Hello, and welcome to Pharming's nine-month 2022 results call. My name is Laurie, and I will be coordinating your call today. If you would like to ask a question during the presentation, you may do so by pressing star followed by one on your telephone keypad. I will now hand you over to your host, Dr. Sijmen de Vries, CEO, to begin. Dr. Sijmen, please go ahead.
Thank you very much, everyone. Good morning, ladies and gentlemen, or good afternoon. Very pleased to have you here at the nine-month 2022 results call. With me here is my colleagues, Anurag Relan, our Chief Medical Officer, and Jeroen Wakkerman, our Chief Financial Officer. Before we do that, of course, I would like you to look at that forward-looking statement slide, because this presentation may contain forward-looking statements that, of course, are based upon our current estimations and beliefs and expectations. As you know, things, circumstances could change towards the future.
Okay. Having said that, I would like to switch to the next slide where you see probably a picture of three gentlemen there that you are. For those of you who've been here before, you know our faces. I would immediately like to flip to slide number five, where I would like to remind you of our strategic objectives as we first have formulated them a while ago, and that are still standing here. That is, we are here to build and continue to build a sustainable business by focusing on the RUCONEST sales. That still is very much the case and will be the case for the foreseeable future.
Of course, the next step is to focus on the market approval, launch, and commercialization of leniolisib in key markets of the U.S., U.K. and the European Union. As you know, we have our own sales force capabilities in all of these three markets. That's exactly that will be the core of the leniolisib business that will be built on top of the RUCONEST business. Thirdly, the ongoing pipeline development from our own internal projects and projects that we have, of course, acquired over the course of time, and the management of these rare disease assets, because that is actually what we are doing.
We are focusing ourselves on rare diseases to bring, you know, patients solutions that are unserved and suffer from rare diseases. As you know, there's quite a few of these rare diseases that still have no cures, of which, you know, APDS is just one of them so far. If you would like to please switch over to the slide number six. There you see the three main pillars of our business. Indeed, you know, the importance for RUCONEST is here, of course, because the positive cash flow from RUCONEST helps to fund all these wonderful things that we are aspiring to do, to fund leniolisib, to fund further pipeline development and management.
In other words, those sales forces that are in the market, working on RUCONEST will continue to do that for the foreseeable future, as our product has a place in the market and will continue to have a place in the market. The next one on the left side is the anticipated approval and commercialization of leniolisib. It's a rare disease. It's a recently discovered rare disease. Disease awareness is still relatively low. There were some publications, of course, that stated that there was estimated to be 1.5 patients per million of population, which works out if you see that on that calculation. According to the literature, there should be 1,350 patients. We have become very active now in starting to search systematically for these patients and are finding them on a regular basis in all sorts of places.
Of course, you see there below that in itself, we believe that the leniolisib compound could become a platform in itself because we found some very interesting additional indications from research alliances that Novartis has been doing with several very renowned institutions and are currently sort of prioritizing which one of these diseases to prioritize for subsequent development and of course, bring them eventually to the markets. On the right-hand side, as I was already alluding to, an ongoing pipeline development for the rare disease assets through internal projects and the potential acquisition of new, preferably late-stage assets to in-licensing and M&A opportunities so that we can actually build a portfolio going forward.
Of course, internally, we already have the in-licensed OTL-105, the ex vivo hematopoietic stem cell gene therapy candidate for hereditary angioedema. Last but not least, from our own platform, recombinant alpha-glucosidase enzyme replacement therapy for Pompe disease. This is an overview of the way we see that we build a sustainable business. Let's just reflect on that one more second here. This is an important stage for the company.
I said this before, and I will continue to say that we are about to basically turn the company yet another big transformation, namely from one product dependency on mainly one geography, RUCONEST for United States , towards a balanced portfolio of two products in the market, and of course, a significant business that we expect outside of the United States in the European Union, but also, as you heard us say before, we're about number seven. You have seen back in time that we have been very pleased that on September 28, we could actually announce the filing and acceptance for priority review of the new drug application to the U.S. FDA, and that we have a PDUFA goal date of 29th of March, 2023.
That is where we are gearing ourselves up to bring the product subsequently as soon as possible to the U.S. market. Very important, we could announce that we have already received ahead, well ahead of time of the approval of the product, an ICD-10 code so that the patients can be classified, diagnosed, and of course, can be reimbursable as well as the product comes to the market. That is not an easy thing in the first quarter because of that PDUFA date of 29 March. We are, of course, planning to bring the product as soon as possible in the second quarter to the U.S. market. You know, we will keep you updated, of course, on progress regarding that.
