Q4 2022 Pharming Group NV Earnings Call

Speaker 1: free kinase delta inhibitor in development or in the regulatory review for APDS where we anticipate in the not too distant future the FDA approval and later on during the year the European approval.

Speaker 1: And we are developed, we have morphed ourselves into a company that is focusing on development and commercialization of rare diseases. And the first thing that goes beyond the APDS indication for lineal is it will be —

Speaker 1: that we are quite far along with investigating Lenny Olliship for additional rare disease indications.

Speaker 1: We are based in Leiden, the Netherlands, and we are here actually in our US headquarters in New Jersey where we speak to you from.

Speaker 1: And of course we are a public company since 1999 in Amsterdam and since 2020 in the NASDAQ. So let's look at our business model on the next slide.

Speaker 1: We're really on our way to building a sustainable rare disease business. Whereas we are now commercializing Brukenest, albeit on both sides of the ocean, the vast majority of sales come from the United States. So we're now one product company with one geography.

Speaker 1: But that we expect to be changing very soon with the anticipated approval of Leniollis for APDS.

Speaker 1: which will represent not only a possibility for very significant growth of our US commercial footprint and revenue base, but also a very significant revenue generator outside of the US. So we're looking forward to this year being a transformative year from which we transform from this one product, one geography.

Speaker 1: company into a multiple products, multiple geographies company. And of course, like I said before, we are quite far on our way and we'll update the market as and when later in the year to actually start additional development programs for lineal and additional diseases.

Speaker 1: And then last but not least, since we have a very scalable commercialization infrastructure in both Europe and in the US, we're actively hunting for additional products in rare diseases either in lysis, that is our preferred mode of action.

Speaker 1: And if not otherwise possible, emerges in acquisition transactions to basically bolster that pipeline further and get that flywheel, really get that flywheel going that we have here with our scalable commercialization operations on both sides of the oceans.

Speaker 1: And in the next slide, you can see the pipeline, and you can see immediately what I mean with that, whereas Ruconess is on the market and LenioLISP very close to the market. And of course, if we start clinical trial programs in secondary indications for LenioLISP, there's still a considerable gap between those two products.

Speaker 1: or those three products in the near future, and the preclinical assets that we have in the form of OTR105, the HAE gene therapy, and alpha-glucosidase from our transgenic platform, just like you can ask for pompous disease.

Speaker 1: So let's look at Rookiness being the strong foundation under our company. We returned it to growth again after the COVID-19 pandemic.

Speaker 1: We returned to growth in 2022 as we were guiding single digit growth over 2021. And that is something we are very proud of. Rookiness was launched at the end of 2014. So it's already quite a mature asset and has found its unique place in the market. It is the only recombinant treatment.

Speaker 1: that targets the root cause of hereditary angioedema by replacing the missing or dysfunctional C1S-3A inhibitor.

Speaker 1: And over the years, it has proven to be very well tolerated and effective, and continues to be a very effective treatment for the treatment of acute hereditary angiodyma attacks, including, and that becomes increasingly important, those breakthrough attacks that people suffer from when they use prophylactic treatments.

Speaker 1: And that indeed continues to be an issue that although prophylactic treatments have become, and I'm especially referring to the United States market of course, where the vast majority of our sales come from, and although the prophylactic treatments have become a lot better, they all have the same issue that up to half of those patients.

Speaker 1: suffer from breakthrough attacks. And breakthrough attacks can come very frequently or very rare, but they come always at a moment and you don't expect it. That's why it is always the case, it is good practice in the United States, that when you are in prophylactic treatments, you always have acute medication at hand, at home, to actually...

Speaker 1: inject yourself in the case of Ruku Nest with the RescuTerapy.

Speaker 1: And that becomes increasingly important.

Speaker 1: That is also why we see increasingly that RukuNest is being used by more doctors and used by more patients to actually treat those breakthrough attacks.

Speaker 1: And it is, we can very proudly say, the second most prescribed product that is detailed for acute attacks.

Speaker 1: And as you can see here, the efficacy numbers speak for themselves on this slide. And we are finding that our patients are, feel very, very confident to administer the treatment themselves. It's a slow IV injection and the very vast majority of patients do that in.

Speaker 1: do inject themselves in or by their loved ones in the privacy of their own homes.

