Good afternoon, and welcome to our 2026 Investor Day. I'm Fabrice Chouraqui, the CEO of Pharming. We are very excited that you're all able to join us, and I really hope that you'll be able to learn more about Pharming and specifically about our financial guidance for the year, as well as our high-value clinical stage pipeline programs. We are going to make forward-looking statements during this presentation, and here are our disclaimers. I also want to remind you that this presentation is intended solely for an investor audience. As you can see on the agenda, we'll have three sections. In the first section, we'll provide a short business and financial update during which we'll cover our financial guidance for the year. Then we'll have two longer sessions dedicated to our pipeline, one on leniolisib in high-prevalence PIDs, and the second one on KL1333 napazimone.
As you can see on the agenda, we have planned for a section with a Q&A at the end of each of these sections. So in just a few years, as you can see, Pharming has transformed from a single-asset company into a fast-growth biotech with two commercial assets growing each double-digit and a late-stage pipeline with two programs with over $1 billion sales potential each. RUCONEST continues to grow after 10 years on the market, and it is poised to remain the on-demand treatment of choice for difficult-to-treat patients because of its mechanism of action. It replaces the missing or deficient C1 esterase inhibitor protein and its IV administration, which provides [audio distortion] patients with the reliability they need as they suffer from more frequent and more severe crises.
RUCONEST is also a product which is produced from the milk of transgenic rabbits, which makes its manufacturing process complex and difficult to replicate. Our second commercial asset, Joenja, is just at the beginning of its lifecycle with multiple growth catalysts that will drive further growth acceleration. While we are disappointed in the FDA response to the submission of our pediatric label expansion in APDS, we are committed to bringing Joenja to this population with significant unmet needs, and we are going to request a Type A meeting, which should be scheduled in March. Joenja has also many other growth opportunities in APDS. The data published in Cell in June last year suggests significantly higher APDS prevalence and also the potential to reclassify about 250 VUS patients as APDS over time.
And the expansion into larger PIDs and CVID, which will be the focus of the second session today, could unlock a much larger market. KL1333 or napazimone for primary mitochondrial disease, which is the other pipeline focus of today, is another billion-dollar-plus opportunity. The program is in a pivotal phase II and has cleared a futility analysis on both primary endpoints. So as you can see, this combination of durable revenues, strong growth drivers, and a high-value late-stage pipeline positions Pharming well for substantial value creation in the near term and in the long term. With this portfolio and pipeline as the foundation, we are now committed to leveraging our strong rare disease capabilities to build a leading global rare disease company with a broad portfolio of rare and ultra-rare drugs and deliver on our vision.
Our two commercial assets perform extremely well in 2025, providing the foundation for our strong financial momentum. We announced primary 2025 revenue of approximately $376 million, an increase of 27% versus 2024, slightly exceeding our already upwardly revised latest guidance provided in November. With this strong revenue growth and our commitment to cost discipline, we achieved significant operating profit and operating cash flows as we stated in our latest financial report in Q3 2025. I will now ask our Chief Financial Officer, Kenneth Lynard, to elaborate on our financials and provide an overview on our 2026 financial guidance.
Thank you, Fabrice. 2025 was a strong year, and I'm happy to provide more insight into our financial performance as well as our guidance for 2026. Before doing so, let me remind you that our financial data for 2025 are preliminary and unaudited. Final results may therefore differ and will be reported during our earnings call for the fourth quarter and full year 2025, which we will be hosting on the 12th of March, 2026. During that call, we will get into further details on the performance of the fourth quarter of 2025. Let me here start by drawing your attention to the right-hand side of this chart, really calling out the strong and accelerated growth in 2025. As Fabrice already mentioned, we were growing 27% over the previous year, 2024.
