year by Sustainalytics, a top-rated performer for management of ESG risks in the pharmaceutical industry, and by CDP on how effectively we are engaging our suppliers on climate change by being included in their 2021 supplier engagement leaderboards. Moving to the next page. Another strong position for 2021.
We ended the year with a very solid balance sheet and a low leverage of 0.5 times net debt on EBITDA. Just reminding our capital allocation priorities. They remain tied to, one, supporting our strategic priorities. Two, ensuring a sustainable return to our shareholders. Three, maintaining a strong and flexible balance sheet. We continue to invest in innovation for patients with high level of R&D. In 2021, the partnerships we were able to sign, recognizing our innovation, our science, contributed to upfront milestones and to cash flow generation. Our CapEx increased to a total of EUR 493 million, reflecting investments in biopharmaceutical activities as well as intangible assets. Our board of directors will propose a EUR 1.30 gross dividend to our next AGM, a three cent growth for this last year dividend.
The strength of our balance sheet allows for seizing strategic inorganic opportunities. As Charles mentioned, we expect to close the Zogenix by the end of Q2. Transaction value, including CVR, is $1.9 billion. The $800 million five-year term loan that will contribute to the funding on top of existing cash sources is now secured. Now moving to the next page regarding 2022 guidance. As a reminder, Jean-Christophe has mentioned it, we will update it with the Zogenix acquisition when we close the transaction. What is on this page is excluding the impact of the Zogenix.
We are entering a transition phase, and the guidance we provide for 2022 incorporates the continued growth of CIMZIA, Briviact, NAYZILAM, EVENITY, the launch of BIMZELX in the U.S. in the first half of the year, as well as the expected impact of Vimpat loss of exclusivity in the U.S. in March, in Europe in September, and the loss of exclusivity of EKeppra in Japan, where generics entered the market early 2022. I'm sure you appreciate that these events come with a certain level of variability, hence the expected range of revenue between EUR 5.15 billion and EUR 5.2 billion. Expected EBITDA margin is between 26% and 27%. We have built a solid plan to support the launch of BIMZELX and prepare the pre-launch activities for rare disease, and we plan a similar level of absolute amount of R&D expense than the 2021 level.
All this translates into a core EPS guidance of EUR 4.80-EUR 5.30 per share, with a tax rate expected in the mid-teens%, excluding the potential effects of any additional tax reforms. On the right part of the page, you can see that we confirm our estimated peak sales for the future sales of Cimzia and Briviact, and that we have achieved the EUR 1.5 billion peak sales ambition for Vimpat in 2021. Moving to next page. With all the phase III positive readouts, we are very confident in our strong growth ahead, and we confirm our 2025 guidance of leading in five specific patient populations of at least EUR 6 billion revenues and low- to mid-30s% adjusted EBITDA margin, as well as improved ESG rating performance.
With this, let me thank you for your attention and hand over to Jean-Christophe for closing remarks.
Thank you, Sandrine. A quick closing. I think, thanks to Iris, Emmanuel, Charl, and Sandrine, you have been able to get a little bit more in depth of what you have read this morning in the press release. I think you have been able to see, next slide please, how we are able to continue to deliver on our commitment, how we are able to unfold our strategy and making sure that we can continue to deliver future growth. Yes, UCB is delivering on our commitments on track to Amplify by 2025 in a great shape to continue to grow. We are confident that we'll be able to continue to deliver value for all stakeholders and shareholders. Thank you. A big thank you for your attention and for participating.
I think now I will hand over to Antje to have the time to answer to your question. Thank you.
Thank you very much, Jean-Christophe. Thank you to all who have posted their questions into the chat or sent them by email. I will now go through them and bring them to the attention of the panelists here. I'd like to start with Wimal Kapadia from Bernstein, and he is saying, "Thank you for confirming R&D in absolute terms will be similar to 2021." He's curious if we could explain the dynamics at play here, given several phase III trials have completed. What is the phase III spend now being used for in the pipeline? He also likes to talk about the selling and marketing spend in 2022. How should we think about the incremental spend for launches versus the reallocation of existing infrastructure? Is it a similar absolute spend to 2021, a reasonable absolute
a reasonable assumption to make? I suggest that perhaps Iris starts with the dynamics on phase III activities, and then Sandrine follows with the financials.
Yeah. Antje, thank you. Thanks for the question. I'm very happy to do that. So, think of our investments into R&D going forward in four different buckets, kind of. First of all, even if the primary phase III studies that we have reported to you are finished, we still continue with open label expansion studies. That's a commitment to the patients we want to serve, and in certain circumstances, also with geographical expansion. There's still continuation. Secondly, I would like to remind you that we still have four phase III programs started or ongoing. We have dapirolizumab in systemic lupus erythematosus, which is in the middle of phase III. With rozanolixizumab, we have ITP, and we have very exciting, the MOG antibody disease program in phase III. Of course, I've talked about Staccato alprazolam.
