Hello, welcome to today's Pharming's full year 2022 results call. My name is Bailey, and I'll be the moderator for today's call. All lines will be muted during the presentation portion of the call, with an opportunity for questions and answers at the end. If you would like to ask a question, please press star followed by one on your telephone keypad. I would now like to pass the conference over to our host, Sijmen de Vries, Chief Executive Officer. Please go ahead.
Thank you very much, Bailey. Good morning or good afternoon, ladies and gentlemen, to our 2022 results call. I would like to start taking you through that, but before I do that, I would like to pay attention to the next slide, which contains a statement on forward-looking statements. As we may be making forward-looking statements in this conversation, they are statements based upon our expectations and assumptions and involve known and unknown risk and uncertainties that could cause actual results, performance or events to differ materially from those expressed or implied in these statements. You can read the rest for yourself, I assume. Today here, next slide, please. I'm joined by my colleagues, Dr.
Anurag Relan , our Chief Medical Officer, and Jeroen Wakkerman, our Chief Financial Officer. We also have here, although not speaking on the conference, but to answer questions, our Chief Commercial Officer, Stephen Toor. I would now like to start with the next slide, please. Then next one. Where are we? We are, we have developed over the years a very strong base with a potential for significant growth. That is based upon the commercialized asset, Ruconest, recombinant human C1 esterase inhibitor for the treatment of acute hereditary angioedema attacks, which is commercialized by ourselves on both sides of the ocean, as you can see in a lot of other markets as well outside of the U.S. and the European Union and of course, the U.K.
The potential for growth is represented here initially by the anticipated approval and launch for leniolisib PI3 kinase delta inhibitor in development or in the regulatory review for APDS, where we anticipate in the not-too-distant future, the FDA approval and later on during the year, the European approval. We have morphed ourselves into a company that is focusing on development and commercialization of rare diseases. The first thing that goes beyond the APDS indication for leniolisib will be that we are quite far along with investigating leniolisib for additional rare disease indications. We are based in Leiden, in the Netherlands, and we are here actually in our U.S. headquarters in Warren, New Jersey, where we speak to you from.
Of course, we're a public company since 1999 in Amsterdam and since 2020 on the Nasdaq. Let's look at our business model on the next slide. We're really on our way to building a sustainable rare disease business, whereas we are now commercializing Ruconest. Albeit on both sides of the ocean, the vast majority of sales come from the United States. We're now a one-product company with one geography. That we expect to be changing very soon with the anticipated approval of leniolisib for APDS, which will represent a, not only a possibility for very significant growth of our U.S. commercial footprint and revenue base, but also a very significant revenue generator outside of the U.S.
We're looking forward to this year being a transformative year from which we transform from this one product, one geography, company into a multiple products, multiple geographies company. Of course, like I said before, we are quite far on our way, and we'll update the market as and when later in the year, to actually start additional development programs for leniolisib in additional diseases. Last but not least, since we have a very scalable commercialization infrastructure in both Europe and in the U.S., we're actively hunting for additional products in rare diseases, to.
either in-license, that is our preferred mode of action, and if, not otherwise possible, mergers and acquisition transactions to basically bolster that pipeline further, and get, and get that flywheel, really get that flywheel, going, that we have here with our scalable commercialization operations on both sides of the oceans. In the next slide, you can see the pipeline and you can see immediately, what I mean with that, whereas Ruconest is on the market and leniolisib very close to the market.
Of course, if we start clinical trial programs in secondary indications for leniolisib, there is still a considerable gap between those two products or those three products for in the near future, and the preclinical assets that we have in the form of OTL-105, the HAE gene therapy and alpha-glucosidase from our transgenic platform, just like Ruconest for Pompe disease. Let's look at Ruconest being the founder, strong foundation under our. Next slide, please. Under our company. We returned it to growth again after the COVID period. We returned to growth in 2022 as we were guiding single-digit growth over 2021. That is something we are very proud of.
