Pharming Group NV (PHAR) 2023 Q4 法說會逐字稿

Good day and thank you for standing by. Welcome to the Pharming Group NV full year 2023 results conference call and webcast. (Operator Instructions) Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Sijmen de Vries, CEO of Pharming Group. Please go ahead, sir.

Thank you very much, operator. Welcome, ladies and gentlemen, good morning, good afternoon wherever you are to our conference. Please next slide, and we are very happy to take you to the full year results and you can give me the next slides, because before I do that, I would like to point out two doubts of forward-looking statements slides that you now see where we will be making no forward-looking statements that are based upon our current beliefs and expectations, which may, of course, differ from what we expect.

So having said that, I would like to now go to the next slide where you can see my face and I move on immediately to the next slide. Thank you very much. That's the one.

Yes, we are indeed, looking back to 2023 as a very successful year, where by delivering strong growth, we built the foundation for that global rare disease company that we are setting out to build and that we can build that. We can all finance that by, of course, the cash flows that come from the marketing of RUCONEST, which delivers considerable positive cash flows and that can help us to build that foundation further.

So we delivered -- we're very pleased that we did deliver to more than $227 million of revenue, which is 10% growth versus last year, which exceeded significantly the expected single-digit growth for RUCONEST. And we saw that because we had some very good parameters of -- forward-looking parameters that were really working, the number of patients increased numbers of prescribers increased and seal.

Basically, it means that patients continue to be reliable RUCONEST despite increased therapy options that are available in the market, which of course, are good for patients. But you can see that RUCONEST continues to be that reliable Cornerstone. And my colleague, Steven will elaborate a little bit further on that obviously.

Now the next exciting bit, of course, that we could therefore start to execute on was the launch in the United States for Joenja leniolisib, which product we in-licensed from Novartis in 2019. And we were very proud to actually -- almost immediately after FDA approval in April, bringing that product to the market and immediately get commercial coverage for that product and bring in more than $18 million of sales, Joenja first nine months in the market.

In addition to that, Joenja has been filed with a number of regulatory authorities in Europe, Canada, Australia, Israel and as of two days ago in United Kingdom. And we are waiting, of course, and we're working with all these like regulatory authorities and we are waiting for the next steps and necessary approvals in the not too distant future.

Then, of course, very important. The label of Joenja is for 12 years and older and we have a number of pediatric trials that are ongoing, which are, of course, important. And last but not least, we also have a completed small Japanese clinical trial. So we are preparing for submission to the Japanese authorities by the end of this year. And my colleague, Anurag Relan, our Chief Medical Officer, will talk more about that. And as it is an ultra-rare disease and a very new disease that we already discovered 10 years ago. We have a very strong focus on patient finding. And again, Dr. Anurag Relan will talk about that later.

And then I move to the right-hand side, which of course, is even more exciting going forward towards the future because we strongly believe that Leniolisib surpass the vast additional potential for further development. And hence, we have basically set out to start a Phase 2 B study in the second quarter of this year for the subsequent indication which is significantly larger than that APDS in patient numbers, BID with immune dysregulation. And again, Anurag will talk about that in more detail a bit later in this presentation.

And last but not least, we are very, very active. We continue to be very active to in-license or acquire clinical stage programs in rare diseases, preferably immunology, hematology, respiratory and gastroenterology to further leverage our commercialization structure that we have been building up and are building up as we speak.

And then on the bottom of the slide, you see that for the first time in our history, we gave total revenue guidance and that will be between $280 million and $295 million, which is driven of course, by Joenja, but strongly supported by RUCONEST during 2024.

And then I would like to go to the next slide, please, where you see then a depiction of the pipeline that we have RUCONEST, obviously in the market, Joenja in the US market. And you see that subsequently under regulatory review by many of the regulatory authorities and the pediatric program that's ongoing in Japan, the Japan program that's ongoing. And then, of course, the very exciting fact that we are going to do this the Phase 2 A study for leniolisib for the subsequent indication. And last but not least, our very early stage program, the HAE gene therapy that is in early preclinical stage.

With that said, I would like to turn it over to my colleague, Stephen Toor, our Chief Commercial Officer, to take you through the commercial updates. Thank you.

Thanks, Sijmen. Good morning. Good afternoon, everybody. So this slide, I think you'll be largely familiar with. I think the key thing to take away from this is that the key features of RUCONEST. So namely the early Recumberency1, treating the root cause of the disease and 97% efficacy in one dose is what continues to fuel the RUCONEST growth and our success over the last nine years.

These product features of allied to the excellent work, our commercial medical and patient services teams deliver for customers and patients and their caregivers, is also why RUCONEST remains highly relevant part of the conversation in the US HAE community and globally. That's remained the case despite three prophylactic launches over the last few years, leading to generally better control patients and the genericization of the [carbon].

And I fully expect it to remain the case even in the face of acute competition in the future. And that's because HAE patients using RUCONEST tend to have generally a more severe course of disease. And in that instance, the need for virtually guaranteed and fast efficacy that stops the attack in its tracks is critical and it typically the patients only real objective. In most cases that overriding need for efficacy won't be replaced by a convenience play.