There are four new phase III programs underway. Third point is, you have heard we are doing disease modification, proof of concept studies in Parkinson's disease and in Alzheimer's disease. Even though we do that in partnership, these are pretty substantial clinical trials, 450 patients each. Observation periods of up to 18 months for each patient. This is when you want to really see that you slow down disease progression. These are quite heavy investments. Then last but not least, we are only talking to you about our clinical stage pipeline as of phase II. We have amazing scientists. We have tremendous research efforts. We have a flourishing and growing, very early-stage pipeline. There's a lot of investment there, and I can tell you there's a lot of excitement coming from the early stage work as well.
I think smart investments, but of course, still costly as always. Thank you.
If I may continue then on the questions on marketing and sales. Well, you should expect to see marketing and sales increase in 2022 as a percentage of revenue. If I first focus, you know, to support the launch of BIMZELX, of course, our sales force, as Emmanuel said, our medical scientists, of course, the payer teams, all this is really fully deployed for the psoriasis worldwide. The major increase that we expect in 2022 will be linked to the DTC investment to support the launch in a very competitive market. On the other dimension, we're very disciplined how we allocate our resources, you know, to create space to support the launches.
For example, we expect to reduce our cost on CIMZIA Rheumatology, support the launch of rozanolixizumab and zilucoplan by shifting resources from epilepsy. You also see that we are getting the benefits from being more effective using advanced analytics, targeted approach to support our sales. Net, we expect an increase, but of course, not all of this will be incremental investments by far.
Thank you, Sandrine. The next question still from Wimal, I think is going to Emmanuel. He likes to talk about BIMZELX. He's quoting that consensus is modeling over EUR 200 million, EUR 215 million to be precise, for BIMZELX sales in 2022. He's curious if you believe this is a fair number and how you are thinking about the sales split by region for this year, assuming launch in the U.S. from the start of Q3. Emmanuel.
Yes, thank you, Wimal. We're not really giving a guidance on BIMZELX yet. First, we would like to gain that U.S. approval. Of course, the U.S., as soon as they launch, will quickly contribute and significantly contribute to BIMZELX sales. My expectation would be that if we were to launch in the second quarter, by the end of the year, the U.S. would already represent the majority of BIMZELX sales.
Thank you very much. You can stay tuned because the next question is coming from Peter Verdult from Citi, and he likes to know how you are thinking about the CIMZIA erosion curve. While CIMZIA will be impacted by Humira biosimilars, there doesn't seem to be a CIMZIA biosimilar set to launch in 2025. Should we begin to think about CIMZIA being a more durable franchise longer term?
Yeah. I think there's some ground to thinking like that indeed. There's really two questions, right? There is what will be the erosion of CIMZIA in the face of Humira biosimilar launches in the U.S. There, I would say that, you know, by and large, CIMZIA is used in a kind of step-edit position as a kind of second, third or fourth drug most of the time, except for women of childbearing age, for non-radiographic axSpA, and at times also with its bio formulations. Now, as it happens, those are three opportunities which Humira is not positioned for, and this will not change with Humira biosimilars. I do think that the erosion of CIMZIA due to the entry of Humira biosimilars will be limited. We've seen that in Europe as well, right?
Remember a few years ago, there was a lot of anxiety around what will happen when Enbrel and Humira go biosimilar, and in fact, the volumes have continued to grow. We've of course had some price erosion, but it's not until the jumbo group inclusion that this really hits significantly. Now, longer term, you've all read that Biogen has licensed the rights to the Xbrane potential first biosimilar of CIMZIA. It's very unlikely that this would reach the market anytime before 2026, and even for 2026, it would require very good execution. Whilst the loss of exclusivity is in 2024, I see it as indeed quite unlikely that there would be an entry of a biosimilar before 2026.
Even then, the question will be how many will follow after that and take the prices down. At this point, I think it's anybody's guess. What is a fact is that there is not a CIMZIA biosimilar in the clinic today. That by itself, I think, probably indicates that it will take a while before more than one biosimilar might reach the market.
Thank you very much. The next question goes to Sandrine, and it's coming from Richard Parkes from Exane BNP . Your 2025 targets imply a 450-750 basis point margin improvement to 2025. Can you discuss the expected pace of that trajectory? To what degree is it dependent on top-line growth from the new portfolio versus easing investment cost pressures? You have flagged R&D spend at a similar level in 2022 to 2021. Could we see that decline in absolute terms in 2023 as trials roll off?