And I'm also happy to now provide the breakdown by-product, starting with RUCONEST, who continued to perform very strong, reaching $318 million in annual revenues, a growth of 26% over the previous year. Joenja grew 29% and delivered $58 million of revenues in 2025. Thereby, we exceeded the $50 million revenue level, triggering the first $5 million milestone payment to Novartis. In our financials, this milestone payment is booked as part of cost of goods sold. For 2025, we expect the gross margin around 88%-89%, excluding the $5 million milestone payment to Novartis. As earlier communicated, we are expecting our operating cost for 2025 within the guidance range of $304 million-$308 million, excluding the one-time restructuring cost of $7 million linked to the structural G&A cost reductions that we announced in October 2025.
Finally, at the end of 2025, the company had $181 million total in cash and marketable securities. Let's now look into the financial guidance for 2026. For 2026, we expect total revenues between $405 million-$425 million, implying full-year growth over 2025 of 8%-13%. The growth is expected driven by mid-single-digit growth for RUCONEST, including continued U.S. volume growth, partly offset by decline in ex-U.S. revenues associated with our exit from these markets, and furthermore, significant growth for Joenja. Our guidance for 2026 compares favorably to analyst consensus guidance, which is approximately $398 million. We see the Joenja growth accelerating with annual growth around 10 percentage points higher, give or take, than in 2025. We continue to see the pediatric APDS indication as a growth driver for Pharming.
However, until we have greater clarity on the revised timeline for Joenja U.S. approval for pediatric age four to 11, we have conservatively removed any such revenues from our 2026 guidance. With Joenja revenue not assuming to exceed $100 million, we are not assuming a commercial milestone payment to Novartis of $10 million that otherwise would have been booked in cost of goods sold. Also aligned with our ex-U.S. commercial rollout plans, we do not assume any other milestones payable during the year. In 2026, we expect total operating expenses between $300 million-$335 million. This assumes more than $60 million incremental R&D investments to advance our pipeline and includes the $9 million favorable impact of the structural G&A cost reductions that we were announcing in October 2025, as well as stable marketing and sales spend.
In 2026, we will continue our strong financial discipline and prioritize our investments into areas that matter the most to spark near and long-term value creation. We estimate for 2026 our cost of goods sold to approximately 10% of revenue, or in other words, a 90% gross margin for the year. Finally, we continue to expect that our available cash and future cash flows will cover investments in the current pipeline and all related pre-launch costs. With that, we will now open for the first Q&A section.
Hi. I'm Michael Levitan, VP Investor Relations and Corporate Communications at Pharming. Analysts and investors are welcome to ask questions during this session. Covering analysts, please feel free to raise your hand to ask a question live or use the Q&A button to type a question. Investors, please feel free to use the Q&A button. We will do our best to get through as many questions as time allows. We'll now take our first question from Joe Pantginis at H.C. Wainwright.
Hey, guys. Can you hear me?
Yes.
Oh, great. Okay. Thank you. So look, it was an unfortunate event to get to CRL, but I think the FDA asked some very important questions. So with regard to the exposure data, are these data that you have in hand that you need to provide analyses for, or do you need to, say, conduct or do you anticipate conducting an early I'm sorry, an additional study to look at these? So I just wanted to get some sense there. And then with regard to OpEx expenses, thank you for all the details there. Do you feel that the company is right-sized currently with regard to sales and marketing? Thank you.
Joe, thank you so much for your question. When it comes to the recent FDA feedback, we have a wealth of data at hand, and obviously, we are planning to engage with the FDA at this forthcoming Type 2 meeting. There is a possibility that the data that we have will satisfy the FDA. Now, it's too soon to speculate before we have this meeting, and so we'll be able to update you on the course of action after the meeting takes place. When it comes to our cost structure and specifically our marketing and sales cost structure, we have the right level of investments behind our products, and we do not intend to increase that investment in the near term.
Thank you.
You're welcome.
Our next question comes from Jeff Jones at Oppenheimer.
Good morning, guys. Can you hear me?
Yes.
