Thank you very much, Jade. Welcome, ladies and gentlemen. I'm very pleased to take you through the Pharming story, and before I do that, I have the obvious forward-looking statement slide, because I will be making some forward-looking statements in this presentation that of course you know in the future may be different from all of that. Yes, so we're building a global rare disease biopharma company. We're based in the Netherlands. We have a very significant commercialization operation here in the U.S., and currently, our commercial business is more than 95% U.S.-driven, and it's based upon two products in the market that we market in the United States.
First of all, Ruconest is our own, from our own research, a recombinant C1 esterase inhibitor, approved for the acute treatment of hereditary angioedema attacks. It was launched already ten years ago and still has a unique position in the market. As you can see, the growth numbers speak for themselves. You know, we went up 16% versus the first half of last year, and the second quarter was especially strong versus last year. And we see an increasing... Despite all these competitive offerings in this market, we see an increasing demand for this product, both from the number of patients that are on the drug and from the number of prescribers that use Ruconest. And Ruconest has a very special place in the market. I'll come to that in a second.
The second product was in-licensed from Novartis back in 2019. It's for an ultra-rare primary immune deficiency called APDS, activated phosphoinositide 3-kinase delta syndrome, a newly discovered disease, ultra-rare, as I said. We launched this in in April of last year, immediately after FDA approval. You see here the numbers, they also speak for themselves. You know, we had $20.7 million in the first half of 2024 sales, which compares very favorably with the results of the full year 2023. Obviously, the name of the game is here and not against competition, but your focus on patient finding. A, it's ultra-rare, B, it's a new disease. I will come to that later.
Obviously, we want to expand this business significantly beyond the United States, and we have regulatory reviews ongoing in a number of territories. The product is approved for 12 years and older, so we have a pediatric program as well, and also we have a Japanese trial that has almost completed. So we're also going into the Japanese market with this compound. And then, of course, we accelerate the growth of the company going forward further by developing new indications for leniolisib. First, we have a primary immune deficiency with immune dysregulation. We are about to start with a phase II dose-finding study, and we are actually having a third indication under review at the moment with the regulators, where we have provided them with a proposal.
And last but not least, because of our commercialization infrastructure in the U.S. and the one that we also are building up outside of the U.S., we are in a unique position to commercialize and do final development stages of other people's products. So we're actively looking for in-licensing or acquisition of clinical-stage, you know, rare disease opportunities. You see the total revenue guidance for this year between $280 million and $295 million, which represents between 14% and 20% growth. So let me just switch over to the base business, as it were, but still the growing base business, Ruconest.
And you hear a lot about competition, and here this slide is not to dazzle you with any science, but you see here the mechanisms of actions on the left-hand side, and on the top, you see the mechanism of action, which the disease is all about. That is actually there is no functioning or no C1 inhibitor protein in that patient, and that's the missing protein. So we're providing protein replacement therapy, and all other competitors are not, and that's mainly also the new competitors are not doing that.
They are actually, and you see here on the right-hand side, three pathways that are involved in this, in an attack of hereditary angioedema, and they are basically working on that axis, that middle axis there, and not taking care of the other touchpoints that a C1 inhibitor has. In other words, you will always see the phenomenon of so-called breakthrough attacks with these compounds, be it if they're used for prophylaxis or be it if they're used for acute. They are, of course, more convenient, these products, because they are partly oral or partly subcutaneous, whereas our Ruconest has to be injected by the patient themselves, by the way, and they're well-trained and very confident to do that via a slow IV infusion, which is done at home by the patients.
When they feel an attack coming, they take care that they actually don't get an attack by using Ruconest. Now, as I said, the competitors are focusing on that middle pathway. That has, of course, brought a lot of new developments and a lot of new potential good therapies for patients, mainly a lot of prophylactic therapies. But as I said, about half of the patients in prophylaxis still have breakthrough attacks, and that's why Ruconest, of course, with a different mode of action, serves a purpose, a very relevant purpose, and other products that are developed are either tested in patients that are responding to the bradykinin, kallikrein pathway products, and that is exactly not the patient population that Ruconest serves.
Because Ruconest, in addition to serving the breakthrough attack therapy patients, it also plays a very important role in the very severe end of the market, where, for instance, Type III patients that are very severely affected by hereditary angioedema and get a lot of frequent attacks, cannot get by on the prophylactic therapies and rely on Ruconest, and there, Ruconest plays a unique position. All those patients have failed the products, mainly icatibant, which is the main volume product in acute markets. All those patients have failed to respond to that and are responding to Ruconest. And as you see here, the numbers speak for themselves. If I may point you to the right-hand side, where you see that, you know, 97% needs just one dose of Ruconest for the attack to very quickly go away.