Thanks. Thank you for the question. You know, talking about the trajectory of what we expect towards 2025, it will largely be a function of the top line evolution. You know, the drivers of the top line being the growth of the existing commercialized assets, BIMZELX ramp-up. You know, to that extent, the launch of zilucoplan and rozanolixizumab are very much in the back end. Of course, loss of exclusivity impacts on the top line that will have an impact, not just this year, but will continue as well in 2023 and then CIMZIA in 2024. How these are impacting the margin. Remember, on the margin drivers, what we have said, we see three levers. One is the gross margin expansion as we are improving the product mix.
There's of course operating leverage as we grow the top line with marketing and sales and R&D decreasing as a percentage of revenues. There's as well EVENITY margin, which as you know mechanically because we consolidate a higher share of contribution of profits versus the share of revenue as an accretive impact on the gross margin. Now, in terms of you know how is this moving from today till 2025 you really have to model the impact of the top line including the LOE effect, which as we say we are entering a transition year, and next year will be and also in transition phase. We also will see the impact of intense launch and pre-launch activity this year and next year.
You should have this in mind when modeling from now till 2025.
Thank you. The next question, I think, is Iris, I think. Richard is talking about KOL feedback suggesting significant interest in combining C5 inhibition with FcRn inhibition in myasthenia gravis as an opportunity. You seem to be positioned uniquely to benefit from it. Can you discuss if this is an opportunity you might look to explore now that you have positive phase III data in-house?
Yeah. Thank you, Richard. As we hold both assets with very broad mechanisms of actions in our hands, of course, there's an ongoing strategic discussion in terms of how do we serve patients best with these assets. We're talking about new patient populations. The point around combination therapy is on our agenda, but no decision taken at this stage. Stay tuned, please, and we will follow up as soon as we are clear about the life cycle that lies ahead for both zilucoplan and rozanolixizumab, and which is very promising.
Thank you very much, Iris. The next question goes to Charl`, and it's coming from Richard Vosser at JP Morgan. First, how should we think about the development of Keppra in Japan now that generics have launched? If I may, the second one, Charl, the myasthenia gravis market is highly competitive. Do you feel that the data you have are sufficient for rozanolixizumab and zilucoplan to be competitive with the already approved agents in both classes?
Thank you, Richard, for your question. Your first question around the generic erosion curve, what we can expect in Japan and what we've of course modeled based also on historical data is a 50% reduction in the first two years from the entry of the generic. This is a general assumption we built into our thinking, and I can expand on that also for the European environment with Vimpat. That is a similar assumption we have mentioned to you in the past.
150% erosion in the first two years. Just to expand that for the U.S. on Vimpat, that is generally 80% erosion in the first 12 months. That's how we look at this, and this is very much based on historical insights on how Keppra was eroded through its history, but also looking at other generic molecules in the epilepsy space. Your question on. Of course, we are not releasing the results yet. We aim to release them in the second quarter at medical conferences. This is still work in progress, and we can come back and discuss more the exact data at that point.
What we see today and with our, you know, results in terms of what we've released, reaching our primary and secondary endpoints, we feel we have a very compelling offer against competition. The way we look at competition, there's a first wave of competition of really three players. It's UCB, it's, of course, Alexion or AstraZeneca and argenx, and all three of us will be in this first wave in the next, five years, in a sense. With what we have in our hands, with our strong portfolio, we feel very competitive and of course, with very strong commercial know-how to build leadership in the patient population.
Thank you, Charl. Richard is continuing his questions. I think this goes to Emmanuel. How should we expect CIMZIA to develop in the U.S. and Europe, given the price pressure on the lyophilized version and the price cuts in Europe? How should we anticipate CIMZIA reaching the EUR 2 billion? Also, do you feel that you now have the cost structure in place at the end of 2021 to execute the BIMZELX launches?
Yeah. Thank you, Richard. First on CIMZIA. For Europe, I think the worst of the price cuts are behind us. The level of prices are relatively low now across the board. I'm not seeing that much downside anymore. In fact, I continue to see upside to volume growth. My sense is what we'll see this year is a positive contribution of Europe to CIMZIA growth, and I foresee this to continue over a few years. In terms of the U.S., indeed, the pricing pressure on the lyo is something that is of course a one-off effect, which then triggers a little bit of erosion as a function of the way the ASP price is computed.