Speaker 1: So Rookiness has been on the market for a long time and will continue to play a very important role supporting our business with sales and with important cash flows that enable us to invest in all those future programs that we are embarking on. So with that said I would like to now switch over to the presentation.

Speaker 2: is review some information that we have on our understanding of the condition APDS, our understanding of the patient journey, and what we've done in terms of developing Leniolasib for APDS and then using all of this information to help identify patients, and then lastly provide an update on where we are in terms of regulatory status.

Speaker 2: So on the next slide, we can see a schematic here of how this genetic defect in one of these two genes leads to this hyperactivity of this pathway. You can see that within the cell there on the left, and that hyperactive pathway then leads to this dysregulated B and T cell development. So these.

Speaker 2: these key components of the immune system do not develop properly and as a result of not developing properly patients suffer from a number of symptoms and conditions that you can see on the right. Most prominently these patients develop recurrent infections. They also because of this abnormal development of their immune system

Speaker 2: have what's called lymphoproliferation. So they get swollen lymph nodes, their spleen is enlarged, they have problems with expansion of lymphoid tissue, especially in the gut, and that can lead to a condition called enteropathy. And not only do these immune system cells not fight infection...

Speaker 2: they actually lead to the opposite problem where they lead to a condition called autoimmunity. And this can lead to autoimmune anemias and cytopenias and other autoimmune disorders.

Speaker 2: But it's also important to note that APDS is a progressive condition. So over time, the disease worsens. And many of these patients, even at a young age, develop a condition called bronchiectasis, which is essentially scarring in the lungs that is irreversible. And many of these patients, unfortunately, go on to develop lymphoma, again, due to this unchecked lymphoproliferitis.

Speaker 2: shortness of breath, coughing, just difficulty to do their normal activities. And you can see that that can impact their social well-being and as well as their mental well-being. But there's a significant treatment burden. These patients are frequently hospitalized, they have numerous surgeries, many of them unnecessary, especially when they've not been properly diagnosed, numerous doctor visits.

Speaker 2: So it's a condition that impacts many facets of these patients' lives.

Speaker 2: On the next slide, we see what's possible now in the current management of APDS, and that's really trying to address the consequences of the condition. So not addressing the root cause, but trying to address the symptoms. So what the symptoms and the manifestations are infections. So

Speaker 2: These patients are frequently on antibiotics, either prophylactically or to treat their infections. Most of these patients are on immune globulin replacement therapy. And then again, on the flip side, when they have autoimmune complications or immune dysregulatory complications, they're put on steroids, other immunosuppressants.

Speaker 2: Unfortunately, even stem cell transplants, although potentially curative, have significant morbidity and mortality associated with them.

Speaker 2: On the next slide, we can see.

Speaker 2: The future now what we've been what we're developing is Lenio Lissive, which is a targeted disease modifying treatment for APDS and Lenio Lissive specifically blocks the PI 3k pathway and thereby modulating and trying to Return to normal the activity in this pathway

Speaker 2: A consequence then of that should be that we can actually develop the immune system properly and then again impact all the other things that are the downstream effects of that abnormal immune system development. And that's and and we've gone on to study that together with Novartis and you can see in the next slide.

Speaker 2: the overall clinical development plan, which includes a number of studies, dose-finding studies, a placebo-controlled study, and at the bottom, a long-term extension study. There are patients now in that long-term extension study that have been treated for a number of years, many patients, several patients over five years, one patient who's been in the study now for seven years.

Speaker 2: So we have extensive data on the use of Laniolus both in a long-term perspective, but also in a placebo-controlled fashion. And in the next slide, we can see some of those results. We see that the study met, the randomized control study met both primary outcomes, which was number one to increase the number of naive T cells.

Speaker 2: Again, these are B cells that were not developing properly as a result of that underlying hyperactive pathway. We were also able to achieve decreased lymphadenopathy. Again, this was a primary manifestation of APDS. On top of that, when we look over in the randomized study as well as over longer periods of time, we were able to achieve decreased lymphadenopathy.

Speaker 2: These patients' spleen size shrinks. We see improvements in those autoimmune complications. We see in general that the drug was also well tolerated in the data package that we submitted to FDA. For example, we have a median exposure of two years for the patient population.