Great. Just if you could provide a little bit more color on RUCONEST, you commented on single-digit growth and [I'm] interested in how much of that could be driven by sales price increases versus patient numbers, and then a little more on the dynamics, if you could, U.S.-EU as you see that play out having come off the market in Europe.
Absolutely, Jeff. So as I mentioned, really, RUCONEST is poised to remain a cornerstone treatment for difficult-to-treat patients. And as such, we believe that the drug will continue to grow in value as well as volume. We've taken a 3% price increase this year, and we expect also to see volume growth beyond this price increase. It's actually important to note that that price increase was in line with CPI, not above. When it comes to where the growth will come from geographically, all the growth will come from the U.S. That's clearly the goal.
Thank you, Jeff. I have a question in from Lucy Codrington at Jefferies. Lucy is asking how much of the incremental growth comes from VUSs versus new geographic launches.
Thank you so much, Lucy, for this question. An important point of clarification, indeed. As you know, we have to be harmless when it comes to letting the clinical genetic testing company work with the author of the paper. And as a consequence, it is very difficult to predict when the reclassification of those VUS patients as APDS patients will start to become effective. As such, we took conservative estimates to take out any VUS patients in our current guidance. And as we see the progress, we will obviously update the investor community.
One more question that came in from Lucy was KalVista has talked about switching of RUCONEST patients. Have we seen this in our data? Do we anticipate switching in our guidance?
We have seen, actually, a few switches. Some patients on RUCONEST are so-called mild patients, and it is absolutely normal that they wanted to try an oral drug. We've also actually heard anecdotal evidence of some of those patients coming back to RUCONEST. However, we haven't seen any significant change, and the bulk of the patients who are on RUCONEST, as you know, RUCONEST is not a treatment that you take by choice. It's a treatment that you take because you need. And the majority of patients who are treated with RUCONEST have already failed other on-demand treatments. And if they are actually well controlled on RUCONEST, they often really want to stay on this drug, which, to their words, often have given their life back.
Great. Next question comes in from Angela Qian at Canaccord Genuity. Angela, please go ahead.
Hi, guys. Thank you for taking our question. I'm on for Whitney this morning. But maybe just another question on the CRL. Can you just give us a bit more color around the underexposure concern in the lower-weight PIDs patients? Remind us what the dose is and what the weight cutoff that was of concern. And how confident are you guys that you already have that PK data in hand?
Thank you, Angela, for this question. I'll let Anurag actually elaborate. It is true that the concerns raised by FDA are specifically related to the lowest two doses, 20 mg and 30 mg. Anurag, would you like to comment?
Sure. So again, the doses that we're referring to are the 20 mg and 30mg doses that apply to children who weigh less than 27 k. Now, we actually have efficacy data in both of those dose groups showing comparable efficacy across doses. So children who weigh more or below 27 kg we see similar efficacy, including those treated with the 20 mg and 30 mg doses. So we are confident that we'll be able to share this data with FDA. And of course, we will share and review the PK concerns that they have raised and be able to address this. I think we'll be able to speak much more confidently after the Type A meeting we have, as Fabrice mentioned, which we expect to take place in March.
Great. I think we have time for one more question in this initial section. A question coming in from Chiara Montanari on behalf of Sushila Hernandez at Van Lanschot Kempen. What do you note for the launch for the first oral HAE treatment? Any color regarding the positioning of RUCONEST?
I think what we've seen prior to the launch and after the launch is that it's a confirmation that RUCONEST is very well entrenched in a subpopulation of the on-demand market. RUCONEST is a treatment of choice for these hard-to-treat patients, those patients who have more frequent crises, more severe crises, often life-threatening crises, patients who need the reliability of a treatment to address their crisis rapidly with only one dose. And so that has been the consistent feedback that we have received. And that's why we believe that over time, RUCONEST is poised to remain a cornerstone treatment of choice for those difficult-to-treat patients, which account for about 20%+ of patients treated with on-demand therapies.
