Pharming Group N.V.

Good morning, or good afternoon, ladies and gentlemen. I'm here, next slide, please. Welcome to our results conference for the first half and second quarter of this year. And I'm here with my colleagues, Steven Thor, our Chief Commercial Officer, Anurag Rallon, our Chief Medical Officer, and Jeroen Markkermann, our Chief Financial Officer, who we will collectively guide you through the story. But before I do that, I would like to have this next slide. and point you to this forward-looking statement slide. So we will be making forward-looking statements in this presentation. And as you well know, these are based upon future expectations that are based on our current expectations and assumptions and may involve unknown risks and uncertainties. As you well know, the results eventually could differ materially from what we have expressed or implied in our statements. Next slide, please. And then you can immediately move on to slide number five, please. So what we're doing is, you know, this is the strategy that we've been embarked on for quite some time now. We're building this leading global rare disease biopharma company. And we do that on the basis of two strong pillars. The first one on the left, of course, is Ruconest, which has now been on the market for close to 10 years in the U.S., and of course deliver sales mainly from the US market. And we were very pleased to see that Rukines continues to grow very significantly, both in context of the comparison to the previous quarters, in the second quarter, 23% versus last year, and both when you compare the first half to last year's first half, 16%, which is, I would say, a very strong performance, which we're very pleased with. We'll a little bit later give you more details on the underlying positive indicators also going forward into the second half of the year. And then, of course, we have Joenja, which we launched last year, which was approved end of March last year, which we brought to the market beginning of the second quarter of last year. And we're very pleased to see that this continues to grow as well. Second quarter compared to the first quarter was 16%. And 44% if you compare the first half of this year to the last half of last year. So we are continuing to grow Joengia into the market. And of course, this, as we all know, is a very new disease and an ultra-rare indication. And our colleagues, Steven and Anurag, will respectively address you and tell you why we are continuing to be very optimistic of the enormous commercial potential for geoengineering, not only in APDS, but also in subsequent therapies, in subsequent indications. And that brings me to the pipeline on the right-hand side. We are very soon embarking on a phase two study for the next indication for lanylysib. And we are also exploring a third indication, and Anurag Rallon will talk to you about that in more detail. And of course, last but not least, we continue to focus on in licensing or acquiring clinical stage opportunities in rare diseases to broaden our portfolio, which we can, of course, given our strong financial performance. And then I would like to have the next slide on the cascade of the disease overview, not this one. Yeah, thank you very much. And this slide is an important one because Ruconest is in a very competitive market. Ruconest, however, is a unique product, as you can see here, because these are the three pathways that represent an attack of hereditary angioedema. And C1 inhibitor is the missing protein, and Ruconest is protein replacement therapy, is the only actively promoted C1 inhibitor on the U.S. market, and addresses all the pathways, as you can see. Rucanest has proven throughout the years to be a reliable product to actually treat those attacks of hereditary angiotema. And there's of course a lot of competition, but all of these competing products and competing products that are in development do not address all the three pathways. And Rucanest, a typical patient profile for Rucanest, therefore over the years has evolved and has become that type of patient that does not respond to products that are actually only serving that, for instance, calicrinin independent pathway in the middle, or the HMWK releasing the BK pathway on the bottom. So Rucanest basically builds its own unique position there, and all those patients that are using these other products suffer from breakthrough attacks. And also in this case, Rucanest comes into view. So in other words, We strongly believe that despite current competition and previous competition, which we have seen, and oncoming competition, which all are serving that single pathway, Rucanest will be the go-to product for those severely affected patients, also known, for instance, as type 3 hereditary angioedema, of which more and more get diagnosed. That explains to you why more and more patients come to Rucanest, and Rucanest becomes the mainstay for their therapy for hereditary angioedema. because they cannot get by on any of these other products. Hence, we are very optimistic and very confident about the future delivery of Ruconest to basically underpin the growth of our company. And let's move then to the next slide. And again, Joangia, we believe, has a significant potential as well. This depicts here, and Steven and Anurag will go into more detail, the fact where we are at the moment with Joangia. a significant portion of the U.S. patients already on pay therapy are the ones that have been identified so far. We, however, have a great potential going forward with regards to finding, validating the variants of uncertain significance. And Anurag will talk about that, when that and how that will happen and what kind of potential big impact that will have on the number of patients that become available in the U.S. market. Outside of the U.S., we started to see sales and will continue to see sales, growing sales from patients on early access and named patient programs. We're working with more regulatory agencies and looking forward to bringing linoleusib for APDS in more territories in the world. And last but not least, an estimated 25% of patients are below 12 and can be served as and when the pediatric studies Will the report and and as and when we get the pediatric label expansions as well. So in other words Lenny Osep, Joenja in APDS has a significant a very significant potential We believe even way beyond RUCONEST at this point in time and that's only for APDS So the other thing on the right hand side there is that we are now of course identifying we have identified the second indication and we'll start a phase two trial and in that second indication, which is, as you can see on this slide, about more than three times the incidence of, the estimated incidence of APDS, the PID, primary immune deficiency. In addition to that, we have, we are now seeking regulatory feedback on the third primary immune deficiency indication. So in other words, we believe that not only does Joenja have an enormous potential over the coming years to develop itself, into a very significant commercial asset for our company in APDS. But on top of that, it has even bigger potential to actually become a pipeline in a product, given that we have now identified at least two indications from which we could start developing programs very soon. So with this said, I happily hand over to our Chief Commercial Officer, Steven Tor, to take you through a little bit more details on the revenues of Rucanest and Joentgen.