So looking at 2023, RUCONEST performance was characterized by the continued growth in both prescribers and new patient enrollments. And it was also successful despite that market wide event we saw in Q1 last year related to government reimbursed patients. Now we have seen some disruption from that this year, but it's been muted by almost half of those patients out of pocket costs in the US.

And moving into '24, we've also seen that the strength of our leading indicators has continued into this year, namely new prescribers and continued support from existing prescribers and new patient enrollments. So despite some continued disruption in that government segment, we're still on track and for where we expect to be in Q1.

Next slide, please. So this is again, some of you are very familiar with pharma has been in this space and committed to this community for over 20 years now. And it's really that commitment combined with the product itself, RUCONEST, our people and the excellence they deliver, which is why you see on the right hand side, there are a prescriber base continues to grow and as a result, our patient base continues to grow, and that's why, as I said, we remain enthused and confident in the continued growth of RUCONEST both this year and in the years ahead.

And next slide, please. So switching gears now to Joenja, we had, as you know, a strong first year. And as we close out that first year at the end of this month -- Now I'd just like to reinforce what a great launch the team here at Pharming delivered for us. So the launch preparation, as you have heard me saying the parts was first class. And I think I wouldn't underplay what Sijmen said earlier, which is that within one week of approval, we had commercially covered patients with product in hand, which is outstanding.

The patient base steadily grew throughout the year. And we actually did, as you know, the end of the year with 81 patients on paid Joenja therapy. In that time importantly, we've seen very few discontinuations and we have adherence rates close to 90%. So as we convert that caseload that we'd already identified at launch, our focus on surprisingly moving forward remains finding those new patients with this rare disease in main, given it's an APDS is not some older Sijmen, dominant condition testing their families to uncover additional patients.

So that they too can benefit from the management of treatment with Joenja, which, as you know, is the only indicated product which you can treat APDS. And then the other important factor to talk about here in addition to the US is, of course, alongside that launch, we continue to build out our ex-US capabilities in preparation for launches in the European Union, United Kingdom, Japan, Australia and other countries in the Asia Pacific region and also in the Middle East and here in North America and Canada.

So with that, I'd like to pass over now to Dr. Relan, who's our Chief Medical Officer for a medical update.

Thanks, Steve. So what I'm going to do today is talk a little bit about APDS and then provide an update on Joenja, as well as where we see some additional possibilities for applying leniolisib in this second indication. So this slide, you can see a little bit of information about APDS, which is a rare primary immune deficiency. That, as Sijmen said, was only characterized in 2013. We estimate the prevalence of APDS at approximately 1.5 patients per million. And to that end, we have already identified more than 840 patients across the world in key global markets.

As with many rare diseases, the signs and symptoms of APDS can vary across patients even within family members who have the same variance. This unfortunately leads to many potential delays in diagnosis and care and a lot of frustration amongst clinicians and patients as they tried to treat these patients. Fortunately, there is simple genetic test can provide a definitive diagnosis of APDS and until the availability of Joenja in the United States. Recently, treatments for APDS have really only been limited to addressing the symptoms of the disease.

Again, these symptoms manifest early in childhood because these patients have this genetic condition that they're born with. But these treatments do not address the root cause of APDS and without a specific indicated treatment this was quite complicated for these patients to manage their condition and physicians to be able to treat them effectively.

Next slide. And you can see now with the launch of Joenja, APDS patients have a choice now. Specifically, patients who are adult and pediatric patients ages 12 years of age and older. And we've been able to demonstrate this by a randomized placebo controlled study where Joenja met both primary and secondary endpoints with significant efficacy results. We also saw positive benefits in other key secondary parameters as well exploratory measures.

On the safety side, we saw no drug-related serious adverse events or study withdrawals in the Joenja studies. And we've also collected quite a bit of data now on long term use of Joenja from the open-label extension studies. And we provided some of this data, including reductions and discontinuations in immunoglobulin replacement therapy or IVIG. We've also shown reductions in infection rates over time. And we've also seen that the safety is consistent with what we see in the short term. So when we these patients are on therapy in the open-label extension study for several years, in many cases, we see the same type of safety profile that we saw in the short term, in the randomized control study.

We continue to collect this data, including showing and sustained benefits in the size of their lymph nodes, the size of their spleen, some of their immune parameters, including their levels of IGM, and we presented some of this data at some medical conferences throughout 2023, and we expect to continue to present more data from these long-term studies in the coming year.

On the next slide, we can see what we're looking at beyond the FDA approval. So as we mentioned in the press release, we are working closely with CHMP to address remaining outstanding issues and now we are now awaiting CHMP's opinion on millennials and MAA. We in fact, expect that leniolisib also will be on the CHMP meeting agenda next week, but we are awaiting CHMP confirmation for this.

As Sijmen mentioned, also the Japan clinical study, the enrollment is completed there now and we are finishing the remaining studies to be able to file in Japan, hopefully toward the end of this year, beginning of next year. Just this earlier this week, we filed our application for the MAA in the UK with the MHRA. And we also have several applications already under review in Canada, Australia and Israel. And we expect regulatory action on these throughout the course of 2024.