Ruconest was launched, at the end of 2014, so is already quite a mature asset and has found its unique place in the market. It is the only recombinant treatment that targets the root cause of hereditary angioedema by replacing the missing or dysfunctional C1 esterase inhibitor. Over the years, it has proven to be very well-tolerated and effective, and continues to be a very effective treatment for the treatment of acute hereditary angioedema attacks, including, and that becomes increasingly important, those breakthrough attacks that people suffer from when they use prophylactic treatments. That is, indeed, continues to be an issue that although prophylactic treatments have become, especially referring to the United States market, of course, where, the vast majority of our sales come from.
Although the prophylactic treatments have become a lot better, they all have the same issue that up to half of those patients suffer from breakthrough attacks. Breakthrough attacks can come very frequently or very rare, but they come always at a moment that you don't expect it. That's why it is always the case. It is good practice in the United States that when you are on prophylactic treatments, you always have acute medication at hand, at home to actually inject yourself in the case of Ruconest with the rescue therapy. That becomes increasingly important. That is also why we see increasingly that Ruconest is being used by more doctors and used by more patients to actually treat those breakthrough attacks.
It is, we can very proudly say, the second most prescribed product that is detailed for acute attacks. As you can see here, the FPCC numbers speak for themselves on this slide. We are finding that our patients feel very confident to administer the treatment to themselves. It's a slow IV injection, and the very vast majority of patients inject themselves in or by their loved ones in the privacy of their own homes. Ruconest, it has been on the market for a long time and will continue to play a very important role supporting our business with sales and with important cash flows that enable us to invest in all those future programs that we are embarking on.
With that said, I would like to now switch over to the promise for significant growth of the company in the very near future, leniolisib for APDS. I would like to hand over to Dr. Anurag Relan, who sits here next to me, to take you through the story of APDS and leniolisib. Anurag, over to you.
Thank you, Sijmen. In the next few slides, what I'd like to do is review some information that we have on our understanding of the condition APDS, our understanding of the patient journey, and what we've done in terms of developing leniolizumab for APDS, and then using this, all of this information to help identify patients. Lastly, provide an update on where we are in terms of regulatory status. On the next slide, we can see a schematic here of how this genetic defect in one of these two genes leads to this hyperactivity of this pathway. You can see that within the cell there on the left, and that hyperactive pathway then leads to this dysregulated B and T cell development.
These key components of the immune system do not develop properly, and as a result of not developing properly, patients suffer from a number of symptoms and conditions that you can see on the right. Most prominently, these patients develop recurrent infections. They also, because of this abnormal development of their immune system, have what's called lymphoproliferation. They get swollen lymph nodes, their spleen is enlarged, they have problems with expansion of lymphoid tissue, especially in the gut, and that can lead to a condition called enteropathy. Not only do these immune system cells not fight infection, they actually lead to the opposite problem, where they lead to a condition called autoimmunity, and this can lead to autoimmune anemias and cytopenias and other autoimmune disorders.
It's also important to note that APDS is a progressive condition, so over time, the disease worsens, and many of these patients, even at a young age, develop a condition called bronchiectasis, which is essentially scarring in the lungs that is irreversible. Many of these patients, unfortunately, go on to develop lymphoma, again, due to this unchecked lymphoproliferation and this abnormal development of their immune system. On the next slide, you know, we can actually see what the consequences of this are on the patient themselves. Of course, we've talked about the physical consequences of recurrent infections. I mentioned bronchiectasis, and that can result in shortness of breath, coughing, just difficulty to do their normal activities. You can see that that can impact their social well-being and as well as their mental well-being, there's a significant treatment burden.
These patients are frequently hospitalized. They have numerous surgeries, many of them unnecessary, especially when they've not been properly diagnosed. Numerous doctor visits. It's a condition that impacts many facets of these patients' lives. On the next slide, we see what's possible now in the current management of APDS, and that's really trying to address the consequences of the condition. Not addressing the root cause, but trying to address the symptoms. What the symptoms or the manifestations are infections. These patients are frequently on antibiotics, either prophylactically or to treat their infections. Most of these patients are on immunoglobulin replacement therapy.