Let's move to the next one, the strategic highlights of leniolisib progress outside of the U.S. on slide number eight. We were, of course, very pleased at the beginning of the year to receive the PIP, the Pediatric Investigation Plan approval for the European authorities. Because the pediatric trials use the same endpoints as our adult 12+ trial on the basis of which leniolisib. That is a very rare event at EMA and grants accelerated assessment and therefore, you know, recognizes that both the innovative character of the treatment is significant and the disease is very significant and needs urgent treatment.
Of course, recently in October, you have seen the announcement that we submitted the authorization application to the EMA, and we are expecting now anytime soon a validation of the file by the Europeans, and that's the review continues. Then on the right-hand side, the U.K. authorities have granted us in April the Promising Innovative Medicine designation. Again, a recognition that there is a serious disease at hand here, and there's an innovative treatment that is making its way through the regular regulatory pathway. We were very pleased that the U.K. government announced that they have extended the ECDRP as a recognition route for the European files until the end of 2023.
As soon as we have the positive opinion from the CHMP, which is expected, of course, somewhere in the second quarter, we will be able to hand over the file to the United Kingdom authority, the MHRA. In that respect, we will expect to get approval from them in early or late in the second half of 2023, because it takes about two months for them to review. That, of course, is very helpful because it means that we will have a, you know, generalized label, generalized packaging throughout the European Union and the United Kingdom rather than a separate product with separate labeling potentially in the United Kingdom, which, you know, gives a lot of additional complication and a lot of additional regulatory work.
We're very pleased with that decision by the U.K. government. Let's move over to the next slide, number nine, on our preclinical compounds, OTL-105, we have made some good progress. I should say our colleagues at Orchard Therapeutics have made some good progress because they are the expert, of course, on developing that lentiviral vector to enhance the C1 inhibitor expression. We're now starting to test this in preclinical HAE disease models. As it says here on the slide, we anticipate to provide further updates as we get, you know, clearer views on when we can actually expect to go forwards to the IND filing and of course, the subsequent clinical trials following an IND filing.
Then on the right-hand side, last but not least in our pipeline, our alpha-glucosidase for Pompe disease, where we are looking for differentiating features. Pompe disease is still a significant unmet medical need, and we believe that our platform may have the potential to have differentiating features versus the existing alpha-glucosidase enzyme replacement therapies. That is why we are continuing to search for that. If we find these, we will start developing these compounds going forward. That brings me, of course, to slide number 10, an overview of the pipeline that is now consisting of a product in the market, of course, a product in regulatory review on both sides of the Atlantic, leniolisib with the accelerated procedures ongoing, OTL-105 gene therapy, and alpha-glucosidase for Pompe disease.
Of course, you see there that there. It would be good for the balance, for the portfolio and the pipeline if there were some additional in-license or acquired products that are in between, that are in the clinical phase, preferably in latest phase of development, to actually get our launch, get our launch calendar even a little bit fuller towards the coming years. This brings me then on my last slide of the operational highlights, on slide number 11. Something we're very proud of, that RUCONEST has again realized significant sales and will continue to generate significant sales. RUCONEST has brought sales of $151 million these nine months.
We are very pleased with a product that is already for such a period of time in the market that it has found its place in the market and is serving in an increasing number of patients and is prescribed by an increasing number of physicians because of the fact that prophylactic therapy patients need a good medication for their breakthrough attacks. RUCONEST, as you know, has a different mode of action than the prophylactic therapy, so it is a very rational choice. If you use bradykinin, kallikrein inhibition, prophylaxis, either oral or injectable, that RUCONEST is a very rational choice as your breakthrough medication. We're very pleased that more physicians continue to see that and more patients continue to see that.
That RUCONEST will continue to play a significant role in that market as a safe and effective acute treatment for hereditary angioedema. Therefore, we guided at the beginning of the year that RUCONEST will continue to have single-digit growth of revenues in 2022. You can see that we are delivering on that, and we think that is a very great compliment to all our colleagues who work very hard every day to bring RUCONEST to additional patients in mainly the U.S. market. With that said, I'm happy to hand over to my colleague, Dr. Anurag Relan, our Chief Medical Officer, to take you through APDS and leniolisib highlights. Anurag, over to you, please.