Actually, in fact, they are protected for another three days to a great extent, for the subsequent attack. Basically, it means that protein replacement therapy in those patients that have the severe end of the disease and have very frequent attacks is the relevant way forward. Whereas convenience-driven products like orals and like subcutaneous products of course serve a purpose for a great deal of patients, thank God for them. Those patients that cannot get by on that right-hand side of the equation on the severe end of the market need Ruconest. Again, the growth numbers speak for themselves. In other words, Ruconest is a product that you need to take, whereas if you want to have...
If you want to have more of those more convenient products, you can make a choice for those convenient products. And that's the difference where we look up. So we look with a lot of confidence towards the future for Ruconest to continue to be the strong support of our business going forward. And that includes actually the fact that in 2026, the regulatory exclusivity expires because nobody will make a C1 inhibitor in a transgenic model, transgenic platform like we have. So therefore, we see that as a non-event as well. So in other words, Ruconest is a pillar for our business and will remain a pillar for our business for the longest of time. Let's switch over to Joenja, our new product.
Joenja was, as I said, in-licensed from Novartis, a PI 3-kinase delta inhibitor, and it actually was approved in double-blind, placebo-controlled trial, and on patients over 12 years old. APDS is a very complex and ultra-rare immune disorder, which basically causes significant morbidity and mortality and is affecting mostly, of course, a younger population. So it's a dominant autosomal mutation that these patients have, and there is no other cures. There's only symptomatic treatments for their, for instance, infections, lots of antibiotics and IVIG. For their immune dysregulation, some of them use sirolimus, but eventually, all these patients deteriorate very significantly, and in a very high percentage, end up with, you know, lymphoma, which has a very bad outcome, of course.
So we were very pleased to see that, Joenja, in a twelve-week, double-blind, placebo-controlled trial, not only controlled the symptoms and brought them, reversed the symptoms, but also in a long-term follow-up study, and we already have data for patients up to more than seven years on treatment, there we also see continued improvement of the symptoms, whereas the product has a very, very good, tolerability profile. That, of course, is quite unique for a PI 3-kinase delta inhibitor. So in other words, all the elements are there for Joenja to be, a successful therapy for those, for those patients. And by the way, it's an oral treatment, so that makes it also easy for these patients to take.
Now, the name of the game, of course, for, is in this rare disease, to find those patients, because, again, it's a new disease, and it is also ultra-rare. So we set out to do in a partnership, Navigate APDS, with Invitae. We set out to do genetic testing. We're yielding some patients there, of course. We're buying, databases from, other, testing panels because this APDS is part of a standard immunology testing, testing panel. And of course, we started family testing because it's autosomal dominant, and therefore, we will find patients in those patients that we already have on drug.
Last but not least, we have found that more than 1,200 patients with so-called VUSs, this Variant of Uncertain Significance, which means that they need to be clarified whether those are actually pathogenic variants or not. We have a number of initiatives ongoing to actually clear, fully clarify the extent of the disease and which of those mutations will actually prove how to be pathogenic. Then you can see this on this slide. We're working very hard on this. We're doing this first and foremost in laboratories on individual basis of blood samples of patients. But we're also setting up a big combinatorial experiment so that by the end of the year, we will have fully described this gene and all the mutations.
And we have some early indications from a small test that we did with about 25 patients, where we found 20% of them to be turning into pathogenic, i.e., confirmed APDS diagnosis, and published literature suggests the same thing. So in other words, if you think about those more than 1,200 patients that we currently have in VUS database, we will, by the end of the year, probably expect that some 20% of those can be diagnosed as APDS. So it means we have another 240 or 250 patients in the United States as a pool to actually offer Joenja to. Now, what is happening beyond FDA approval? We have a lot of reviews ongoing at the moment by regulators.
We had a small hiccup with the European regulators, and we have to fix our regulatory starting materials, which is ongoing and will be clarified by the end of next year, so that we can go back to the Europeans in the first quarter and expect a positive opinion on the first quarter of 2026. Because the good news is, the Europeans actually recognize the positive clinical benefit and safety that was concluded. So in other words, first quarter of 2026, we expect to have the European approval. It's different in the U.K. There, we submitted the U.S. dossier, and we expect to get regulatory action there in the fourth quarter of this year.
The Japanese study, as I said, is also more or less complete, so we're expecting to bring the file to the Japanese authorities in the beginning of next year, and there also can expect an expedited approval so that by the end of next year or in 2026, we can expect that the Japanese market will also be accessible. We have a number of patients in expanded access programs and also named patient programs. Some of the expanded programs are all paid for as well in some of the European countries that is actually taking place, most notably, for instance, in France, where there's a well-defined early access program.
We have, of course, named patient programs everywhere, for instance, in Southeast Asia, where patients one by one come in, and in the Middle East. Then we had the Israeli marketing authorization approved. We have Canadian and Australian on the review. And of course, you know, since 25% of the patients are younger than 12 years of age, we have two pediatric studies. One of them is about to complete and the results will be submitted to the FDA in the very near future, and therefore, we expect to be having a more complete label as well in about, let's say, a year and a half, from now going forward.