Thank you, Simon. Good morning and good afternoon, everybody. We go to the next slide. So I will, as Simon said, take you through the Rukanest and the Geoengine performance so far. And then on the last slide, for me, before handing over to Anurag, just give you a little update on our kind of medium-term expectations of why we're so confident in the business. So looking at this slide and specifically Rukanest. You can see, I think, in those first four boxes at the top that the consistent strength in performance really relates to the unique attributes of Ruconest and the patient population we serve that Simon alluded to, that more severely affected group. Ruconest is, as you know, the only recombinant C1S to raise inhibitor, and those key core benefits of 97% of patients whose attack is resolved in a single dose and that sustained effect over a period of days is really why those patients that why those patients for whom Acatabat and other products don't work as well find a home with Ruconest, and it's what drives our continued strong performance. And that performance over a decade now has made Ruconest the second most prescribed acute therapy in the US, and of course still posting solid results. In the first half of 2024, sorry, yeah, first half of 2024, new patient enrollments have continued to strengthen over and above last year. And in that first half, we actually enrolled 170 new patients. And that represents an increase of 18% over the first half of 23. That, as you would expect, is driven by an increase in new prescribers as well as maintaining our existing ones. And our sales teams added another 36 new prescribers in the first half of 24, taking the total to over 760, which is an all-time high. So as you would expect, this translates into that quarterly growth of 23% and that plus 16% versus the first half of last year that Simon alluded to. And I think for the attributes I mentioned, the patient population we serve, and also the clinical overview Simon gave of where Ruconest operates in all three pathways is why we're very confident that we're well positioned, even as the market evolves in the second half of next year. Next slide, please. So switching gears now to Joengia. That is, as Simon said, a product that we launched on the 31st of March last year to treat the ultra-rare disease APDS. And just as a reminder, that's a serious and progressive disease with high mortality. And until Joengia was launched, there was no indicated disease-modifying treatment. As you also know, we were strung out the gate with the U.S. launch, and patients were on Joengia and fully reimbursed within days, within less than a week, in fact. So we continue to make good progress in 2024. At the end of Q2, 91 patients were on Joengia. Another two were in process at the end of the quarter, and we should come onto therapy early in Q3. We added 10 newly diagnosed patients in the quarter, taking us past 230, which is close to half the total number the literature suggests are out there already, just 15 months post-launch. And we believe it's highly likely, as with any ultra-rare disease, now that we're out there more actively patient-finding, that actually there'll be more patients than the literature suggests. We also have in our pipeline 40 more diagnosed patients whose doctors we're working with to enroll in our program, plus 60 and counting pediatric patients who've been diagnosed within our pipeline who'll be ready to go on Joe Engine when we get the label expansion in the fullness of time. So just to summarize Joe Engine performance, we exited Q2 with $11.1 million in sales, which, as Simon said, is an increase of 16% over quarter one. Next slide, please. Our teams remain, as you would expect, firmly focused on finding new patients, and then when found, mapping and testing the whole family, given this is an autosomal dominant disease. And this approach, SeriAware netted an additional 28 patient leads in Q2 that we're now working through to confirm whether they're actually APDS patients. And it's through these efforts we remain excited and confident in the value we can bring to the APDS community, both in the U.S. and ultimately globally. And as a result, our financial results keep us on track and are in line with the guidance that we've given for the year. Now, if we look a little bit further forward, you know, I think we've expressed confidence in both Rukanest and, of course, the future of Joengia. And that's based on a few key factors. So the first is the continued strength of Rukanest and the reasons that we've already mentioned for why that holds the position it does in the market, which is of course underpinned by growth in prescribers, new enrollments, and sales year on year. The second is the execution around the JOENJA launch, and the progress being made in patient finding, family testing, and building a pipeline for future months and years. But also for JOENJA, and I just want to expand briefly on some of the bullets on this slide, there are another four factors that give us good confidence in the future. So one is the VUS resolution efforts that Simon alluded to and that Anurag will discuss. That'll be a significant inflection point for us and should deliver a bonus of patients in 