Good morning. I am Anurag Relan, Chief Medical Officer at Pharming. I'm very excited now to begin our presentation on our pipeline, which will be the focus of today's session. As you see, the pipeline has evolved significantly over the last couple of years. First, we have the addition of two new phase II studies with leniolisib being developed for the treatment of PIDs with immune dysregulation. Then last year, we added KL1333, now formally napazimone, being developed for the treatment of primary mitochondrial disease, both of which we'll be speaking about next. We're also moving forward on APDS. As mentioned, we are seeking a Type A meeting with FDA to discuss the path forward to bringing leniolisib to children with APDS between ages four to 11.
In addition, I'm very pleased to announce that we have now completed our responses to all outstanding questions with the EMA and expect to receive approval in the first half of this year. Lastly, we continue to make progress with bringing leniolisib to Japan and other countries across the world and expect further approvals for 2026. The two phase II studies I just mentioned are on track for readouts in the second half of this year. And napazimone, in our registrational phase II program in PMD, is active with more than 20 sites up and running, recruiting patients, with enrollment expected to complete this year, which will enable a readout in late 2027. Here is the agenda for our first program that we'll be covering, beginning with the unmet need and then onto the science of the PI3K pathway and the role it plays in immune cells.
And here is an overview of the diseases that we will be discussing today. Specifically, we'll be talking about primary immune deficiencies with immune dysregulation, with an emphasis on common variable immune deficiency, or CVID. APDS, in fact, is often classified under the CVID umbrella. And the experience with leniolisib in APDS serves as a proof of concept, in fact, to treating the broader CVID population. And with that, it's my great pleasure to introduce Dr. Jocelyn Farmer next. Dr. Farmer earned her MD and PhD in microbiology and immunology from the University of Michigan. She completed her allergy immunology fellowship training at Mass General. And then she pursued postdoctoral research at the Ragon Institute of Mass General, Brigham, MIT, and Harvard, where she studied the PI3K pathway and its impact on signaling in B-cell biology. In 2023, Dr.
Farmer was recruited to Beth Israel Lahey Health as Director of the Clinical Immunodeficiency Program, where she now cares for a large and complex population of patients with PIDs. That same year, she founded the New England Immune Deficiency Consortium to enable collaborative clinical research across broader patient cohorts. She established her own research lab focused on B-cell biology in CVID. This work, in fact, led her to propose exploring leniolisib in CVID based on these research findings, suggesting a shared disease mechanism between APDS and CVID. We are very fortunate to have Dr. Farmer with us today to share how leniolisib may help transform treatment across these conditions. And with that, I'll turn it over to Dr. Farmer.
Good morning, everyone. I'm thrilled to be here. So I'll be speaking to you on leniolisib transforming treatment of immune dysregulation in primary immune deficiencies. Here are my disclosures. Okay. So why am I here specifically speaking to you today? That was a wonderful introduction and a whole litany of degrees that I have in immunology. But I think the top reason that I am here today is the last comment that was said. And this really came about from physician scientists who both were treating patients with CVID, which in the rare disease space is the most common primary immune deficiency we see worldwide. And we didn't have great treatments for these patients. And we started to see a lot of parallels, both between the clinical presentation of these patients in APDS and the underlying biology. And that's what I'm going to speak to you about today. All right.
Primary immune deficiency, that's a little bit of a complicated term. Let's step back from that. What is PID or primary immune deficiency? Deficiency really suggests low. I want everyone on this call to take a pause and reinvent that term, okay? I want you to leave here today thinking about primary immune deficiency as more of an unbalanced immunity. On one side of that, patients can get really terrible, frequent infections. But on the other side of that, they can also have a break in their immune tolerance. This can lead the immune system to actually attack our own bodies. That can be very hard for a patient both to deal with clinically and to understand. Immune deficiency today, we're going to equate that to this unbalanced immunity. Now, what comes in the door in the clinic?