Speaker 2: On top of that, when we start looking at the longer term outcomes, we see that these patients are getting less infections, and they're using less immune globulin replacement therapies. So despite using less of the therapies that needed to control infections, they're actually getting less infections. So it's actually very nice to see how impacting that pathway can impact the outcome of the vaccine.

Speaker 2: the immune system and then can actually have an impact on all of these clinically relevant endpoints in terms of infections and also reduction of immune volume and replacement therapy.

Speaker 2: On the next slide, we can see where we are now in terms of safety. And what we see when we look at the randomized controlled trial data is a comparison of Lenulosib on the left with placebo on the right, and you see a very similar profile in terms of the grade of adverse events that were experienced by these patients.

Speaker 2: And that mimics what we see in the long-term extension data. So in general, lineal has been well tolerated. And again, as I mentioned earlier, we have some patients who've been on the therapy in the studies for several years now.

Speaker 2: On the next slide.

Speaker 2: We can see the activities that we've been conducting to help find patients. And there's a number of activities as we begin to understand the disease and this patient journey that help us inform how to go about finding these patients. We again estimate that based on a prevalence of one to two per million, there's more than 1,500 patients.

Speaker 2: in the key markets where we intend to commercialize lineal zib first. We've already identified 500 patients in these markets. Much of this has been done through a partnership with Invite, which involves a genetic testing program that is at no cost to patients that can make a definitive diagnosis for these patients.

Speaker 2: We also have a number of partnerships with medical organizations, patient organizations, and these are critical in helping us to uncover these patients who have this rare primary immune deficiency. And we've received tremendous support in these partnerships, again, these patient organizations who are

Speaker 2: who really have the same goal that we do, which is to help improve the lives of these patients with these rare and ultra-rare diseases.

Speaker 2: On the next slide, we can see where we are now with our regulatory status. As Simon mentioned, we have filed in the U.S. It's under review with a priority review designation for patients who are enrolled in the U.S.

Speaker 2: in the programs that I described, which were adults and adolescents age 12 and over. We also have an ICD-10 code in place, and we have a number of positions already using that code, so that's also nice to see. And we have coming up at the end of this month, the expected decision from FDA on the 29th of March. And we expect that later this year, still in the second quarter of this year, we expect to be able to commercialize.

Speaker 2: data. We still, however, anticipate that CHMP will be able to provide an opinion later this year and the second half of this year with an approval to follow approximately two months later. And with the UK regulators, we expect to be able to file soon after the CHMP.

Speaker 2: On the next slide, you can see this over time, some of the key anticipated milestones. Earlier this year, we were able to begin the first of two pediatric studies. And again, we have FDA regulatory decision coming later this month with the US commercial launch soon after that. We're also going to be getting a new.

Speaker 2: study in Japan and we expect that to also occur in the first half of this year. And as I mentioned earlier, we're expecting a CHMP opinion as well as a UK filing in the second half of this year.

Speaker 2: And I will now turn it over to my colleague, Jeroen

Speaker 3: Thank you very much, Anurag. So the financial highlights for 2022 versus last year related to the P&L to start off with. Our sales grew by 3.4% in 2022 to 205.6 million.

Speaker 3: and in Q4 sales were 54.6 million, also a growth of 3% in line with the single digit growth guidance that we've given throughout the year. Gross profit increased from 178 million to 188.1 million.

Speaker 3: That's an increase of 5.8% and therefore we improved our gross margin.

Speaker 3: Operating costs grew from 167 million to 184.4 million, an increase of 10.5 percent, and the operating profit grew to 18.2 million, which is an increase from last year of 34.5 million.

Speaker 3: The net profit decreased from 16 to 13.7 million in 2022, which is a decline of 14.5%.

Speaker 3: In the next few slides I'm going to give you a bit more color and detail on the results on what happened. Next slide please.

Speaker 3: The overall message is that we grew our sales and we also grew our investments in the launch and the preparation of the launch in Lenny Ellis.

Speaker 3: Revenue grew to 205.6 and that was supported by a price increase which was well below the CPI level. But also an increase in the number of doctors prescribing Riconest and an increase in the number of patients.

Speaker 3: Regional split is that we had a growth in the US of 3% and the EU sales were flat over the two years.

Speaker 3: And moving to gross profit, gross profit increased and that was amongst others obviously by the sales growth but also by the improvement in gross margin from 89% to 91% and that was driven by favorable production results but also in the...