On the flip side, when they have autoimmune complications or immune dysregulatory complications, they're put on steroids, other immunosuppressants or a class of drugs called mTOR inhibitors to try to modulate their immune system. None of these therapies, of course, are FDA approved for the specific treatment of APDS. The worst condition, worst possible outcome for these patients is that they need a stem cell transplant. Unfortunately, even stem cell transplants, although potentially curative, have significant morbidity and mortality associated with them. On the next slide, we can see the future now, what we're developing is leniolisib, which is a targeted disease-modifying treatment for APDS. Leniolisib specifically blocks the PI3K pathway and thereby modulating and trying to return to normal the activity in this pathway.
A consequence of that should be that we can actually develop the immune system properly and then again, impact all the other things that are the downstream effects of that abnormal immune system development. When we've gone on to study that together with Novartis, and you can see in the next slide the overall clinical development plan, which includes a number of studies, dose-finding studies, a placebo-controlled study, and at the bottom, a long-term extension study. There are patients now in that long-term extension study that have been treated for a number of years, many patients, several patients over 5 years, one patient who's been in the study now for 7 years. We have extensive data on the use of leniolisib, both in a long-term perspective, but also in a placebo-controlled fashion.
In the next slide, we can see some of those results. The randomized control study met both primary outcomes, which was number one, to increase the number of naive B cells. Again, these are B cells that were not developing properly as a result of that underlying, hyperactive pathway. We were also able to achieve decreased lymphadenopathy. Again, this was a primary manifestation of APDS. On top of that, when we look over, in the randomized study, as well as over longer periods of time, these patients' spleen size shrinks. We see improvements in those autoimmune complications. We see in general that the drug was also well-tolerated. In the data package that we submitted to FDA, for example, we have a median exposure of two years for the patient population.
When we start looking at the longer-term outcomes, we see that these patients are getting less infections, and they're using less immunoglobulin replacement therapy. Despite using less of the therapies that are needed to control infections, they're actually getting less infections. It's, it's actually very nice to see how impacting that pathway can impact the immune system and then can actually have an impact on all of these clinically relevant endpoints in terms of infections and also reduction of immunoglobulin replacement therapy. On the next slide, we can see where we are now in terms of safety.
What we see when we look at the randomized controlled trial data is a comparison of Leniolisib on the left with placebo on the right, and you see a very similar profile in terms of the grade of adverse events that were experienced by these patients. That mimics what we see in the long-term extension data. In general, Leniolisib has been well-tolerated. Again, as I mentioned earlier, we have some patients who've been on the therapy in the studies for several years now. On the next slide, we can see the activities that we've been conducting to help find patients. There's a number of activities as we begin to understand the disease and this patient journey that help us inform how to go about finding these patients.
We, again, estimate that based on a prevalence of 1-2 per million, there's more than 1,500 patients in the key markets where we intend to commercialize leniolisib first. We've already identified 500 patients in these markets. Much of this has been done through a partnership with Invitae, which involves a genetic testing program that is at no cost to patients to that can make a definitive diagnosis for these patients. We also have a number of partnerships with medical organizations, patient organizations, and these are critical in helping us to uncover these patients who have this rare primary immunodeficiency. We receive tremendous support in these partnerships.
Again, these patient organizations who are, who really have the same goal that we do, which is to help improve the lives of these patients with these rare and ultra-rare diseases. On the next slide, we can see where we are now with our regulatory status. As Sijmen mentioned, we have filed in the U.S., it's under review with a priority review designation for patients who are enrolled in the programs that I described, which were adults and adolescents age 12 and over. We also have an ICD-10 code in place, and we have a number of physicians already using that code, so that's also nice to see. We have coming up at the end of this month, the expected decision from FDA on the 29th of March.
We expect that later this year, still in the second quarter of this year, we expect to be able to commercialize, pending a positive decision from FDA. In Europe, we've also filed an application there. We also have a positive designation on our paediatric investigation plan, which of course is necessary to begin the filing process. We originally received accelerated assessment. This has now been switched to a standard assessment as EMA have requested additional data. We still, however, anticipate that CHMP will be able to provide an opinion later this year, in the H2 of this year, with an approval to follow approximately two months later.