Thank you, Sijmen. We can jump to slide 13. Here you see that APDS is a primary immune deficiency, and you see on this slide, with many serious clinical manifestations. At the heart of it's an abnormal development of the immune system. Because of that abnormal development, you have what's called non-malignant lymphoproliferation. This is. You see this manifest itself as swollen lymph nodes, an enlarged spleen and liver. You can also see this in the GI tract. Another key feature of APDS, because of this abnormal development of the immune system, are the recurrent infections, and a whole variety of infections are seen in these patients.
Because of these recurrent infections and because of this abnormal development, these patients also develop a progressive lung disease and worsening of their airways with recurrent infections, but also a condition called bronchiectasis, which is irreversible loss of function. On top of that, these patients have, because of this, lymphoproliferation, they have the ability to transform into something a malignant process such as lymphoma. This is a serious consequence of the condition, and it's observed, unfortunately, quite frequently in these patients. Lastly, these patients, although they have an immune deficiency, they also have an immune dysregulatory disorder, so they also exhibit some autoimmune phenomenon.
We can see this manifest itself in anemias and other types of cytopenias, but it can also be seen in GI tract as long as in liver disease. On the next slide, we have the results from the randomized double-blind placebo-controlled study with leniolisib, and this outcome analysis showing a statistically significant reduction versus placebo in the size of these so-called index lesions. You can see that on an individual basis also, you can see the placebo patients, for example, either remaining stable largely or in some cases worsening. You can see the leniolisib-treated patients, you can see the size of their lymph nodes decreasing.
On the next slide, we have the other co-primary endpoint. I mentioned earlier that you see an abnormal development of B cells in APDS patients. Because of that abnormal development, they have all of those other clinical consequences we've talked about. One type of B cell that doesn't develop properly, one manifestation of this abnormal development, are what we call naive B cells. What we see is in APDS patients, they have a low proportion of naive B cells. When we treat them with leniolisib, you can see on the left with the primary analysis, again, a statistically significant increase in the proportion of naive B cells. You can see on the right panel where we included the full set of patients, you can see, first of all, it's quite rapid.
You see even by the first month, there's a significant jump in this proportion of naive B cells, and you see that that's sustained over time for these patients versus the placebo patients who do not respond. This, I think, the double-blind placebo-controlled study, where we see that leniolisib was generally well-tolerated with the severity and the grade of the AEs across placebo and leniolisib patients were similar. There were no deaths reported in this study, and again, there were no AEs that led to study discontinuation during this randomized study. Then lastly, there were no severe adverse events or serious adverse events that were related to study treatment.
Now moving on. These patients, I mentioned, were treated for 12 weeks in the double-blind placebo-controlled study, but then they went on into an open-label extension study. Here are some data that were recently presented at a conference in Europe just a couple of weeks ago. This is showing patients who were in the randomized study and then went on to receive leniolisib, and you can see data out to almost a year in these patients. On the left panel, you can see that their lymph nodes actually continued to decrease in size. You see that initial decrease that they had, and then over time, that continued further out. On the right side, you can see some images showing some representative samples of what this looks like.
Again, on the top, you have patients who were treated with leniolisib in the double-blind study, and then you can see their lymph nodes decrease in time at the 12-week mark, and then further out at the day 252 mark. On the bottom panel, you see a placebo patient. You see actually very nicely that there's almost no change in the size of this patient's lymph node between the screening time period and the day 85 time period. The patient receives leniolisib, and you can start to see that lymph node decrease in size. Similarly, we can see this on slide 18 with the size of the spleen.
I mentioned earlier, because of this abnormal development, these patients' immune system, they also get lymphoproliferation, and that can also be manifest in this, these massively enlarged spleens that these patients have. On the left panel, you can see, again, these patients have a large spleen that comes sort of decreased in size during the first 12 weeks of the study, but then that continued to decrease over the course of the extension study, the long-term study. If we look on the right side with the images, you can see in the top panel, a patient who was treated with leniolisib, you can see that improvement. Again, rapid improvement in the first 12 weeks and then continued and sustained decrease in the size of the spleen.
On the bottom panel, you see a placebo patient whose spleen actually increased in size over the first 12 weeks. Then over the course of the following, you know, nearly a year, you see that spleen significantly decrease in size. I think these are all consistent aspects that we're seeing with the treatment of leniolisib. Then I think the slide 19 also highlights another important aspect is that because of these abnormal development of the immune system, and specifically B cells, they have what's called a class switch defect. These patients do not transition to produce IgG-type antibodies, but they, their immune system gets stuck producing IgM antibodies.