Speaker 3: impairment on the inventory in 2021 of 2 million that we didn't need to take this year.

Speaker 3: The other income is you see a sharp increase from 2.6 million to 14.5 million and that includes the transaction that we did with BioConnection, our fill and finish partner, which in Q2 we reduced our minority stake from 44% to 20%.

Speaker 3: 184 million and you see that overall the costs were flat on a like-for-like basis so to say and you see the growth in in Lenny Ellisip out-of-pocket expenses so we consider out-of-pocket expenses mainly third-party providers

Speaker 3: And that almost doubled from 18 million to 34 million.

Speaker 3: almost doubled from 18 million to 34 million.

Speaker 3: Please be reminded that in that normal operating cost there are also linealocip costs, for example the 25 disease educators for linealocip that started on the 1st of August last year. So the overall cost for linealocip increased more than what you see here.

Speaker 3: They're going to the course category development. R&D in this picture declines, but I'd like to remind you that last year we had a one-off impact of 18.5 million, so we should deduct that from the 70 million to come to a like-for-like number. That one-off was related to OTR 105.

Speaker 3: IT costs just to strengthen the backbone of the organization with the growth that we foresee in the near future. We see a growth in marketing and sales costs.

Speaker 3: 26 million up from 59 million to 86 million almost and that was mainly in L'Annuelle L'Ocip and mainly in categories like marketing and market access development. The operating profits increased from 13.6 to 18.2 and that's the effect of the increase in the gross profits.

Speaker 3: And moving on to the next slide where you can see in a different way what happened to the profit before tax. Last year it was 23.1 million. We had some one-off costs in 2021, again due to LTL 105 and some impairments.

Speaker 3: So you could argue that the like-for-like profit before tax last year was 43.1 million. So what happened in 2022 starting from that base? We grew the gross profit by 10.3 million. As I said, the R&D expenditure was relatively flat, although within that pot...

Speaker 3: There were quite some changes. So we increased the investment in Lenny Ellis hip we increased the investment in OTL 105 We had more cost for a ki and cattle the program that we have stopped by now, so that will reduce in 2023 and we reduce the cost in 2022

Speaker 3: on Pompa and on the COVID R&D.

Speaker 3: Pompa and on the COVID R&D.

Speaker 3: So a mix of things and I think a good reflection of our strategic intent.

Speaker 3: So a mix of things and I think a good reflection of our strategic intent.

Speaker 3: Increased G&A expenditure was mainly as I said because of payroll, additional people and IT costs and the marketing and sales was largely driven by Lenny Od cruise ship.

Speaker 3: See again the bioconnexion transaction result and a decrease in the financial results and hence we come to a profit before tax of 15 million in 2022.

Speaker 3: Not on this slide, but important for those who are modeling. You will see that we have a low effective tax rate in 2022. It was only 9% versus 31% the year before, so that's very positive.

Speaker 3: The reason for that is that the gain on disposal on the BioConnection transaction was tax exempt.

Speaker 3: reason for that is that the gain on disposal on the BioConnection transaction was tax-exempt.

Speaker 3: The cash flow development on the next slide please. We started off the year with 192 million of cash. The operational cash flow was plus 22.9 with working capital almost flat during the years and no cash outflow.

Speaker 3: The investment cash flow was largely related to two items, CapEx in both PP&E and software, but very limited, it was only 2 million in total, and incoming cash from the bioconnection transaction.

Speaker 3: The cash flow from financing activities was largely related to interest on the convertible and some regular lease costs. We had negative exchange rate effects on the cash and we ended up with a cash and cash equivalent balance of $50 million more than we started the year with at $207 million.

Speaker 3: finishing the year at 207.3. We can confirm that we have full access to all of this cash or our cash deposits.

Then on the next slide, the outlook for 2023, we continue to see low single digit growth for recognized revenues.

The key event for 2023 is obviously the developments on Lanyola SIP. So we expect a US FDA approval in the first quarter. In fact, it's 13 days from now. The PDUFA date is the 29th of March and the US.

Launch and commercialization will start shortly after it In the first half of this year. For the EU we expect a positive CHMP opinion from EMA in the second half of this year and a marketing authorization for Europe that will follow two months later

For the UK we will file afterwards, after the EU approval with the UK's MHRA, following the European Commission Decision Reliance procedure.