With the U.K. regulators, we expect to be able to file soon after the CHMP. On the next slide, you can see this over time, some of the key anticipated milestones. Earlier this year, we were able to begin the first of two pediatric studies. Again, we have FDA regulatory decision coming later this month with the U.S. commercial launch soon after that. We're also gonna be getting a new study in Japan, and we expect that to also occur in the H1 of this year. As I mentioned earlier, we are expecting a CHMP opinion, as well as a U.K. filing in the second half of this year. I will now turn it over to my colleague, Jeroen Wakkerman, our CFO.
Thank you very much, Anurag. The financial highlights for 2022 versus last year related to the P&L. To start off with, our sales grew by 3.4% in 2022 to EUR 205.6 million. In Q4, sales were EUR 54.6 million, also a growth of 3%, in line with the single digit growth guidance that we've given throughout the year. Gross profit increased from EUR 178 million to EUR 188.1 million. That's an increase of 5.8%. Therefore, we improved our gross margin. Operating costs grew from EUR 167 million to EUR 184.4 million, an increase of 10.5%.
The operating profit grew to EUR 18.2 million, which is an increase from last year of EUR 34.5 million. The net profit decreased from EUR 16 million to EUR 13.7 million in 2022, which is a decline of 14.5%. In the next few slides, I'm gonna give you a bit more color and detail on the results on what happened. Next slide, please. The overall message is that we grew our sales and we also grew our investments in the launch and the preparation of the launch in leniolisib.
Revenue grew to EUR 205.6. That was supported by a price increase, which was well below the CPI level, also an increase in the number of doctors prescribing Ruconest and an increase in the number of patients. Regional split is that we had a growth in the US of 3%. The EU sales were flat over the two years. Moving to gross profit. Gross profit increased. That was amongst others obviously by the sales growth, also by the improvement in gross margin from 89%- 91%.
That was driven by favorable production results, but also an impairment on the inventory in 2021 of EUR 2 million that we didn't need to take this year. The other income is you see a sharp increase from EUR 2.6 million- EUR 14.5 million, and that includes the transaction that we did with BioConnection, our fill and finish partner, in which in Q2, we reduced our minority stake from 44%- 23%, and we had a gain of gain on disposal of EUR 12.2 million. The remainder of that other income is mainly grants that we receive in the Netherlands on research and development. The operating costs increased from EUR 166.8 million- EUR 184 million.
You see that overall the costs were flat on a like for like basis, so to say. You see the growth in leniolisib out-of-pocket expenses. We consider out-of-pocket expenses mainly third-party providers. That almost doubled to from EUR 18 million- EUR 34 million. Please be reminded that in that normal operating cost, there are also leniolisib costs. For example, the 25 disease educators for leniolisib that started on the 1st of August last year. The overall cost for leniolisib increased more than what you see here. Going to the cost category developments. R&D in this picture declines.
I'd like to remind you that last year we had a one-off impact of EUR 18.5 million. We should we deduct that from the EUR 70 million to come to a like for like number. That one-off was related to OTL-105, the collaboration agreement with Orchard Therapeutics, and also an impairment of, on a intangible assets. On a like for like basis, the R&D costs were largely flat. G&A costs, we increased, that was mainly because of payroll and IT costs, just to strengthen the backbone of the organization with the growth that we foresee in the near future. We see a growth in marketing and sales costs.
EUR 26 million up from EUR 59 million- EUR 86 million almost, and that was mainly in leniolisib, and mainly in categories like marketing and market access development. The operating profits increased from EUR 13.6- EUR 18.2, and that's the effect of the increase in the gross profits, the BioConnection gain on disposal and offset by the higher cost from our investments in the leniolisib launch preparation. The net profit reduced, and that is mainly because of the financial results that reduced from EUR 8.8 last year to EUR -2.2, and that is mainly foreign exchange driven. Moving on to the next slide, where you can see in a different way what happened to the profit before tax. Last year it was EUR 23.1 million.