What you see here are three lines showing that patients who were, let's say, treated or not treated with leniolisib in the placebo study. Those are in the red line. That's no previous leniolisib. You see they have high levels, and those come down over time and continue to decrease. Then patients who were treated with leniolisib, you see they see that they started at a lower level, but they also continue to decrease over time. Then when we take all patients together, you can see that same trend, that these patients now, their immune system is functioning properly, because they are not stuck making this, just this one type of antibody, and they're able to class switch and produce specifically the IgG antibodies.
On the last slide or next slide, excuse me. On slide 20, you can see some of the milestones for leniolisib that Sijmen highlighted that we have now received acceptance of the FDA file with priority review. We have completed the submission to the EMA also earlier this month. Later this year, we hope to start recruitment for the pediatric studies, and then you know followed by some significant events also in 2023 with regulatory approvals that are anticipated as well as commercial launches. With that, I will turn it over to our CFO, Jeroen Wakkerman.
Thank you very much, Anurag. First, the financial highlights of the first nine months. We had an increase in revenues of 3% from EUR 146 million to EUR 151 million. In Q3 specifically, we had a turnover of EUR 54.2 million, which means a growth of 2.6% in the quarter versus the previous year. Gross profit increased by 7% to EUR 139.7 million, and that was driven by, in the first place, growth in revenues, but also by production efficiencies and favorable tailwinds from currency translation effects. You probably all know that our sales is mainly in U.S. dollars and our cost of goods are in euros. That is being reflected here.
Our net profit increased by more than 100% compared to the same period last year, and that was driven by an increase in other income. You may remember that is largely due to the reduction in the stake of BioConnection, our fill-finish partner, transaction that we did in Q2. The profit on that transaction was $13.8 million. The cash and cash equivalents, together with the restricted cash, decreased from EUR 193 million at the end of last year to EUR 189.9 million at the end of the third quarter 2022.
Driven by, on the positive side, a strong operational cash flow, offset by a foreign exchange effect because we've got a lot of cash in euros. Still a strong treasure chest also to be able to fund future growth in Oxford by potential acquisitions. Moving to slide 23. Again, the key numbers, a growth of 3.4% to EUR 151 million in revenue. A growth of 7% in gross profit to EUR 139.7 million. Operating profits going up by 85% to EUR 28.4 million.
Here again, you see reflected the gain on the BioConnection share sale in Q2, and a net profit of EUR 28.3 million, which is an increase of more than 100%. The quarterly development over the last two years, in H1, we have sales of EUR 96.8 million. So far this year, Q3, EURO 151 million. That means sales of EUR 54.2 million in Q3, compared to EUR 52.9 million in Q3 last year. I would say a steady growth in revenue, which is seen here.
Moving to slide 25, explaining the profits before tax growth from EUR 21.3 million in Q3 last year to EUR 33.1 million year-to-date at Q3 this year. Starting off with the growth in the business, as I just explained, that's the growth profit increase. Then an increase in costs. You see the different categories. First one is R&D expenditure that was largely related to leniolisib, the preparation for the launch. This includes also manufacturing costs, and also additional costs in OTL-105, as Sijmen just described as well. Increased G&A expenditure, that's a collection of many costs. Think about IT costs, think about recruitment costs, because we have recruited a lot of people, also to identify patients in the U.S. for leniolisib.
The latter category is marketing and sales expenditure that grew by almost $13 million. Again, that is largely due to out-of-pocket costs for leniolisib, almost $8 million, and a big chunk of it is because of payroll, so for increased marketing and sales staff. The next two bars are pretty high. First one, they almost wash out, but the one is the negative impact on profit last year from the OTL-105 investment, the collaboration with Orchard Therapeutics. This year, the BioConnection sale of the shares. That overall brings us to a profit before tax of $33.1 million. Moving to slide 26, you see the development of cash from beginning of the year till the end of Q3.
Starting off with $192 million at the beginning of the year. As I said, strong operational cash flow. Operational cash flow before working capital was plus $26.7 million. Cash because of an increase in working capital, especially in inventory, was $4.6 million, and we paid taxes of $5 million. You get to the net cash flow generated from operating activities of $17.2 million. Cash flow from investing activities was largely a cash flow because of the BioConnection transaction. The cash part of that was plus $7.4 million, and that was offset by capital expenditure, and that was mainly in IT.
The cash flow from financing activities, $-5.3 million, is regular lease costs and interest. The exchange rate effects of $-20.9 million is because mainly because we have euro cash in a euro reporting entity, but we are reporting our results here in U.S. dollars. Overall, that brings us to a cash and cash equivalents of at the end of Q3 of $188.7 million. We're very pleased with this development, especially on the operational cash flow and a strong balance of cash for to support future growth. With that, I would like to hand over back to Sijmen.