To accelerate future growth, our investments mainly in Lenny Olesip will continue to impact profits in 2023 as you have seen in the previous slides that I've showed. We are working hard on lifecycle management for Lenny Olesip.

the new indications besides for APDS. Further details on our plans to develop Leneosib in additional indications will be provided in the second half of this year.

And as Simon said, we continue to look for potential in-licensing and acquisition opportunities and focusing on late-stage developments and assets in rare diseases.

So overall we've had a good year, we've had sales growth, we've had an increase in operating profit, we've had good cash generation and cash in excess of $200 million. And we are 13 days away from the Lenny Elliship PDUFA date.

With that, I would like to go to the next slide and open up for Q&A with my colleagues Simon De Vries, Anurag Raland and also our CCO Stephen Taw. Thank you very much.

With that I would like to go to the next slide and open up for Q&A With my colleagues Simon de Vries, Anne Raghuram and also our CCO Stephen Taw. Thank you very much Thank you

If you would like to ask a question, please press style followed by 1 on your telephone keypad. If for any reason you would like to remove that question, please press style followed by 2. Again, to ask a question, please press style followed by 1. As a reminder, if you are using a speakerphone, please remember to pick up your handset before asking your question. Our first question today.

comes from the line. Altusuja Hernandez from Kempen, please go ahead. Your line is now open.

Thank you for taking my question. I just have two questions. The first one on Lenio Unisip. So you have identified now more than 500 patients with a confirmed APDS diagnosis. Can you comment on what a realistic target is for the number of patients that you can identify and that can receive Lenio Unisip once approved? And could you also provide an update on your reimbursement discussion? Thank you. Thank you.

I missed the first part of the question. On the potential numbers. Well, Sheila, the, I think you're referring to the label is now 12 and upwards, right? So we've started our first periodic trial. And I'm looking here at anorak. I think it's about 25% of patients are below 12 years of age.

So they would initially not qualify for treatment until such time that we have the pediatric approval in our hands. Furthermore, I think all of the other APDS patients, we have not seen so far APDS patients that would not qualify for treatment, because the diagnosis is made by this genetic test.

And that's basically a yes or no answer. It's pretty clear in that respect. And there's a small number of patients, of course, that have already been transplanted, some of those successfully, so those also would not qualify. But again, the vast majority of the other patients that Simon mentioned would potentially be eligible for treatment.

And then with regards to your second question about reimbursement, obviously these discussions are relevant for the European, for outside of the US. Those have not started because we had, we don't, we're not approved yet and in Europe normally speaking those discussions start after you have the approval for the product.

in the United States. We will be bringing Leniolyship to the market as soon as possible after the due date and will of course inform the market about the pricing in the United States as and when.

Okay, thank you. And then just one more question.

Yes, thank you. And just one more question. When can we expect to see additional assets entering your pipeline via internal projects or in licensing acquisitions next to a second indication for a lineal lip or your gene therapy candidate?

Yeah, so basically the secondary indication of the second half of this year will be informing the market about that. And with regards to in-licensing and acquisitions, we're very active. We have a small but very efficient business development group turning over a lot of incoming assets.

that we get offered, a slash that we find ourselves. We've had evaluation in several stages. We've done a few due diligence even over the last year. And of course, as you can see, nothing had resulted in a deal. So until such time, you know.

we keep working, beavering away at it and trying to find those assets that fit our portfolio. And we're really looking for serious rare diseases. I think Leniolycip is a very good case in point where we are very comfortable to take a phase 3 risk because Leniolycip, we only could look at the first cohort of patients.

that had to undergo the dose finding study and the phase 3 study was ongoing. We're very comfortable with that, provided that we have a good clinical proof of concept in our hands when we actually start to engage with the asset. Our preferred mode obviously for this is in licensing.

as we are still a relatively small company. And of course, name licensing transaction is much easier to handle than mergers and acquisitions. Especially of course when you are launching a product like Lenio di Sip that we do with Lenio di Sip this year, which requires a lot of our focus.

are still a relatively small company and of course an in-licensing transaction is much easier to handle than mergers and acquisitions. Especially of course when you are launching a product like Lenny Olesip that we do with Lenny Olesip this year which requires a lot of our focus. That answer your question Sushila?