We had some one-off costs in 2021, again, due to OTL-105 and some impairments. You could argue that the like-for-like profit before tax last year was EUR 43.1 million. What happened in 2022, starting from that base? We grew the gross profit by EUR 10.3 million. As I said, the R&D expenditure was relatively flat. Although within that pot, there were quite some changes. We increased the investment in leniolisib, we increased the investment in OTL-105. We had more costs for AKI and Cattle, the program that we have stopped by now, so that will reduce in 2023.
We reduced the cost in 2020 on Pompe and on the COVID R&D. So a mix of things, and I think a good reflection of our strategic intent. The increased G&A expenditure was mainly, as I said, because of payroll, additional people and IT costs, and the marketing and sales was largely driven by leniolisib. See again, the BioConnection transaction result and a decrease in the financial results. Hence we come to a profit before tax of EUR 15 million in 2022. Not on this slide, but important for those who have, who are modeling, you will see that we have a low tax rate, low effective tax rate in 2022.
It was only 9% versus 31% the year before. That's very positive. The reason for that is that the gain on disposal on the BioConnection transaction was tax-exempt. The cash flow development on the next slide, please. We started off the year with EUR 192 million of cash. The operational cash flow was +EUR 22.9, with working capital almost flat during the year, no cash outflow. The investment cash flow was largely related to two items, CapEx in both PP&E and software, but very limited, was only EUR 2 million in total, and incoming cash from the BioConnection transaction. The cash flow from financing activities was largely related to interest on the convertible and some regular lease costs.
We had negative exchange rate effects on the cash, we ended up with a cash and cash equivalent balance, $50 million more than we started the year with at $207.3, finishing the year at $207.3. We can confirm that we have full access to all of this cash or our cash deposits. On the next slide, the outlook for 2023. We continue to see low single-digit growth for Ruconest revenues. The key event for 2023 is obviously the developments on leniolisib. So we expect a U.S. FDA approval in the first quarter. In fact, it's 13 days from now.
The PDUFA date is the 29th of March. The U.S. launch and commercialization will start shortly after it in the first half of this year. For the EU, we expect a positive CHMP opinion from EMA in the second half of this year and a marketing authorization for Europe that will follow two months later. For the UK, we will file afterwards, after the EU approval with the UK's MHRA, following the European Commission Decision Reliance Procedure. To accelerate future growth, our investments, mainly in leniolisib, will continue to impact profits in 2023, as you have seen in the previous slides that I've showed. We're working hard on the lifecycle management for leniolisib.
The new indications, besides for APDS and further details on our plans to develop leniolisib in additional indications will be provided in the second half of this year. As Sijmen said, we continue to look for potential in-licensing and acquisition opportunities and focusing on late-stage developments and assets in rare diseases. Overall, we've had a good year. We've had sales growth, we have had an increase in operating profit. We've had good cash generation and cash in excess of $200 million. We are 13 days away from the leniolisib PDUFA date. With that, I would like to go to the next slide and open up for Q&A with my colleagues, Sijmen de Vries, Anurag Relan, and also our CCO, Stephen Toor. Thank you very much.
Thank you. If you would like to ask a question, please press star followed by one on your telephone keypad. If for any reason you would like to remove that question, please press star followed by two. Again, to ask a question, please press star followed by one. As a reminder, if you are using a speakerphone, please remember to pick up your handset before asking your question. Our first question today comes from the line of Sushila Hernandez from Kempen. Please go ahead. Your line is now open.
Okay. Thank you for taking my question. I just have two questions. The first one on leniolisib. You have identified now more than 500 patients with a confirmed APDS diagnosis. Can you comment on what a realistic target is for the number of patients that you can identify and that can receive leniolisib once approved? Could you also provide an update on your reimbursement discussions? Thank you.