On the pediatric side, we have two studies that are ongoing. The first is in children ages 4 to 11, and this study is expected to complete enrollment very soon. And then the other study which we just started with the first patient dosed in November 2023 is continuing as planned. On top of that, we mentioned that we have a number of patients in expanded access programs across the world as well as some new patients that are on getting access to therapy through named patient programs.

And then I'll talk a little bit more in the next couple of slides about some work that we're doing for the second indication and where that progress is on target with the initiation of the development for the second indication.

Next slide. So let's talk a little bit about the patient finding because I think this is critical for any rare disease, but also for a one of these newer rare diseases such as APDS. One key pillar of that is medical education, and we're doing a number of activities to support this education. Obviously, we attend numerous conferences and conferences that we make present abstracts both on APDS and the seriousness of APDS as well as some of the emerging data that we have and ongoing data that we have on the use of leniolisib in these patients. And we, of course, publish a number of these results. And we've done that throughout the course of this year.

You see a list of some of the conferences that we presented at during 2023. And there'll be a similarly long list for 2024. Because the simple genetic test can make the diagnosis of APDS quite easy. We have a sponsored no cost testing program in place with genetic counselors available to help them review test results with patients and physicians as well as and loans to provide pretest and post-test guidance. We've also partnered with a number of genetic testing companies to identify patients that have already been tested and diagnosed with APDS.

So really reaching out in numerous ways other genetic testing front. And then as Steve mentioned, APDS is an autosomal dominant condition. What we're finding through our work is that most family members haven't actually been tested for APDS and this is due to a number of factors that we're trying to address one by making genetic testing more widely available, but also education. So we're doing a number of things to work with clinicians and patients to encourage family testing. And we have a program in place now that allows patients to directly request this through genome Medical, if they suspect APDS or if they have a family member that has APDS. With really the goal here is to remove barriers to testing for patients that may be having APDS.

On the next slide, you can see a little bit more about the activities that we're doing on what's called variance of uncertain significance. We previously mentioned that there are more than 1,100 patients that we're aware of in the United States alone that have this category of diagnosis, which is called VUS. And what that means is that they have some symptoms that led them to get a genetic test done, but the genetic test result is inconclusive. And it's inconclusive primarily because that genetic variant hasn't been previously seen and that hasn't been evaluated whether it's disease causing or not.

So we're doing a number of things here to help resolve this frustration for patients and clinicians. The first is we're working with experts, including those at ClinGen to develop specific criteria for classifying variants. We're also partnering with a number of companies, including Genomenon to make clearly available what variants are causing disease. We're trying to gather data. And these efforts that I mentioned here have already led to a number of patients getting correctly diagnosed with APDS.

On top of that, we're really trying to make functional testing more widely available and we're doing a number of things here to support this type of activity, working with a number of research first allow labs to trying to make this test more widely available because ultimately, this is the way to resolve a variant of uncertain significance.

And then it's not only one thing to test patients, but then also to share these results. And we're doing that through a number of databases, including the one sponsored by the NIH called ClinVar. And then lastly, we are involved in a project with high throughput methods that will allow testing nearly all possible variants and creating a variant effect map, including variants that haven't been tested yet or haven't been observed yet. And this will allow us to eventually make it possible so that in the future, there won't be any patient that has this type of diagnosis or has this inconclusive result. And those efforts are continuing on plan, and we expect later this year to be able to talk more about the results from that project.

And another one, the next slide, you can see some of the medical conferences that we presented at over the past year. These data talk about the seriousness of APDS and you can see the data on mortality that we presented the data on lymphoma, but they also present data from the ongoing use of leniolisib in APDS in the long-term results, we've seen data as well presented on the different manifestations, including manifestations in these patients got in their lungs.

And then lastly, we presented just last month new data on the use of our navigate APDS sponsored genetic testing program and how that is uncovering patients and helping patients get the correct diagnosis. So as I said earlier, we're going to continue to present at a number of conferences this year have a number of abstracts, a number of publications that are coming out where we can really educate the broader physician patient community about APDS about the seriousness of the condition as well as the ongoing data that we're collecting.

Next slide. Now turning a bit to the next indication that we're pursuing. So obviously, APDS is a primary immune deficiency with immune dysregulation, but there are other immune deficiencies with immune dysregulation, and they often have similar clinical phenotypes or clinical presentations, as you see with APDS. Specifically, what we see is that these patients often get similar problems related to lympho proliferation or enlarged spleen and livers, accessing the enlarged spleens and lymph nodes, but also they also have this problem of autoimmunity where not only is their immune system not functioning properly. It's also attacking the body.

And what we're seeing is that there is a number of these PIDs or primary immune deficiencies with immune dysregulation that have a clinical phenotype that is similar to APDS and oftentimes or even managed before the available of Joenja for APDS in the same way. So there's a strong rationale to see what's going on here. And I think if you see on the next slide, the clinical presentation of these diseases looks very similar to what we've seen with APDS.

In fact, when you look at the right, you see all of the same types of things or many of the same types of things that we see with APDS. We also know that these patients have high unmet need. And again, the standard of care immunosuppressive therapies such as, sirolimus rapamycin that had been used, have a lot of limited concerns due to limited efficacy and tolerability.