Thank you, Jeroen. That takes me to slide number 27, the outlook, the final slide of this presentation. We, as we said before, continue to guide for the single digit growth of the remainder of this year for RUCONEST sales. We already alluded to the commercial approval subject to the positive outcome of the FDA review that we anticipate with the due date on 29th of March with the anticipated launch in the US soon thereafter, so in the first half of 2023. Of course, subject to the positive review of the EMA, the positive opinion from the CHMP, followed by the issuance of the MAA by the European Commission.
As you know, there's some timing between there, so you can anticipate both of them in the first half of 2023. That means that as soon as possible thereafter, we will start rolling out the individual European markets in the second half of next year. Then the very pleasant surprise, as I was alluding to earlier, of the extension of the ECDRP filing for leniolisib by the MHRA, which means that we can, by submitting the European file to the U.K. authority and expect a much quicker decision, namely about two months after the CHMP positive opinion and can go to market in the U.K. faster than anticipated as well.
Of course, we continue, as you saw from the numbers that Jeroen was outlining, we continue to allocate significant resources towards the anticipated launch and commercialization of leniolisib. With the view that we are accelerating future growth as we, you know, start to build, next year expect to build the leniolisib business on top of the RUCONEST business. Last but not least, we are continuing to hunt for new opportunities to fill the pipeline, potential acquisition in licensing of new late stage, preferably late-stage development opportunities in rare diseases. Last but not least, you know, all of the current activities can be funded, as is very clear from our current balance sheet. Only in the case of acquisitions, we think we may actually have to do additional financing, of course, depending on the size of the acquisitions.
I think that concludes the outlook and that concludes the presentation. Operator, we could now turn the floor over to the Q&A section of this presentation. Thank you very much.
Thank you. If you would like to ask a question, then please press star followed by one on your telephone keypad. If you change your mind, please press star followed by two. When preparing to ask your question, please ensure that your phone is unmuted locally. As a reminder, that is star followed by one to ask a question. Our first question comes from Hartaj Singh from Oppenheimer. Hartaj, please go ahead.
Great. Thank you for the update, and the question. You know, a couple of questions. One is different, one is on RUCONEST, one is on leniolisib. One, you know, just what we're hearing, Sijmen, your own is that, you know, the increased use of prophylaxis therapies, especially the orals out there, is leading to an increased use or at least, you know, patients having acute treatments on hand, you know, like a RUCONEST. How do you expect that, you know, going forward? Do you expect that to be sort of a tailwind to your revenues for RUCONEST going forward? How long could that last?
And then, leniolisib. You know, we get a lot of calls from investors who are interested in which other immune sort of conditions, primary immunodeficiency disorders could you go after? When could we start seeing some, you know, some thoughts or some insights there? Thank you for the question.
Okay. Let me try to answer that first one, first, Hartaj. Good morning, by the way. RUCONEST prophylaxis. Yes, I was alluding already to this, we see a continuing positive trend in the number of physicians and patients using RUCONEST. In the past, RUCONEST was never used for breakthrough attacks, also because the prophylactic therapy was mainly C1 inhibitor, and it did not make much sense then in this case to use it. RUCONEST was typically used for the very severely affected patients. Now, those very severely affected patients are still a lot of the core of business of RUCONEST because they can't get anywhere else. Although there's also patients who then switch over to prophylaxis and reducing their use of RUCONEST because they continue to have breakthrough attacks.
That's exactly why we are very pleased to see with the paradigm shift that has taken place over the past few years and towards bradykinin kallikrein submission. Although prophylactic therapies have significantly improved, there is still for a considerable, and sometimes people tell me that it is more than half the patients that should expect, either on a regular basis or incidental basis, have breakthrough attacks. Even worse, I was recently at a international patient conference, and opinion leaders were warning these patients that, you know, please, even if you don't have any breakthrough attacks for a considerable period of time, please always have rescue therapy at hand because this is a nasty disease, it's stress driven, and you can never know when a breakthrough attack can come by.
Because now the biggest danger is that people are sort of, you know, getting comfortable with their prophylaxis and that they get an attack still, which because of this unpredictable disease and have nowhere to go without any rescue therapy. That emphasis is being brought out more and more also from the key opinion leaders to the patients and make them aware of that. That is actually the trend that we see. That is, of course, supporting and will continue to support the, you know, the RUCONEST business towards the future. It's of course, when, you know, a very high and high using patient switches over to prophylaxis, we have to replace that patient with several patients that are of course on breakthrough medications.