I missed the first part of the question. On the potential numbers. Well, Sushila, I think you're referring to, the label is now 12 and upwards. Right. We've started our first pediatric trial, and I'm looking here at Anurag. I think it's about 25% of patients are below 12 years of age, so they would initially not qualify for treatment until such time that we have the pediatric approval in our hands. Furthermore, I think all of the other APDS patients, we have not seen so far APDS patient that would not qualify for treatment because the diagnosis is made by this genetic test, and that's basically, you know, a yes or no answer. It's pretty clear in that respect.
There is a small number of patients, of course, that have already been transplanted, some of those successfully, so those also would not qualify. Again, the vast majority of the other patients that Sijmen mentioned would potentially be eligible for treatment.
With regards to your second question about reimbursement, obviously, these discussions are relevant for outside of the U.S. Those have not started because we don't we're not approved yet. In Europe, normally speaking, those discussions start after you have the approval for for the product. In the United States, we will be bringing leniolisib to the market as soon as possible after the PDUFA date. We'll, of course, inform the market about the pricing in the United States as and when.
Talk about their discussions.
Okay, thank you.
Was that all your questions, Sushila?
Yes, thank you. Just then one more question. When can we expect to see additional assets entering your pipeline via internal projects or in-licensing acquisitions next to a second indication for leniolisib or your gene therapy candidates?
Yeah. Basically, you know, the secondary indications for leniolisib, second half of this year, we'll be informing the market about that. With regards to in-licensing and acquisitions, we're very active. We have a small but very efficient business development group, turning over a lot of incoming assets that we get offered/that we find ourselves. We've had evaluation in several stages. We've done a few due diligences even over the last year. Of course, you know, as you can see, nothing has resulted in a deal. Until such time, you know, we keep working, beavering away at it, and trying to find those assets that fit our portfolio. We're really looking for serious rare diseases.
I think leniolisiib is a very good case in point, where we are very comfortable to take a phase III risk because leniolisiib, we only could look at the first cohort of patients that had undergone the dose-finding study and the phase III study was ongoing. We're very comfortable with that, provided that we have a good clinical proof of concept in our hands, when we actually start to engage with the asset. Our preferred mode, obviously, for this is in-licensing, as we are still a relatively small company. Of course, an in-licensing transaction is much easier to handle than mergers and acquisitions, especially, of course, when you are launching a product like leniolisiib, that we do with leniolisiib this year, which requires a lot of our focus. Does that answer your question, Sushila?
Yes, that's clear. Thank you.
Thank you.
Thank you. The next question today comes from the line of Joseph Pantginis from H.C. Wainwright. Please go ahead. Your line is now open.
Hey, guys. Thanks for taking the question.
Hey, Joe.
Just looking at some of the internal workings of the company and the decisions that you're making. I've been covering you guys for a while, so now I've been also sort of BC and AC, before cattle and after cattle. Sorry for the bad joke. Yeah, with that said, I guess I wanted to get into the continuum of that decision where, you know, obviously you needed that potential capacity as Ruconest was looking to expand into, you know, pre-eclampsia and AKI. I'm just wondering what percentage of your decision factored into sort of the projected needs for Ruconest in HAE with regard, you know, versus, you know, your ability to expand your current rabbit populations for any needs.
Thanks, Joe. The answer to that is that there is more than sufficient production capacity, manufacturing capacity in the rabbit platform to serve hereditary angioedema, and even, you know, has significant growth possibilities. It is a very flexible system. It takes a while to upscale, but it is a very flexible system, and it is a very flexible manufacturing process. It takes also a while, and it's a complex manufacturing system, but it is really, you know, has the capacity to actually, you know, deliver a lot more products than we currently deliver. If we were to get a significant increase in market share in hereditary angioedema, we could actually master that.
That's great. Just curiosity with cattle, is there any potential here to monetize the platform that you already have in place?
No. Unfortunately, we came to the conclusion that there's no significant possibility to actually monetize that, and therefore, we have halted all the activities there. It's a different product, right?
Fair enough.