2025. Another important factor is geographic expansion. Right now we're launching in the US, but we will launch in other key markets which include Japan, the world's second biggest market in the broader APAC region, the United Kingdom, the European Union, Canada, the Middle East, and across these countries and regions, we've so far found almost 900 patients, which represents almost half of the 2,000 that the prevalence data would suggest are in these markets. And additionally, we're currently assessing, while we work through those other key markets, the key countries in LATAM and our options there. We have, as I alluded to, the pediatric patients, and we're building that pipeline up globally, and over time, when we get that indication, that'll be another bolus of patients that comes through in the future. And then finally, and Simon talked about this, the life cycle management of Leniolisib to create a pipeline of new indications for the molecule. And as these launches and events occur, we see multiple years of growth ahead from Joenger for APDS and potentially those other indications. So to expand on these and other related themes, I'd like now to hand over to our chief medical officer, Anurag Rella.

Thanks, Steve. And then we can jump to the next slide. And we can review first some detail about Joengia. So Joengia is FDA approved to treat activated PI3K Delta Syndrome or APDS in adult and pediatric patients who are 12 years of age and older. APDS, as Steve mentioned, is a rare, serious genetic disease caused by hyperactivity in this PI3K pathway. And it's associated with early mortality, often due to lymphoma. And it's also important to note that APDS is progressive. So experts state that early treatment is important. Joenja is a PI3K Delta inhibitor which regulates this hyperactive signaling pathway that's found in APDS patients. The FDA approval last year was based on a randomized pivotal study as well as an open-label long-term extension study. And Joenja treats the root cause of APDS by correcting the underlying immune defects thereby addressing both the immune deficiency and immune dysregulation that's found in APDS patients. The safety of Joengel was evaluated in this placebo-controlled study as well as the long-term study that is just wrapping up, in fact. And no drug-related serious adverse events or study withdrawals were seen in these trials. And on the next slide, we can see some of our patient-finding efforts. Specifically, we are supporting numerous activities to raise the awareness of APDS and share data about laniolus evangelangia. So on the left, you can see the medical education types of things that we engage with and the organizations that we're working with to raise this type of awareness. But also importantly, we have several efforts to help patients get an accurate diagnosis. The first of which is genetic testing, and we have a sponsored no-cost genetic testing program. We have support from genetic counselors, and as Steve mentioned, we're also working to help perform family testing among patients who've already been diagnosed with APDS. Because APDS is an inherited disease, we expect to find patients within families. But most APDS that patients that have been diagnosed and that are in our databases actually don't have family members diagnosed. So we're supporting clinicians, to be able to educate and encourage family testing and also offering patient-initiated testing so that patients with family members can get those family members tested easily. And then on the right side, one large area where we're focused on is when a patient actually goes through all of this process and receives their genetic test results, but unfortunately it's what's called a variant of uncertain significance or a VUS. And in essence, this is an inconclusive result that indicates that a patient has a novel gene abnormality, but it is not known whether this abnormality causes APDS or not. To help doctors and patients, we have several projects which will enable these BUS results to be definitively classified. So some ways that we do this is first just what's called variant curation, which is collecting known data about the variant. In addition, we also make available and support programs to allow functional testing to occur in patients, so actually measuring the activity of the pathway in a patient who has a VUS diagnosis or a VUS result. And then lastly, we're supporting a large-scale experiment, what's called a multiplex assay of a variant effect, which is a high-throughput method whereby we can do in vitro testing of every or almost every possible variant that could exist. And this is a study that's going to read out later this year, which we think will be very important in helping these VUS resolution efforts. And on the next slide, we can talk a little bit more about the scale of the problem. Because this VUS problem is something that frustrates patients and doctors and limits the diagnosis of genetic diseases such as APDS. And we are aware of more than 1,200 or approximately 1,200 patients in the U.S. that have received a VUS result in either of the PIK3CD gene or the PIK3R1 gene. This figure will continue to grow over time because any time that a patient gets a genetic test