That's exactly what our people are doing and what our people continue to do and where we continue to make progress and see a lot of opportunity there because we still have a relatively modest market share, as you know, in this market. In other words, sorry for the long-winded answer. We see that, you know, for the foreseeable future, RUCONEST will continue to play that role in the market. You know, for the foreseeable future, this will be a necessity.
Also, when other additional, you know, bradykinin kallikrein inhibitors may come to the market, there's always the danger for breakthrough attacks, and RUCONEST is there to be there with the unique mode of action that RUCONEST now has compared to all of its competitors and future competitors, because we see no C1 inhibitor being in development anywhere in the pipelines of any of the companies, simply because C1 inhibitor is a notoriously difficult compound to make and to develop, other than that you get it from blood donors, and those products are indeed not actively promoted anymore for active treatment. Sorry for a long-winded answer, Hartaj. I hope that answers your first question.
I would like to move to maybe Anurag. Could you shine the light on that question about new indications for leniolisib, probably because you're more at the heart of it than I was recently.
Sure. Thanks, Sijmen. Hi, good morning, Hartaj. We are looking at additional indications for leniolisib. These are not actually in the area of other primary immune deficiencies, but we are looking at a number of indications. As Sijmen mentioned, these include areas where Novartis had actually started some work and has already some research collaborations ongoing, so we're trying to leverage that, but we're also looking at some new areas. I don't think we're ready yet to disclose what those areas are today, but as soon as we make some more progress with this and then I think we'll be able to talk about that in the near future, which specific areas these include.
Great. Thank you everyone.
Thank you, Hartaj.
Thank you. Our next question comes from Joe Pantginis from H.C. Wainwright. Joe, please go ahead.
Hey, everybody. Good morning, and thanks for taking the questions.
Thanks, Joe.
Hartaj's asking some really good questions about the market dynamic. I guess as you guys continue to block and tackle, you know, getting more patients on RUCONEST because of the ongoing need for rescue therapies, can you remind us first about the current patients and how often they need to get a new prescription, either through expiration or other?
That's an interesting question, Joe. Typically, this is 12 months, the prior authorizations in the U.S. So every 12 months they need to be renewed. We've seen some trends, disturbances of that due to COVID, where plans, because they couldn't handle the 12 months, extended that to a number of years. They took that back and did it for three or six months. Generally speaking, I think it's still the 12 months prior authorization that is actually very valid in the U.S. market.
A lot of that is concentrated in the beginning of the year, so patients that have been on drug for a long time mostly are getting their prior authorizations renewed in the sort of sometimes during the first quarter, which is then of course a lot of admin work for those offices, doctor's offices. You know, we have our teams to help the doctor's offices process that paperwork and you know facilitate there whichever way we can. That is, of course, what all rare disease companies do to actually make sure that patients are not without any medication any time during that process, because it can be a bit of a tedious process from time to time.
Got it. Makes sense. My main set of questions really focuses on logistics and maybe some information that might be a little out of your hands, so I appreciate that ahead of time. First, with regard to BD, obviously you've been saying for quite some time now you're looking to be opportunistic with regard to expanding the pipeline in rare diseases and what have you. Just wanted to do a bit of a status check with regard to, you know, where some of these discussions stand and, you know, level of maturities.
Yeah. Yeah, we get a lot of inbound, Joe, from various banks that we work with and consultancies and of course our own folk. We get a lot of inbound stuff, and a lot of it is unfortunately repurposed molecules, and then for some rare indication where sometimes, you know, the one rare disease, not the other one, you know, leniolisib serves a APDS disease, which is very severe and has a very high unmet medical need. As you know, some of these rare diseases may not be so severe, and these repurposed molecules may not be the business model that you're looking for because there's either already generics available inside or outside the U.S.
We do not believe that this is a sustainable business model. We're looking for more truly innovative treatments, and leniolisib is a good example in a case in point here. In other words, we're being very, very precise, also because it's our first M&A deal, of course, so we better get that right. That's why it takes maybe a little bit more critical approach from our side. On the other hand, we've been very close with one or two companies over this year.
We came very, very close, and at the end, you know, decided to still step away because we couldn't validate in a specific rare disease, we couldn't really validate the numbers that this company was quoting for these patients. Of course, that's always the case in rare diseases, right? In rare diseases, the numbers of patients that you find is a critical issue. We have built up a significant database in the meanwhile with our genetic testing of genetic diseases. We also have bought a significant amount of other data that we have. We think we have very good insights in a number of mutation patterns that leads to certain diseases and therefore, you know, that helps our business development folk to actually make a choice.