Yes, that's clear. Thank you. Thank you.

that's clear. Thank you. Thank you. Thank you.

The next question today comes from the line of Joe Panginis from HC Wainwright. Please go ahead your line is now open. Hey guys, thanks for taking the questions. So, just looking at some of the internal workings of the company and the decisions that you're making. I've been covering you guys for a while, so now I've been also sort of BC and AC.

RukaNest was looking to expand into preeclampsia and AKI. So I'm just wondering what percentage of your decision factored into sort of the projected needs for RukaNest in HAE versus your ability to expand your current rabbit populations for any needs. Yeah, yeah, thanks Joe.

So the answer to that is that there is more than sufficient production capacity, manufacturing capacity in the Revit platform to serve Eritrea and Geodema and even has significant growth possibilities. It is a very flexible system. It takes a while to upscale, but it is a very flexible system and it is a very flexible manufacturing process. It takes also a while.

It's a complex manufacturing system, but it really has the capacity to actually deliver a lot more products than we currently deliver. So if we were to get a significant increase in market share in heritage in JIMA, we could actually master that.

That's great. And then just curiosity with cattle, is there any potential here to monetize the platform that you already have in place? No, unfortunately we came to the conclusion that there is no significant possibility to actually monetize that.

and therefore we have halted all the activities there.

It's a different product. Yep, absolutely. And I guess for your own, you know, obviously you said, you know, profits might be impacted further based on further investments in LenioLysib. So I'm just curious how much of that is, you know, the new indications that you'll give visibility on for the second half of this year versus, you know, where

just to support the launch in the EU and in the US obviously. On the lifecycle management, we hope to start with a clinical trial, for example, by the end of this year, but it will depend on the design of the trial, how much money we need to put into that, and probably for 2023.

that impact will be fairly limited because if it happens it would be towards the end of this year anyway. So the impact of that would be more in 2024 than in 2023. We foresee an increase again in the marketing and sales costs for Lenny Ellison.

Got it. Thanks a lot, guys. Good job. Thank you.

The next question today comes from the line of Hartaj Singh from Oppenheimer. Please go ahead your line is now open.

Great, thank you, and thanks for the questions. Really nice update. We missed you all at our healthcare conference, but glad to hear your voices over the phone today. So, you know, maybe just talk a little bit about the 500 patients. There's a question before.

I just want to build on that a little bit. You've estimated about 1,500 patients as your market opportunity. You've already identified 500. How do you think Simon off just the overall opportunity sort of you know the incident patient the prevalent patient I mean you think that

that 1500 is now a reasonable figure, or do you think it could be larger? And I just had a follow-up question after that.

You want to? Sure. So we've, you know, when we look at the prevalence, and we have good data, for example, in some European countries, if we take France, for instance, where there's already 60 patients identified in a country that's a population that's about 60 million. So we know the minimum prevalence.

Again, really without our involvement and without a therapy being available is about one per million. So we've conservatively estimated about one to two per million in terms of the prevalence and that's where that 1,500 number comes from. Now, as we've been out there talking about the condition, obviously we're finding more and more pain.

So I think as you know and then hopefully we can have a therapy available for these patients soon, but once such a therapy is available I think that will drive even further diagnosis. I think we're fairly right now with the estimates that we're providing in terms of the prevalence.

But certainly, I don't think it would surprise any of us if the numbers were significantly higher.

That makes sense, Anwar. Just from being at ASH and talking to positions and whatnot, that's our sense also in doing our call check. Just another question, got to ask the obligatory regulatory question. I know you're very close to the approval, but just where are you in terms of any vo-fi information over just one layer, and finally all of a sudden what lots

regular contact with FDA and that contact includes the routine types of things including inspections, audits, as well as labeling discussions that are occurring.

Great, thank you everyone. Good luck and good talk. Thank you, Alex. Thank you. As a reminder, if you would like to ask a question, please press star followed by one on your telephone keypad. The next question today comes from the line of Christian Glenney from Stiefel. Please go ahead. Your line is now open. Hi, good afternoon, guys. Thanks for taking the question.

Let's start with Rook and S, just to get an idea about the 3% growth last year in the US. The price versus the volume mix in terms of what was driving that and what your expectations are for 23.