So there's an unmet need here. And we know that these patients, based on the work that's already been done in these various genetic disorders have altered PI3K signaling. And we know that that altered signaling leads to the clinical symptoms that you see on the right, and as such, we think that leniolisib is well suited to restore that signaling to normal, thereby helping these patients on clinical presentation also.

And to that end on the next slide, what we're doing is advancing this with a clinical trial, to about the using leniolisib in this patient population. Again, the principle is that by reducing this PI3K delta activity. We're trying to rebalance the immune dysregulation and improve their clinical symptoms. We've been partnered with the NIH on this, and we're expecting to start a clinical trial soon.

The data suggests that when we looked at the patients with specific mutations that have in this type of immune dysregulation, the prevalence is approximately five per million, which is a little bit more than what we've seen with APS in fact three times more than we've seen with APDS, we have been engaged with FDA on this, and we've gotten feedback on the clinical trial plans, and we are underway now to begin that clinical trial shortly, which you can see on the next slide describing the study design for that, it's a Phase two proof of concept study. Single arm was 12 patients where we will ramp patients up starting at 10 milligrams and progressing to 30 milligrams and 70 milligrams.

This study will include patients where we know that the genetic defect and you see that some of the genetic effects listed there out CTLA4 have loaned insufficiency and PTEN deficiency among others where we're there. These patients have this altered PI3K delta signaling. So we think that leniolisib is appropriately suited to be able to alter and restore that signal in back to normal.

The primary objective of the study, of course, is safety and tolerability, but we will be looking at PK and PD measures, efficacy measures similar to the types of measures that we studied in the APDS population. And the goal really is to confirm the safety and tolerability and then pick the best dose regimen for a Phase three study. And as I mentioned earlier, we're partnered with the NIH on this. So look for more updates to come soon about the initiation of this study.

And with that, I'll turn it over to my colleague, Jeroen to discuss the financials.

Yes, thank you very much Anurag and very happy to take you through the financial highlights to start off with the Q4 2023 versus last year, we had a revenue growth in the quarter of 49% and revenue grew by 34% in Q4 and recorded -- had a record revenue of $73.3 million. You may remember that we were at a growth of 2% year to date at the end of Q3. So we're very happy with these Q4 sales results.

And we saw strong performance in leading key revenue indicators in the US, including new physicians prescribing RUCONEST, new patient enrollments, including high frequency attack patients and the total number of patients. Joenja revenue grew by 21% versus the previous quarter, so Q3 2023 and the revenue was $7.9 million. And by year end, we had, as Steve also said, 92 APDS patients enrolled in the US and 81 patients on therapy on Joenja.

The gross profit in the fourth quarter of 2023 increased by $25.8 million compared to the fourth quarter last year. And this growth was driven by higher revenues, partially offset by increased RUCONEST production cost, Arrow royalty payments on Joenja sales. The operating cost increased by $16 million into the fourth quarter compared to last year. And about half of this $8.3 million was directly related to R&D and marketing and sales expenses for leniolisib, respectively Joenja.

And our expansion efforts driven by preparation for the launch and further commercialization of Joenja led to a $7.1 million increase in payroll expense.

The operating profit of $1.1 million was realized in contrast to an operating loss of $10.2 million in the fourth quarter of 2022. And this improvement was primarily driven by the rise in gross profit and partially offset by the increase in operating expenses. Net loss was $2.7 million and our cash position improved and grew from $209 million at the beginning of the year, $215 million year-end.

If I then go to the next slide, with the full year results, our revenues grew by 19%, which was a result of higher RUCONEST sales volumes and supported by a price increase, which was below CPI in the US market. The initial sales of Joenja was $18.2 million in 2023 following the launch in April of the same year. And revenues in Europe and the rest of the world increased by 12% to $6.2 million in 2023.

Gross profit increased by $32 million or 17% one seven, and this development was broadly in line with revenue growth. Our other income reflects for this year or well, 2023, the sale of the priority review voucher to Novartis, which was for a pre-agreed price of one $21.3 million and is a somewhat flat, partly because of (Technical Difficulty) reduction of our minority stake in bio connection. And at the time we recognized a gain of $12.2 million, so that was 2022.

The operating costs increased by $64.5 million, of which $10.4 million is attributed to milestone payments for Joenja following the first commercial sale in the second quarter of last year. An additional $25.7 million of expenses is directly related to R&D expenses and marketing and sales expenses for the leniolisib stroke Joenja and $24.2 million increase was from payroll expenses driven by our expansion efforts in preparation for the launch and the further commercialization of Joenja.

Finally, we incurred impairment expenses related to our DSP facility, and that was for an amount of $4.7 million in 2023. So the operating profit decreased from $18.2 million to minus $5.4 million. And that was as a result of the increase in operating costs to build our Joenja business. The total net loss in 2023 amounted to $10.1 million compared to a net profit of $13.7 million in the year before. And the decrease was primarily caused by higher operating costs. And in addition, fluctuations in foreign exchange rates adversely impacted the foreign currency results in the statements of income.

On the next slide, we give a overview of the revenue in RUCONEST over the last years. And obviously for last year, you see also Joenja but and RUCONEST has grown by 10% in 2022. And we saw a record RUCONEST revenue since the launch of the product in the US over nine years ago. leniolisib is driving enhanced growth. We achieved overall 19% revenue growth in 2023, and we're very pleased with these results and with the continued growth of RUCONEST from 2021.