Anurag, who is an integral part of that group, you know, sits here nodding his head opposite me, that this is really always a challenge here. You know, we're very active in this market. As you know, with business development, can never say could be, you know, very soon, could be that another one, you know, bounces off and we continue our search. We have increased our capacity significantly over the last years, or over the last year also, having learned from some of these experience where you spend a lot of time and then eventually decide not to do it. You want to add something here, Anurag?
Got it.
No, I think. Sorry, go ahead, Joe.
No, I was just going to say no, that's really helpful, and it's always great to see when Anurag and Sijmen agree, nodding at each other at the table. Go ahead, Anurag. Sorry.
No, I was just going to add that, yeah, we look at a whole range of different opportunities, and we do it in a systematic way. I think as Sijmen said, we want to be cautious and careful and make sure that we bring in the right opportunity that where we can add value and we can leverage the work that's already been done.
Got it. Then just lastly, this is really the part I alluded to where your hands might be tied with regard to how you answer it. With OTL-105, obviously there's a bit of growing excitement for potential gene therapy around HAE, and you know, this certainly came out at the recent HAE conference that we hosted. I was just wondering, you know, right now it's, you know, you'll give us information as it comes out. Is there anything that we could look to, even without timing, that says, you know, the plan would be to release X type of preclinical data, you know, to be able to tease the profile of the asset?
That, Joe, that's really the goal here, right? I think first of all, you know, what got us into this position or why did we enter this partnership with Orchard was that we believed, again, around C1 inhibitor. We believe C1 inhibitor is the root cause. We know it's the root cause in these patients, and we wanted to be able to provide these patients with C1 inhibitor in the same way that we do with RUCONEST, to be able to do that with a gene therapy. The other modalities that we looked at really didn't, you know, present themselves with a reliable way to do that.
The goal now in terms of these preclinical models is to be able to use a vector that now has been refined by the team at Orchard and to be able to show that you can actually increase the C1 inhibitor levels in these disease models. These are disease models being knockout mice that don't have the C1 inhibitor gene in place. Now can you increase those levels to levels that we think would be meaningful in a clinical situation? We're doing that testing now, so I'm hopeful to be able to provide, you know, an update on that soon.
That's the type of information that we can look for, say, can we show meaningful increases in C1 inhibitor expression levels in these preclinical disease models that could translate into, you know, the type of benefit that we would need to see in patients.
Thank you, guys.
Thank you, Joe.
Thank you. Our next question comes from Simon Scholes from First Berlin. Simon, please go ahead.
Yes. Hello. Thanks for taking my questions. I've got four. So you've mentioned that you've identified 400 potential leniolisib patients. I was just wondering if you could tell us how many of those are, if any, pediatric patients. Then on the ICD-10 designation, in this call as well, you've mentioned that this gives you the open sesame to start reimbursement discussions. I was just wondering how those reimbursement discussions are progressing. I mean, presumably you expect to complete them by the time of approval in the U.S. in March. Then on pricing of leniolisib, I mean, I don't know to what extent you can comment, but I was just wondering if you expect...
I mean, presumably the difference in pricing with this product between Europe and the U.S. is not likely to be any way as large as it is with RUCONEST. I was just wondering if you expect any pricing differential at all, or I mean, what the size of the pricing differential might be like compared with RUCONEST. Lastly, you mentioned that there aren't any C1 inhibitor products currently under development. Does that also extend to C1 gene therapies besides your own pipeline product?
Okay. Maybe, Anurag, you want to say something about the patients and the first?
Maybe I'll take the first question, Simon, and then the last one.
Yeah.
With respect to the patients that we're finding and the patients that were in the study, it's important to note that first of all, this is a genetic disease. These patients are born with this genetic abnormality. They have these variants in one of these two genes at birth. The disease can begin to manifest itself very early in life. It is a serious disease and it can manifest very early, and it's progressive, it gets worse over time. In the clinical trial, we identified and treated patients that were at least 12 years of age, and about half of the patients were actually in this age range between 12 and 18. I think the median age was actually 19.
There was a significant portion of patients between 12 and 18 years old, which, you know, they're adolescents, but they're, you know, in a formal definition, they're still pediatric patients. Beyond that, in this younger age group, we are finding patients in that age group as well. It's probably in the range of around 20%-30% of patients that we're finding that are even below the age of 12. Hopefully that gives you some idea of the types of patients that have been treated so far in the clinical program and the types of patients that we're finding, but also that we're planning, of course, clinical trials in this younger population too, because there certainly is an unmet need there.