I foresee the lyo price to continue to erode, of course, at a much slower pace than the one-step 17% decrease we saw on July first last year. However, for the pre-filled syringe, I do think that the price will be reasonably stable in that segment. From a growth point of view, last year we had 12% growth in the U.S. in volumes, so it'll be hard to match, but I do think that we'll stay at, you know, at a, let's say, high single digit or something like that in terms of volumes. Their contribution as well. International markets, let's not forget from a growth perspective, they're a very important contributor to our growth.
The way that these markets function is slightly different in terms of impact of biosimilars, et cetera. We also have more recent launches in spondyloarthropathies and psoriasis. I see continued good contribution from emerging markets, certainly on a constant rate. In terms of the footprint, I would say that like at exit 2021, we probably have the necessary footprint in terms of fixed costs that will take us through BIMZELX, both in dermatology and in rheumatology. That would really be kind of looking at the fourth quarter.
In terms of variable spend, of course, we're going to invest more this year as BIMZELX is being rolled out in other European countries, in Canada, in Australia, and of course, most importantly, in the United States, where there's a heavy component related to direct to patient activities as well as services.
Thank you, Emmanuel. Please stay tuned because the next question from Graham Parry, Bank of America. He's asking about the BIMZELX launch experience in Europe so far. What line of therapy are you seeing? For Germany, you quoted 11.1% share in dynamic market, but what is the reimbursement situation? Is this unrestricted access and pricing at this stage? He would like to know.
Thank you. I partially answered the question with my presentation. In terms of line of therapy, I think it's probably a little early to comment. I mean, the robustness of the data is not that strong yet. But there's probably more early line use than what we had anticipated, and that I think is pointing out to quite some depth with the early adopters who seem not to hesitate to use BIMZELX in very early lines.
This drug being picked up by smaller dermatology offices in function of its clinical advantages. You know, I see that as something that's really encouraging, but again, it's early days, and I would like a few more months behind our belt before commenting more and also looking at that kind of data in more markets. In terms of our access and reimbursement, I'll briefly comment on Germany, but also on the U.K. In Germany, it's free pricing up to the point that the reimbursement price gets agreed, which we foresee will happen over the next few months. Then there can be arrangements with sick funds. Let's say the national reimbursement is unrestricted. Arrangements with sick funds may sometimes restrict or favor certain drugs.
However, I think with the profile and the data that we've shown, I'm expecting pretty broad access at the reimbursed price in Germany very soon. Whereas the NICE endorsement and approval in England is essentially equivalent to what one would call an unrestricted first line in the United States. It means BIMZELX is reimbursed at that level across the country. Of course, clinical groups and hospitals can add a layer of formulary management, but by and large, the product is recommended for use in all lines of therapy in England.
Thank you, Emmanuel. The next question goes to Iris. It's coming from Jeroen van den Bossche from KBC, and he's asking if there are patient populations in which zilucoplan or C5 inhibition is preferred over FcRn. Are there any competitive advantages that rozanolixizumab may have over VYVGART, that you could comment on? For clarity, he's looking for excluding the subcutaneous administration, what profile would be here, the safety versus VYVGART?
Yeah. Thank you, Jeroen . Of course, as mentioned several times, right, we have distinctly different mechanisms of action. zilucoplan, with its inhibition of the complement C5 cleavage, in the end, avoids formation of the membrane attack complex and as such, lends itself to very different diseases than rozanolixizumab, which inhibits the neonatal Fc receptor and thereby enhances the degradation of autoantibodies. If your question is more focused on generalized myasthenia gravis, where we have both mechanisms together, then of course it's very clear that C5 inhibition is focused on those patients with acetylcholine receptor-positive autoantibodies that's driven by the mechanism of action.
You know, you have seen it in Charl presentation that we believe that for these patients, zilucoplan provides an advantage based on its daily subcutaneous injection and/or with the opportunity to really become a stabilizing maintenance therapy. FcRn inhibition, and for rozanolixizumab, we have proven that is targeting both populations, acetylcholine receptor-positive and MuSK autoantibody-positive patients. Of course, we see the opportunity to stabilize patients who have an exacerbation of their disease or who do not respond to zilucoplan also with a very easy-to-use subcutaneous short infusion. There is complementarity. You have seen that. Of course, there is the opportunity to really provide tailored solutions to patients with generalized myasthenia gravis in need. We are very mindful that no one patient is the same.
We are very mindful that patients need tailored solutions. We're very pleased, and we're working very hard with patient advocacy groups and physicians in the field to ensure that all of this is visible and that we prepare our offerings accordingly. I hope that answers your question. If I missed something, please let me know.