On the next slide, you see the OpEx in cost category breakdown by quarter and the messages that we continue to invest in Pharming's future growth. And I have provided more detail on the growth of the operational costs earlier and specific to Q4, the operating expenses increased by $16 million in the fourth quarter compared to last year and $8 million. Almost half of it was related to leniolisib and Joenja in terms of marketing, sales and R&D and $7 million was related to payroll expenses to support the growth of the organization. And for 2024, we expect quarterly OpEx to be less than the OpEx in Q4 2023.

Moving on the next slide to the cash flow. As I said before, it increased from $209 million to $215 million. And the graph shows the key changes in our cash position -- the cash flow from operating activities was negative and offset by the cash from the sale of the earlier mentioned priority review voucher. And in addition, there were favorable currency exchange rate fluctuations with a positive impact on the cash and that was amongst others on the cash that we hold in euros and the euro-dollar exchange rate increase throughout the year.

Again to the revenue guidance for 2024 on the next slide. We give a revenue guidance of between $280 million to $295 million for 2024. And that means a growth between 14% and 20%. We, as in earlier years, expect quarterly fluctuations. And Joenja is a significant driver of this revenue growth. But also we expect continued growth from RUCONEST and the RUCONEST growth rate is higher than the guidance that we gave in 2023 because we expect some of the momentum from the second half of 2023 to continue.

Last year's guidance was low single digit, and we are confident to move that now to low to mid-single digit growth for RUCONEST. The Joenja assumptions are that we expect continued growth in patients on therapy. And the pricing in the US is at an annual weighted average cost of USD566,000 per year per patient.

And moving on to the outlook for 2024. As I said, total revenue between expected to be $280 million and $295 million. Joenja in the US, we expect continued drug progress finding additional APDS patients, and that is supported by family testing and VUS validation efforts, as mentioned by Anurag and subsequently converting patients to bait therapy.

For leniolisib, outside of the US, we expect increasing revenues from commercial availability or through our named patient program and other funded early access programs in key global markets. We expect to complete leniolisib clinical trials to support the regulatory filings for approval in Japan and for the pediatric label expansion in key global markets.

And we expect progress towards regulatory approvals for leniolisib in Europe, the UK, Canada, Australia and Israel. We will initiate and advance a Phase 2 clinical trial for leniolisib in PIDs with immune dysregulation linked to PI3K delta signaling, to significantly expand the long-term commercial potential of leniolisib. And we continue to focus on potential acquisitions and in-licensing of clinical stage opportunities in rare diseases in therapeutic areas like immunology, hematology, respiratory and gastroenterology. And that is to further leverage our commercial infrastructure globally.

With that, I would like to move on to the next slide and open up for Q&A and then hand over to the operator.

(Operator Instructions)

Christian Glennie, Stifel.

Hi, good afternoon, guys, and let's start off with (Inaudible). I guess and just to get a bit more of a sense for some of these underlying drivers of the very strong fourth quarter, you seem to be guiding for mid-single-digit growth in 2024 now? And is there a scenario in which it could get north of that onto another sort of 10%? I'm just trying to get a bit more sense for some of the drivers on RUCONEST this year?

Thanks for the question. On the very nice. Yeah, RUCONEST indeed has had some very strong and Steve has already alluded to it, some very strong underlying indicators in the market, which you said continue into the first quarter. We are, of course, aware of the fact that we are in a market, which is base lower competition around. And we continue to be optimistic, let's say it's year 10 right as the RUCONEST is in the market. So we can be optimistic by saying that we have the low to mid single digit growth. And as and when we see indicators moving for certain of the north, obviously we will update guidance during the year, but now we would like to stick to that. And then in respect of Ruconest.

A natural follow-up to that, I mean, you touched on this, Steven touched on this in the remarks around some potential new entrants here on overall convenience next year. Just if you could get a bit more insight, I guess in terms of the patient profile here and what the sort of your market intelligence tells you that you are going to lose patients effectively to that convenience option?

Yeah. Anurag and Stephen both -- sorry, Stephen alluded to it already. Of course, we'd see a very different patient profile that are using RUCONEST and basically speaking, when you look at the clinical results of those new acute options. You see there is a necessity to, A have multiple doses. And B, I still need rescue therapy. If you look at the RUCONEST results, the word rescue therapy doesn't figured out because reconnect this protein replacement therapy for that missing C1 or not functioning C1 inhibitor protein in patients with hereditary angioedema.

Hence, why we believe that these products, in fact, or serve a different segment of the population that suffers from territory angioedema, where we will see -- we expect, therefore, that these oral acute products if approved, of course, it will serve that patient segment that is now currently, of course, using a lot of convenience products as well, such as our subcutaneous injections that are and by the way, pay stinging and painful and which you have to give repeatedly often to treat one attack and that the hurdle for those patients to actually step over into an oral would be a fairly low.

Whereas I think that patients that rely on RUCONEST that are not used to any convenience in therapy, but are relying on the reliability of efficacy of RUCONEST. That hurdle will be a lot higher. What can never totally exclude, of course, that patients will try it, may be successful. But in the other hand, like we said, we serve a very different patient profile with very higher attack frequencies than we see in all those clinical trials that are being that are being done by those new oncoming competitors. I hope that answers your question. Sorry to be in a long line of your question.