Yep, absolutely. I guess for Jeroen, you know, obviously you said, you know, profits might be impacted further based on further investments in leniolisib. I'm just curious how much of that is, you know, the new indications that you'll give visibility on for the second half of this year versus, you know, where do you stand with regard to right sizing the marketing and sales costs and the in-investments that you still might have to do.
Yeah. No, exactly. We expect that the marketing and sales cost for leniolisib will further increase in 2023, Joe. That's just to support the launch in the EU and in the U.S. obviously. On the life cycle management, we hope to start with a clinical trial, for example, by the end of this year. It will all depend on the design of the trial, how much money we need to put into that. Probably for 2023, that impact will be fairly limited because if it happens, it would be towards the end of this year anyway. The impact of that would be more in 2024 than in 2023. We foresee an increase again, in the marketing and sales cost in, for leniolisib.
Got it. Thanks a lot, guys.
Good. Joe.
Thank you. The next question today comes from the line of Hartaj Singh from Oppenheimer. Please go ahead. Your line is now open.
Great. Thank you. Thanks for the questions. A really nice update. We missed you all in our, at our healthcare conference, but glad to hearing your voices over the phone today. You know, maybe just talk a little bit about the 500 patients. There was a question before. I just wanna build on that a little bit. You've estimated about 1,500 patients as your market opportunity. You know, you've already identified 500. H ow do you think, Sijmen, of just the... and Anurag, of the overall opportunity, sort of, you know, the incident patient and the prevalent patient. I mean, do you think that that 1,500 is now a reasonable figure, or do you think it could be larger? I just had a question on, a follow-up question after that. Thank you.
W hen we look at the prevalence, and we have good data, for example, in some European countries, if we take France, for instance, where there's already 60 patients identified in a country that's a population that's about 60 million. We know the minimum prevalence, again, really without our involvement, is, and without a therapy being available, is about 1 per million. We've conservatively estimated about 1 to 2 per million in terms of the prevalence, and that's where that 1,500 number comes from. Now, as we've been out there talking about the condition, obviously we're finding more and more patients, including in places like France and across Europe as well as in the U.S. That number we expect to continue to increase.
I think a big driver also of diagnosis though is the availability of a potential therapy, a targeted therapy. I think as, you know, and then hopefully we there, you know, we can have a therapy available for these patients soon, but once such a therapy is available, I think that will drive even further diagnosis. I think we're fairly right now with the estimates that we're providing in terms of the prevalence. Certainly, it, you know, I don't think it would surprise any of us if the numbers were significantly higher.
Yeah, that makes sense, Anurag. I mean, just from being at ASH and talking to physicians and whatnot, that's our sense also in doing our call checks. You know, just another question. Gotta ask the obligatory regulatory question. I know you're very close to the approval, but just where are you in terms of, you know, any FDA audits or facility inspections? You know, have you already had the labeling discussions and all? Thanks for all the questions.
Sure. I can't comment on any specifics other than to say we're engaged in regular contact with FDA and those, that contact includes in the routine types of things, including inspections, audits, as well as labeling discussions that are that have that are occurring.
Great. Thank you, everyone. Good luck, and we'll talk soon. Bye.
Thank you, Hartaj.
Thank you. As a reminder, if you would like to ask a question, please press star followed by one on your telephone keypad. The next question today comes from the line of Christian Glennie from Stifel. Please go ahead. Your line is now open.
Hi. Good afternoon, guys. Thanks for taking the question.
Thanks, Christian.
First question, on Ruconest, just to get an idea about, you know, the 3% growth last year in the U.S. You know, the price versus the volume mix in terms of what was driving that and what your expectations are for 2023?
Yeah, we stated that we took a price decrease below the CPI. That's our normal modus operandi, or has been our normal modus operandi over the years. I think the price increase, of course, is the biggest driver of this growth. You could say that the underlying volume growth is more or less now flat to slightly maybe going up or down, and there's some quarterly fluctuations there as well. I think that's how you should see that. It means that Ruconest continues to basically be prescribed by a wider audience of physicians. We think that's important. As I was saying in my earlier part of the presentation.