Sure, I will. Thank you so much, Iris. We stay in the field, and this next question goes to Charl. It's coming from Jean-Jacques Le Fur from Bryan Garnier. He likes to know about GMG drug pricing. Anti-C5, Soliris and Ultomiris are priced in the U.S. at about $460,000 per year, while VYVGART price is around $225,000 per year. Therefore, do you think that anti-C5 and FcRn drugs will continue to have a price difference, or will it converge over time, particularly since anti-C5 should be used for chronic treatment?
Thank you, Jean-Jacques, for your question. Of course, generally, I would not comment on competitive pricing. Overall, I think this is a new market, so we will see, you know, change over time in the pricing dynamics. What I would just say is our philosophy is, of course, we take into account some view of the competitive pricing, but we are aiming to think more about sustainable pricing, in a sense, thinking about how we price responsibly, based on the value of the product or the asset and what it offers, and of course, also respecting the affordability and seeing how many patients or the number of patients we can reach.
On a global level as opposed to just a single market. That's our philosophy going into this, but of course, more work will be done on pricing, and when we are ready, we will be happy to communicate that, of course, with you as well.
Thank you, Charl. I have still a lot of questions. We have 10 minutes to go, so I apologize. I'm making a selection on those topics we haven't talked about yet. And of course, we are there for you in the aftermath of this call to answer your individual question. The next question is coming from Charles Pitman from Redburn. It's going to Emmanuel. Charles is asking, could you provide some idea around the split of patients treated with EVENITY between Europe and the U.S.? Any update on the commercial launch in Europe as sales continue to disappoint versus consensus? How much impact has COVID had, and what might be a peak sales estimate?
Thank you, Charles. I would say for the coming year, Europe versus U.S., maybe 10%-20%. It really depends on how access will unfold in the south of Europe, which are really the markets where treating post-fracture with a bone builder is established, and that is not yet the case in Germany. One could say the performance is disappointing, and I agree that I would like to see more patients treated. If one looks at the market share, we're gonna tend to the same kind of shares than what we're seeing in Japan and the U.S., in Germany and other European markets. The launch curves really run in parallel, so it's a matter of time to entry.
More importantly, it's a matter of expanding the market, and that's what Amgen and ourselves are working hard at doing. It takes time. I think there's good support and good alignment of stakeholders. Europe is a long game for EVENITY, but eventually, this will be a very significant drug for patients and even for Amgen and ourselves. Of course, the COVID pandemic has had a lot of impact because EVENITY is administered in the office once a month for a year. You can imagine that your typical patient suffering from post-menopausal osteoporosis and a recent fracture aren't the most keen patients to go and visit the clinical sites for 12 times in a year. That slowed down things quite considerably.
However, we're really seeing signs of business picking up and I think this will further increase if the current scenario plays out for the pandemic.
Thank you.
I hope I answered all the questions.
Thank you so much, Emmanuel. I have a next question still going into myasthenia gravis, Charl. It's coming from Stacy Ku from Cowen. She likes you to discuss your expected commercial strategy for zilucoplan. With the phase III data in hand, what are your thoughts on pricing, target population, especially as it relates to the current availability of C-5 inhibitors versus potential pricing for rozanolixizumab?
Yeah, thank you for that question. Thank you, Stacy. I would just at this point say that it's a bit early for us to discuss pricing specifically. Let us, you know, publish the data. We are continuing to develop our pricing strategy, of course, over the next months as we get prepared for launch, and we will come back to you on that. I would just say that on a commercial strategy level, we are very much now in the mode after phase III to start continuing to shape the market together with others and, of course, working in the medical community. We have roughly 100 people deployed, different functions of medical affairs, access.
We are in seven international congresses and 35 local congresses and working very strongly with the medical community of around 600 key opinion leaders across the world. We are active in the market today to continue to bring forward the data, of course, the clinical guidelines that will shape the future of this space. We will, of course, update you, of course, in more detail in the future on our commercial strategy in detail.
Looking forward to this. Thank you, Charl. The last question is going to Iris, and it's coming from Diana Na from Berenberg. She's asking for bimekizumab and the rare diseases, zilucoplan and rozanolixizumab, how should we think about your confidence to show meaningful data differentiation versus competitor drugs?
Yeah. I think I hope you have heard my confidence in the presentation, and I can only reiterate that. You know, at this point with data presentations hopefully coming up at the important congresses over the next month, I would really like to see the data speak for themselves. We have always been very clear about our expectations for our molecules. I have every reason to believe, looking at the data, that we have delivered on our expectations and that our hypotheses are intact.
Okay. Thank you so much. This closes today's call. I thank you very much for your attention, your interesting questions. I hope we were able to answer most of them. Please, you know where to find us. We are happy to follow up in the aftermath of this call. Thank you so much. Best wishes. Stay well. Thank you.