That's very helpful. Thank you. And then one final one on Joenja and I get back in the queue. I guess your guidance implying your RUCONEST, 5% gets to about [$240 million]. So Joenja, the balance is somewhere between $40 million and $55 million for this year, if I'm understanding correctly? And therefore, what are your assumptions around the sales and markets that will contribute to that growth and what gets you to the low and high end of that? So is it mostly still US or should they be reasonable contributions from other markets?

I think what we first and foremost, obviously, as you heard from Anurag a lot -- and Steve, look at your activities are going to find those patients in the US. However, the first numbers of patient that we had, of course, our own drug. We will see inflow steady inflow in the United States during this year from, for instance, the family testing efforts that will be systematically applied as we as you heard.

The other thing is, of course, there will be small batches of initially small batches or VUS's tested and that will actually deliver, albeit in the beginning a limited number of additional patients as well, whereas by the end of the year, but that's more for '25. Of course, we expect that may experiment where Anurag talked about a combinatorial experiment to deliver the bulk of the VUS and assumes a bit more indication of what kind of percentage we actually have on the VUS. We will, of course, update the market as well, but it's a little early days for that at this point in time. Now that's for the US market.

With respect to ex-US. Well, we don't expect any significant sales from the European markets because obviously, as you know, reimbursement takes a lot of time. So the European markets sales will only cut in '25 and further on even further on because some of those markets will take multiple years before you get to an approval. So the ex-US sales will mainly come from those early access programs, fairly early access programs and some of those markets and from the nine patients that are actually already being served. And that's what you can also expect, of course, a for instance, in the fruit in the 1Q results, you will see that there is some sales reported ex US because that's ongoing as we speak.

So in other words, the fluctuation in the Joenja numbers, I think depend on mainly I think on the numbers of patients that will come, of course, from the US market. I hope I answered that for that question, Christian?

Yeah, thank you. Thanks, Sijmen.

Alistair Campbell, Royal Bank of Canada.

Thanks everyone. Thanks for taking my questions this morning, and I have a couple on you Joenja, if that's right. First of all, obviously, Joenja's launching well, and you talked about 90% adherence rate, which is which is good. But just in the context of that's what you're actually seeing in real world use is kind of a light, so to get a sense of that.

And then secondly, just thinking about the second indication, the PID with immune dysregulation, obviously that's going to cover a variety of different genetic causes. I guess what I'm trying to get for myself is the feeling of the risk around the profile of this program, as they basically is your expectation that some all of those genetic function areas really biologically should respond or do you think some of them will or do you think they all will? I'm just trying to get a sense of what the risk profile looks like there. My feeling is that at least some of those should probably come through just to get some sense on how you beat that. Thank you.

Yes, I'm happy to hand it over to Anurag, of course here in the stage. Anurag, would you mind asking that question?

Sure. So maybe we'll start with the second question. First about the additional indication in primary immune deficiencies with immune dysregulation. And you're right, we're looking at a number of specific genetic variants, genetic mutations that are causing these altered signaling. And that already has been described, right. So it's known that patients with ALPS that patients with CTLA4, patients with a PTEN deficiency, have this abnormal signaling through that pathway.

It's also known that they have immune dysregulation as a result of that. And then lastly, they're being treated with immunosuppressive therapies, such as rapid mice and to modulate that pathway. So we think it's quite logical to trying to modulate the pathway with leniolisib in the same way that we did with APDS patients. So I think I think from our perspective -- and really this program came to us through our interactions with the immunology community. They -- through numerous work through all the work that we're doing on APDS, they kept on saying, look, there are other patients that they believe could benefit and they listed all of these reasons that I just mentioned to you.

And it was really on that basis that we partnered again with the NIH and who are leaders in these in the specifically in this areas of ALPS and CTLA-4 haplo insufficiency to come up with this clinical trial program because they were so enthusiastic about being able to, one, address the unmet need, but two, to be able to use something that they were very comfortable using for APDS and they didn't work. You have to have confidence because they had been treating patients with APDS with Gleneagles that for several years.

And I think that comes to your second or your first question, which was on the on really the real-world use of leniolisib and how does that compared to what we've seen in the clinical trials. And I think what we're seeing is number one, we're seeing that it is continues to be generally safe and well tolerated. So we're seeing nothing new from our pharmacovigilance efforts on the real world use suggesting a different safety or efficacy profile.

And two, I think what we're also hearing of a lot of the other benefits that we didn't even capture in the clinical trial program. So and we're going -- we're trying to get all of that data. We in fact, we have a registry underway in the US. We're going to be following APDS patients longitudinally in the hope actually that tried to capture a lot of data that we didn't address in the original clinical trial because we weren't aware of all of the possible benefits that these patients experienced. So I think that's something else to look forward to us as the year continues.

Just a quick follow-up. And that is when do you think your incentive and incentive timing, you might have something from the registry that we be worth, sharing with us.