Used by more patients and used by more prescribers, reflecting the fact that there is a continued need for this product in terms of especially the breakthrough attacks that continue to occur under all the prophylactic treatments that are available on the market. Yes, some of them have improved significantly from the past, but no, patients will always need and always have acute treatment at hand to be treating that unexpected breakthrough attack. Do not forget this is a stress-related disease and people can be very nastily surprised by breakthrough attacks. Does that answer your question, Christian?
Yeah. Thanks. Previous sort of similar outlet then for 2023 in terms of that price. Volume mix. Yeah. Okay. Then on lenolisib then, couple here. Just on the 500 patients, you've already said yeah, to about 25% under the 12 years. What's the rough sub-split of the 500 in terms of the U.S. and Europe?
Stephen, would you like to comment on that?
I would. Yeah, maybe I can take that one. I think they're about equally distributed.
We've done check. Yeah. I will also comment that a lot of the work that was done in finding patients was actually initiated in Europe, through this group called the European Society for Immunodeficiencies. They have done a lot of the work. In the U.S., there wasn't such a coordinated effort, so we're a little bit behind in terms of the process, but we're quickly catching up, I think, in the U.S., in terms of, you know, disease state education and finding patients.
It is fair to say that, Europe had head start, right, on this whole thing?
Exactly.
We're getting, we're getting there in the U.S. Yeah.
Sorry, just to clarify, I think I thought, Is the 500 just Europe and U.S., or I think it included some other markets maybe or not?
No, it does include other markets. Well, I was saying that amongst the. If we look just at the U.S., and Europe alone, they're about an equal number.
It is more than 500 by now, right?
That as well, yes.
Keep finding them all the time.
Okay. Then, on the EMA side, obviously we, you had the initial shift from accelerated to standard review. The way you described at the time was obviously further, you know, data from the open label extension. You know, subsequent interaction with the EMA, is that still the case? I mean, is anything additional thrown out there?
There's been no change there. We're collecting that additional year of data and intend to provide it to EMA in our responses. We're still expecting an opinion from the CHMP in the second half of this year.
Okay, thank you. Finally, if I may, in terms of thinking about, you know, a bit of on the modeling side, I mean, obviously you know, obviously the nature of the agreement with Novartis is probably confidential, but an idea of the potential milestones that might be applicable to Novartis on FDA approval and to what extent that might actually be offset by them exercising the option on the priority review voucher that they should get. Just a bit of any insight you can give us there would be helpful.
Yeah, happy to do that, and give you some guidance. I think, for modeling purposes, it's probably a pretty neutral operation.
Okay. The PRV might offset the milestone. Yeah. Okay.
Along those lines.
Thank you.
Okay.
Thank you. There are no additional questions waiting at this time, so I'd like to pass the conference back over to Sijmen de Vries for any closing remarks. Please go ahead.
Thank you very much. Yes, ladies and gentlemen, as we were referring to, we had a very good year, 2022. We laid a very good base for transferring our company from the one product, one geography company into two products, multiple geography company. We believe that the leniolisib has a very significant commercial potential, significantly larger than the Ruconest franchise. Of course, we're very proud what we have achieved and continue to achieve with Ruconest, which is, of course, a very strong supporter, and foundation, and cash flow generator going forward.
We believe also that the, you know, the high hurdle to entry, the complex manufacturing of the recombinant C1 esterase inhibitor, by means of our transgenic platform, will therefore mean that there will be, for the significant period going forward, Ruconest will continue to create those, generate those cash flows that enable us to invest in all these plans, including leniolisib secondary indications and also in licensing of additional assets, to actually start launching products on a very regular basis, going forward. The other nice thing is we are, having a very nice scalable commercialization operations on both sides of the ocean, and therefore, we can easily handle additional assets for commercialization over the coming years.
We look forward to, you know, catching up with you later in the year when we have the next set of results available, and continue to embark on our journey into 2022, the important transformative year for the company. Thank you very much for attending this conference. Like I said, we look forward to updating you on the next occasion. Goodbye.