We stated that we took a price decrease below the CPI, that's our normal modus operandi over the years. I think the price increase, of course, is...

the biggest driver of this growth. So you could say that the underlying volume growth is more or less flat to slightly, maybe going up or down, and there's some quarterly fluctuations there as well. But I think that's how you should see that. So it means that the Nucleus continues to basically be prescribed.

by a wider audience of physicians. We think that's important. As I was saying in my earlier part of the presentation, also used by more patients and used by more prescribers, reflecting the fact that there is a continued need for this product.

in terms of especially the breakthrough attacks that continue to occur under all the prophylactic treatments that are available on the market. And yes, some of them have improved significantly from the past, but no, patients will always need and always have acute treatment at hand.

to be treating that unexpected breakthrough attack.

Do not forget this is a stress related disease and people can be very nasty surprised by breakthrough attacks.

Does that answer your question Christian? Yeah thanks and a similar outlet for 23 in terms of that price. Yeah. Okay and then on Lenulisib then a couple here so just on the 500 patients.

You've already said, yeah, it took about 25 minutes under the 12 years, but what's the rough Sub split of the 500 in terms of the US and Europe

Steven, would you like to comment on that? I would, maybe I can take that one. So I think they're about equally distributed. Yeah. Now we have a gun check. Yeah, so I will also comment that...

A lot of the work that was done in finding patients was actually initiated in Europe through this group called the European Society for Immune Deficiencies. So they have done a lot of the work and in the U.S. there wasn't such a coordinated effort. So we're a little bit behind in terms of the process.

But we're quickly catching up, I think, in the US in terms of disease state education and finding patients. So it's fair to say that Europe had a head start right on this whole thing. Exactly. But we're getting there. We're getting there in the US. Yep.

Sorry, but just to clarify, I think I thought the 500 just Europe and US or I think it included some other markets maybe or not. No, it does include other markets. I was saying that amongst the if we look just at the US and Europe alone, they're about an equal number. There's more than five on the right now, right? That is well, yes. Because I'm on Anishinaabe, I'mmi posting as pointed as US or just six 6 6 6 6 is notams

Okay, and then on the EMA side, obviously you had the initial shift from accelerator to standard review. The way you described it at the time was obviously further data from the openable extension.

Is that subsequent interaction with the AMA, is that still the case? I mean, is there anything additional thrown up there? There's been no change there. We're collecting that additional year of data and intend to provide it to EMA in our responses. We're still expecting an opinion from the CHMP in the second half of this year.

And finally, if I may, in terms of thinking about, you know, a bit on the modeling side, I mean, obviously, you know, obviously, the nature of the agreement with Novartis is probably confidential, but an idea of the potential milestones that might be applicable to Novartis on FDA approval.

and to what extent that might actually be offset by them exercising the option on the priority review voucher that they should get. Just a bit of any insight you can give us there would be helpful.

Yeah, happy to do that and give you some guidance. I think for modeling purposes it's probably a pretty neutral operation.

Okay, so the PRV might offset the milestone.

Okay, so the PRV might offset the milestone. Okay, along those lines.

Thank you. Thank you. There are no additional questions waiting at this time, so I'd like to pass the conference back over to Simon De Vries for any closing remarks. Please go ahead. Thank you very much. Yes, ladies and gentlemen, as we were referring to, we had a very good year 2022.

We laid a very good base for transferring our company from the one product, one geography company into two products, multiple geography company. We believe that LenioLicep has a very significant commercial potential.

significantly larger than the RQNest franchise. And of course we're very proud what we have achieved and continue to achieve with RQNest, which is of course a very strong supporter and foundation and cash flow generator going forward. And we believe also that.

the high hurdle to entry, the complex manufacturing of the recombinant C1S trace inhibitor by means of our trigenetic platform will therefore mean that it will be for the significant period going forward, RQNES will continue to create those cash flows.

that enable us to invest in all these plans, including many secondary indications and also in licensing of additional assets to actually start launching products on a very irregular basis going forward. Because the other nice thing is we are...

having a very nice and scalable commercialization operations on both sides of the ocean and therefore we can easily handle additional assets for commercialization over the coming years.

So we look forward to catching up with you later in the year when we have the next set of results available and continue to embark on our journey into 2022, the important transformative year for the company. Thank you very much for attending this conference and like I said, we look forward to seeing you again.

to updating you on the next occasion. Goodbye. abstract audio

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