So the registry is just underway, but we are continuing to collect and publish data for the use of expanded access. So these are again, this is essentially compassionate use patients in the US who don't qualify for commercial drug or outside the US, who are on therapy. We are collecting that data and we've shared some of that last year. You'll see a lot more of that our data from the expanded access program or the case reports or case series of patients in the expanded access program. You'll see that at conferences this year.

I think the registry because it's just started. I think that's more likely to be a '25 type of data. But I think that you're going to see through the expanded access program data coming out this year that reinforces what we saw and the clinical trial program and really extends even beyond that.

Great, Thank you.

Joe Pantginis, H.C. Wainwright.

Hello, gentlemen. Thank you for taking the question. So I have a couple of questions on Joenja. I'm going to start very specific and then just talk more to the broader disease, if you don't mind. So first, Stephen earlier was talking about and of course, you guys have great adherence rates. So I was curious on the other end, what are some of the reasons you see for a lack of it, in the drug?

Thanks, Joe. Anurag, do you have any insights that you can share with, Joe.?

Yeah. I think it's really just one-off cases, Joe, where, in fact, some of the cases where we've seen as patients are underweight and they need to be put on a lower dose. So that's not possible in the commercial program. So that's one example. And it comes to the top of my mind, but it's not anything we're seeing from a safety point of view, that suggests any concern or something that we saw didn't see in the clinical trial program. So I don't think there's anything substantive here.

Very helpful. Thanks. And then I guess Sijmen, if I heard you correctly earlier, it sounded like you might be disclosing in the future, the role or the raw amount or proportion of VUS is as part of your, you know, Joenja revenue profile was first, was that correct? And then second, when do you anticipate I know this is really forward looking that the US could start to have a real impact on the revenue growth for Joenja.

Yes, Joe, that is indeed forward looking. Yes, I said, indeed something whether we're seeing like that, you see that slide from Anurag, you saw in the middle there that those individual VUS's are now being evaluated. And that's actually starting and happening as we speak. So the first small batches of those are expected to come through in the very near future, which may give us some early insights on that. It's not like I said earlier, it's not going to deliver bulk of patients, but it will deliver patients.

And the bulk, I think, will be seen following the closure of the may experiment we should expect of us and direct was alluding to by the end of this year. So I think '25 will be the year where the bulk of the US patients will become will become available for us for treatment. I think that's a reasonable a forward looking statement from now, Joe.

Got it. No, that's fair. And my broader question about the disease sort of ties in your recent data at Quad AI, obviously very intriguing data with regard to the molecular diagnostics. And I guess I would ask, Anurag, the role that Joenja could pull with regard to multiple statements made in describing the disease where some patients do not clinical actionability. So I'm just curious, first, can you -- for all of us help define why patient might not be actionable from a clinical standpoint or medical standpoint? And if Joenja could have an impact on that.

Yes, I think it's a good question, and it's something we're doing a lot of work on -- really educating patients and clinicians about APDS. I think it's a foregone conclusion amongst our team, of course, that this is a serious disease and that there's a significant mortality associated with it. But many of these patients, unfortunately go on to develop lymphoma. And lymphomas is a key reason for the high mortality in these patients, the lymphoma that these patients develop is often not easy to treat and the mortality rates are much higher than you would see in other lymphomas, for example, or in other patients.

So I think there's a lot of education to talk to talk about that. I think it's also important to recognize that these patients do have different clinical manifestations. So some patients it may be very obvious without a high infection rate. Some patients, infections may not be the most predominant feature, but it could be the lymphadenopathy or the large spleen. So I think it's really educating clinicians also on what to look for in these patients and to be able to monitor these patients. But really all of these patients, I think have a serious condition and they all are potentially eligible for Joenja. So I hope that answers your question.

It certainly does. And my last question and thank you for bearing with me is more towards on your continued strengthening balance sheet and with feel that your increased cash helps leverage additional business development discussions. And can you talk to the potential or can you talk to that relative maturity of some of your ongoing discussions in License potential asset?

Yeah, Joe, yeah, things you have. Of course, it always helps to have a bit more cash on hand in case one wants to do an in-licensing of a pursue an in-licensing opportunity, which of course, as we said before, is our preferred modus operandi because that's much easier to deal with than the emergent acquisitions.

Having said that, you know, I think with the arrival of Alexander Breidenbach, our Chief Business Officer and he's been really proactively working, and we've got a very nice pipeline and we are in advanced stage of discussions with a couple of possibilities. So we have a nice line of sight as we call it for opportunities that we are evaluating.

However, as you know, in business development, and that is before, it doesn't come sale until you have a deal so yes, but we remain very active. And I think what also is what we see is with our commercial success and with the ongoing ability that we are very successful in being able to market against competition in the HIV market and that we are basically know how to develop a new market even in a new disease.

We got a lot more visibility now that we are a company that is potentially an interesting partner of choice for those companies that deal should not go into commercialization because they will become single-product companies and commercialization is very expensive, very risky. And we basically therefore, like I said, because we have now got this under our belt and become more and more. We see on the radar screen and we're getting a lot more inbound than we used to get. So we are continued to be optimistic that we get some opportunity this year to be able to update you on a deal that we have crunched who have two assembly and that we have actually expanded our pipeline.

Very helpful. Thank you for all the answers, guys.

Pleasure, Joe.