done, this remains a possibility. And in fact, VUS results or VUS patients are identified at approximately four times the rate of an APDS or what's called a likely pathogenic or a pathogenic variant. Of course, this is a worldwide problem since these patients who get genetic testing can get this type of result anywhere. And when we look in the literature, what we see is across all genes, what we see is that when there are reclassification efforts put in place, that approximately 20% of all of the VUSs that are out there get upgraded to a likely pathogenic or pathogenic or what's called disease-causing. And this, again, is across many genes. In the case of APDS, we've done a pilot study with 25 patients who have a BUS result, and we found consistent findings of APDS in five of these 25 patients, or 20%. And one of these patients is already preparing for enrollment now. So the key takeaway for us is that there's a significant opportunity to identify incremental patients with APDS through these VUS resolution efforts. And we'll look for more news for this as the year goes on, especially toward the end of the year. On the next slide, I'd like to talk to you a little bit about some of the other efforts beyond the current FDA approval. As we've previously discussed, The CHMP review has been extended to January 2026. There is a single outstanding CMC request and the CHMP have determined positive clinical benefit as well as safety, which has now concluded. In addition, we are expecting a decision from the UK MHRA later this year. And importantly, no major objections were noted in our day 70 questions from the MHRA. We've also completed our Japanese clinical study and we're engaged with PMDA to discuss the filing strategy there following the completion of the necessary studies. And you've seen in our press release too, there is significant clinician interest in our expanded access and named patient programs. Again, reflecting the number of patients that are diagnosed out there, but also the unmet need in this patient population. And as previously mentioned, we received marketing authorization in Israel earlier this year. We have submissions under review in Canada as well as Australia. And we have two pediatric studies which are also very important because as we mentioned, this is a progressive disease. We've already identified a significant number of patients who are below the age of 12. And we have now completed enrollment in our first study that goes down to age four. And then there's a second study where enrollment is continuing. And then I'll spend the next couple of slides talking to you a little bit about our plans beyond APDS with linoleicid. So when we think about that, we see several development opportunities for linoleicid. Just as a review, primary immune deficiencies are a broad group of disorders with several key features. Often they have a genetic basis. Of course, as an immune deficiency, they have an increased risk of infection. But there's also a subset of these immune deficiencies that also have a feature of immune dysregulation, specifically that immune dysregulation causes lymphoproliferation, autoimmunity, and other autoinflammatory conditions. And because of that, these PIDs are associated with high morbidity and mortality. APDS, of course, is an example of one of these immune deficiencies with dysregulation. And now we're looking at laniolisib for other PIDs with these same features. The first of which will be we're looking at PIDs with immune dysregulation linked to this specific signaling pathway. And we'll talk a little bit about this in the next slide. But these are, again, the patients who have clinical manifestations, disease onset, and severity very similar to APDS. There are no specifically approved therapies for this. And we're beginning with a phase two study imminently. In addition, as Simon mentioned, we are working on another disease in the same area, and we're in the midst of obtaining regulatory feedback on the proposed clinical development plan. But in essence, this is another primary immune deficiency with the same clinical phenotype of immune dysregulation. So something obviously very common across these three indications that we're pursuing. And then on the next slide, you can see some details about the phase two study that's about to start. And this is a phase two proof of concept study that's going to be starting soon at the NIH with 12 patients. These are going to be patients that are known to have hyperactive signaling based on a genetic diagnosis of one of the, and you see there are several of the genes that are involved, including what's called the ALPS FAST gene, CTLA-4, P10, as well as a couple others. Overall, this represents a treatable population estimated at approximately five per million, which is about three times as large as APDS. This phase two study will look at dosing, but also safety and tolerability, and we'll also have some exploratory efficacy measures here. And the goal is to pick the best dose regimen for the phase three study. And as I mentioned, we're expecting the final IRB approval imminently, which will enable us to start the study this month. So with that, I will turn over to my colleague, Jeroen, to review our financials.