Looking into the future, wouldn't it be, Anurag, that as the disease becomes more known and more recognized, that you know these patients are you know caught earlier because now you see that it takes many years for them to get diagnosed, right? So the earlier that you catch them, the better, right, Anurag?
I think certainly as we increase disease awareness, but as also, hopefully a treatment becomes available, a specific treatment becomes available. That also, oftentimes can drive, further diagnosis. I think those were all sorts of trends in a favorable direction. On the question of other C1 inhibitor therapies in development. I think really Simon was alluding to, there's no acute C1 inhibitor therapy in development. And there's really no actively promoted acute C1 inhibitor therapy other than, you know, there is a plasma-derived therapy also. But there are gene therapies aside from our program that are in development, and you know, think different modalities, different mechanisms to deliver the vector and to be able to produce C1 inhibitor.
I do think that we have still a unique method and partnership here with Orchard that could be differentiating with respect to this ability to express C1 inhibitor. Okay.
Simon, you had a couple of questions about pricing. Of course, we do not give any guidance on that, because, you know, we always think that analysts are the experts on this to make up their minds what they think is typical pricing. With regards to your question about, you know, the difference between pricing in Europe and the U.S., I think there's also a number of quite a number of rare disease compounds are on the market. You can actually see what the difference is between Europe and the U.S. We think it's typically in the 60%-70%, European prices are typically in the 60%-70% range of what the U.S. price is.
The price gap has significantly narrowed or significantly narrower in these rare diseases than in maybe mass-market diseases where all sorts of reference pricing systems kick in. That's of course not the case necessarily with the rare diseases. I hope that answers your question there as well. Lastly, ICD-10 code is important because you can work ahead and indeed you got it right there. You can work ahead to actually discuss coverage, not necessarily reimbursement, because the U.S. of course has decentralized healthcare systems where you serve a number of the government funded like Medicare and Medicaid systems, for instance, to mention two. The majority of the market is of course a private market, commercial market, as we call it.
There you get coverage by the big insurance companies and the big healthcare plans. That's of course having an ICD-10 code is incredibly helpful in this respect. Otherwise, it may take quite a long time before these patients could be reimbursed. Yes, our folk are really preparing their and to actually get coverage for the patients immediately after the product comes on the market. That is of course the nice thing of the United States market, that these things are progressing way faster than sometimes in the European markets.
Because that's also the issue in the European markets. Often despite the fact that you have a rare disease, it takes quite a considerable amount of time before you get a reimbursement. Of course, your own country is a positive exception, Germany, to that. As you know, many more European countries take a lot longer to, unfortunately, you know, give patients that therapy that they so badly need. We will do our utmost best obviously also to accelerate the rollout of this unique and very severe rare disease as quickly as possible in the European markets. The good news is, again, there is positive exceptions possible if you have a good dossier and if you have a good, you know, good health economic underpinning.
That's of course where our teams are working, around the clock on to actually make sure that happens so that we can, swiftly get hopefully reimbursed in the, in all of the European Union markets as well. I hope that answers your question. Sorry for a bit long-winded answer.
No, that's very helpful. Thanks very much.
Thank you. As a reminder to ask any further questions, please press star followed by one on your telephone keypads. We currently have no further questions registered, so I'll now hand you back to the management team for closing remarks.
Thank you very much, operator. Yes, ladies and gentlemen, thank you for attending our nine-month 2022 conference call on the results. As we come to the end of this exciting year, 2022, where we were very successful not only with of course continuing the growth of RUCONEST sales, but also securing the you know, the FDA and EMA accelerated review, which again is very rare that you get it on both sides of the oceans. As we look forward towards moving into the next year where we anticipate that we have the PDUFA date of 29 March, and could go into the U.S. market soon thereafter.
Of course, the accelerated review by the Europeans, where we could actually also go into the market, you know, at the and get a positive marketing authorization before the end of the first half and go as soon as possible into the European markets. Lastly, you know, the UK market of course where we can work on that recognition. We look back to a very busy 2022, and we look also forward to a very intense 2023 where we will be starting to execute on the significant transformation of our company from a one-product company in one geography towards a multiple product company in multiple geographies, driven by our own commercialization infrastructure on both sides of the oceans.
That concludes this conference. Thank you very much for your attendance again, and we look forward to updating you, probably somewhere in March on our full year results, 2022. Thank you and have a nice day. Goodbye.