Hartaj Singh, Oppenheimer.

Hey, everyone on this. If I am hopeful, Hartaj, we do. Thanks for the questions. Few questions from our end. So first one for RUCONEST, can we still expect the seasonality for RUCONEST in first quarter sales of previous years? Any color on that?

And the second one for Joenja, can you provide any color on the duration of the patients Joenja, so far since Joenja us was launched around like three quarters, nine months ended. And your estimate on the APDS patient number in 2024. Thank you.

Yeah, today does hand you hand it over to you, Stephen, those questions, though.

I could you repeat the questions because they weren't completely clear.

Sure. The first one for RUCONEST, can you still expect the seasonality for RUCONEST in first quarter sales as previous year?

Yes. So thank you for clarifying. So yeah, I think you can broadly expect to see similar patterns to those which you saw last year because the same types of events are happening in the quarter. So for example, Q1 is the deprioritization season. And as we indicated last year, there is some disruption to government patients. So as I said, we remain on track for what we expect to do this quarter, but the leading indicators and the performance is where it was expected to be, but you should expect to see the same overall pattern through the year, I imagine, certainly in the first half.

Thank you. For Joenja, so can we know some color on the duration of the patients on Joenja, so far, since it was launched around three quarters, nine models?

The duration of the patients --

Patients, on Joenja, I don't know like I said, physicians, these prescriptive like 30 days for each patient are like hormone for your patients and --

I've got you now. So as we mentioned earlier, but patients are adhering Well, unless there's some reason or a weight issue or some such. So they're typically being prescribed on a monthly basis and dispensed on a monthly basis. And we see that cadence with patients.

Thanks. And so any estimate on a projection on the APDS patient's numbers growth in 2024, more specifically?

Yes. So we like I said before, we said, we will continue to get new patients on products in the USA, right. The adherence rate is very high. It's of course, chronic therapy. And we don't give any -- we will update sorry, we'll update the numbers of patients to watch the future on a quarterly basis, right, when we get these results. Does that answer your question?

Yeah, understood. Thank you very much.

Simon Scholes, First Berlin.

Hello. Thanks for taking my question. So the exclusivity on RUCONEST, the US expires in two years' time, the more than two years' time was just wondering if you what kind of impact if any you, I think that I have on RUCONEST?

Yeah, we expect no impact whatsoever on RUCONEST and that perspective because we believe that there is nobody that's actually is working on or has any appetite to develop a transgenic platform to make a biosimilar for this product. And given also that it is now it is, of course, a great product, but it has in the greater context, not a huge commercial, not a huge commercial opportunity. So therefore, no effect, no impact.

Okay. And just I mean, just a follow-up on that? I mean, what's your current thinking on the likely timing of the first gene therapy in HAE? I mean, besides your own products, of course.

I think it will be still a lot of years away only the first patients are being tested. Now gene therapy is not the quickest development pathway forward, I would say a better maybe you can say something on that Anurag?

No, I think that's the time and that there's some initial results in a small number of patients. But I think this will require the typical development path Phase two, Phase three as well as long-term follow-up, which will take several years at the minimum.

Okay. Thanks very much.

Thank you, Simon.

I will now hand the call back closing remarks.

Thank you very much. Yes, ladies and gentlemen, thank you for attending our full year conference. Like I said at the beginning, we late in 2023 because of our very significant 19% growth in revenues. We laid the foundation and the start of a long trajectory of growth, which this company is now going on, embarking on.

And of course, that's why we guide this year for additional significant growth for the revenues of that fueled by, of course, the continued growth expectations for RUCONEST and the continued growth of Joenja. And we feel very confident about the fact that we have started now all the systematic efforts to find those patients. I would that be US patients, the US validation efforts you mentioned family testing will serve as mentioned.

And of course, the and the increasing availability of leniolisib ex US, where through our named patient programs and other early-access programs we expect revenues and of course, the completion of the clinical trials going forward that will support the approval in Japan in the future. This is, of course, not a 2024 story as we all understand, because the file will only be ready to be submitted by the end of 2024.

We look forward to receiving the regulatory feedback from the various regulatory authorities and expect approvals during that during '24. And we are very, very excited, of course, that we can significantly and launch the potential of leniolisib with that second indication, BID with immune dysregulation linked to the PI3K kinase delta signaling, which Anurag alluded to, which is a significantly larger opportunity going forward and when there is, whether we believe there's a very, very strong scientific rationale underpinning for that.

But of course, not something that we'll report in 2024. But we will be very happy to update you, of course, once this trial has started. And once this trial, of course, has the results and hopefully brings us to the next stage in development of leniolisib for that second indication. And that is my Ladies and gentlemen, not even the beginning because we are looking at additional opportunities to apply leniolisib in this or in adjacent areas and more of that, no news that will be coming in the future about about our efforts in that respect.

And last but not least, as I was alluding to, we have a very interesting line of sight of opportunities to in-license or do M&A activities for clinical stage opportunities in rare diseases where we are feeling most comfortable to deal in immunology, hematology, respiratory and gastroenterology.

So thank you again for attending our conference our full year 2023 results conference, and we look forward to updating you on the next quarter results sometime in May. Thank you very much and goodbye.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.