Then, of course, like I said earlier, we start a phase two for the second indication, PIDs with immune dysregulation. In other words, there's a big cascade here. You can see the numbers of patients that are already on therapy. We reported ninety-one patients on leniolisib therapy after the first half. We have a number of those patients that are still undiagnosed and still can be offered Joenja in the United States. I talked about how significant in 2025 and 2026 the growth potentially is from those new patients coming from the VUS, clarifying the VUS efforts. It probably doubles it, so we can come very close already to the expected one and a half patients per million of this disease.
Then, of course, I talked about the opportunity outside of Europe, and you can see we found already more than 870 patients worldwide. That will be significantly expanded as well with the VUS clarification, because also those patients will have received a number of VUS outcomes from the testing. We talked about the pediatric studies, and of course, we already have 150 patients in the EAP or the clinical studies and NPPs. The next steps, of course, is the phase 2 development for PID with immune dysregulation, similar symptomatology to APDS, and we're waiting for feedback on the third indication, and the second indication is more or less the same story as APDS.
You see, APDS is depicted here. It is also a PID with immune dysregulation, but this one is actually has the same symptomatology as APDS. You see all the complications that these patients get from a not functioning immune system that is in overdrive and producing lots of not functioning immune cells, and therefore lead to this lymphoproliferation that can lead to eventually in a great number of cases to lymphomas with a very high mortality and all the other associated nasty side effects of the clinical effects that this disease has. This indication is associated with a number of well-known mutations that are actually already linked to the hyperactive PI3 kinase delta pathway.
So ALPS, FAS, CTLA-4, and PTEN are the deficiencies that we're looking for. And we have agreed with the FDA to start a dose-finding study and are about to start at the NIH, the same place where Joenja was developed for the APDS. So this is very exciting. Of course, this is a three times as big population as APDS, and of course, we expect the same price setting because it's still ultra-rare, it's ultra-rare disease. So briefly, at the end, towards the end of this presentation, I have a few slides on the financial outlooks.
As you can see, in 2023, we restarted the growth pattern of the company, driven by not only the increasing sales of Ruconest again, but also by the sales, of course, of Joenja, and we expect this trajectory to go on for many years. Because as I just explained, there's many sources of growth of sales from the various opportunities that Joenja actually represents. And of course, we're very confident that Ruconest will keep its place in the market going forward, despite the increasing competition. And here you see some of the more detailed financial results. You saw the 33% increase in the first half versus last year's half in sales.
You also see, of course, the increasing operating expenses that are associated with, of course, clinical trials that we're doing with the commercialization and launch of Joenja. However, since we had a bit of the delay with the European authorities, we do not expect that the growth of the operating expenses going forward will continue. So therefore, if you look at those operating expenses here, they will probably represent the level that we will stay at for the remainder of this year. And you can also see we had a very healthy cash balance. After closing a new convertible bond that was 25 million EUR smaller than the previous one, we obviously have a slightly lower cash balance.
But the company has a very solid balance sheet, in other words, and is also basically possible to not only finance all the development programs that we currently have in our portfolio from our own means without having to go to the market, but can also afford to do in-licensing, and without much problem, and of course can do acquisitions. But then, of course, we have to go and seek for financing, which is obvious. So, the guidance here $280-$295. We expect a continued Ruconest underlying Ruconest growth in the single digits. We continue to have these Joenja patients coming online, although this year, of course, we had the majority of the patients that are directly available already on drug.
And of course, I'd already made a remark about the operating expenses that will stay more or less stable in the second half of the year. Finally, the outlook, again, I'll just repeat it, $280-$295, and all the activities that we are doing with Joenja. I think it's important to see that there's a significant acceleration in patient numbers to be gotten on therapy next year when we find the VUS patients and, of course, the subsequent year.
Then the commercialization ex U.S., of course, starting with probably a launch in the first half of the year in the United Kingdom, followed by, of course, other launches somewhat later in Europe and in, of course, in Japan in the future. Then the clinical trials for leniolisib and of course further progress with other regulatory authorities. And then the phase II, which is about to start for that new indication, PIDs with immune dysfunction. And last but not least, we're focusing on potential acquisitions and in-licensing of clinical stage clinical proof of concept type of opportunities in rare diseases, and in those areas that you see I depicted here.
We prefer, obviously, an in-licensing, which is much easier, but we will also be happy to do an acquisition to broaden our portfolio and further leverage our commercialization, our proven commercialization capabilities that we have, both in markets where we compete against competition, like in hereditary angioedema, and where we actually have to develop the market, like in APDS. This concludes my presentation here, and I see we have fifteen seconds, and now we have five minutes for questions, I believe. Is that correct?
No, unfortunately-
Oh.
... 20 minutes is all we have time for.
Oh.
But thank you for that fantastic presentation, and I'm sure that people will be happy to ask you questions on their own time, or they can submit things through the online system.
Yeah, we're very happy to answer any questions, of course, that you may have just outside here or indeed via the IR system. Thank you, Jade. Thank you very much for being here.
Thank you.