So in terms of primary immune deficiency, this is a nice pictorial diagram from our European colleagues. The most common one that we see in the clinic is called predominantly antibody deficiency, or PAD. That's that large patch of blue that you're observing in the circle. So it's most patients that we see in the clinic. Now, APDS sits right up at the top. It is a very small cut of that blue circle. So it's amazing that we have now leniolisib. But in terms of the number of patients that come in my door on a day-in and day-out basis, I want to be able to treat a much wider cut of patients. So again, CVID is at the bottom of that blue circle. It is the most common primary immune deficiency in the world.
So I would love, as a clinical immunologist, to be able to broaden from APDS to potentially all patients with CVID who are suffering from similar complications and don't have a single FDA-approved therapy for their care. Okay. So that's what PID is. Now, why should you care about it? And I hope you do when you leave this call. All right. So first, I want to highlight there are no FDA-approved therapies. This is really fresh snow when you think about a therapeutic space. Patients with immune deficiencies do get recurrent infections. And we have good treatments to manage that. We have antibody replacement therapy that is FDA-approved. We can use antimicrobials to treat their infections. We're doing pretty well as clinical immunologists here. And we can pat ourselves on the back. But where we're really falling short for our patients is the second side of their disease course.
These patients can get really catastrophic, life-threatening autoinflammatory disease. It can impact their lungs, so they can't breathe. It can impact their gut lumen, so they can have wasting to the point of needing supplementation to sustain their weight. They can have life-threatening liver disease. We really need better treatments in this space. We have no FDA-approved therapies. And quite excitingly, hopefully to this audience, there are no products currently in development except for leniolisib. Again, this is fresh snow. Okay. So the second part of this is that patients with CVID who experience that other side of the disease spectrum, in orange that I presented on the last slide, have an 11-fold higher risk of death. It matters. So I'm going to show you that in two large cohorts. On the very left-hand side of your slide, this is the New York CVID cohort.
In the dotted line, you're seeing patients with those non-infectious complications compared to the solid line without. In the middle graph, you're looking at Germany's CVID cohort. Again, the blue line with those non-infectious complications compared to the orange line without. You can see a clear difference there, right? So 11-fold higher risk of death if you have those non-infectious complications. The patients themselves report a worse quality of life with those non-infectious complications. That's what I'm showing you from our cohort on the very right-hand side of your slide, so mental health being worse with those complications. You don't have to take it from me. This is what patients with CVID say. This is a quote from one individual that I'm currently treating.
And she writes, "For decades, I faced the systemic complexities of CVID without the benefit of any approved therapeutic treatment. It was a lonely and depressing predicament knowing that my organs would never last long enough to see my sons grow up and perhaps make me a grandmother." So there is an urgent and an unmet need in this disease space. Okay. So that's the downside, the depressing side of it. So can we do better? And I think that's what we're here to discuss today. So can we apply clinical lessons from APDS, this rare disease, and expand it into CVID? So CVID is an umbrella diagnosis. So we use these diagnostic tools. And I'll go through them. First, low antibody levels. So these are patients who have vaccines just like you or I, but they can't get a protective benefit from those vaccines.
So low antibody levels, impaired vaccine responses. And I have to make darn sure they don't have a secondary cause that's driving that. If a patient fulfills those diagnostic criteria, then yes, I can call them CVID. But in fact, there are a lot of different varieties of disease that live underneath that broad umbrella. So as was mentioned before, a patient with APDS might fit these diagnostic criteria. And these are the genes associated with APDS. There are also genes that link to the PI3K pathway, examples being CTLA-4 or NF-κB1 that they will go through in detail in a moment. And those as well can live under this diagnostic umbrella. And finally, a patient can present to my clinic, and I cannot frustratingly find the genetic cause. And yet, they fit under this diagnostic umbrella.
So the take-home is that the clinical spectrum of CVID and APDS commonly overlap. Okay. We have done genetic sequencing in CVID cohorts. And this is one example of it. And when I genetically sequence those patients in fact, I do find APDS. And that's in the yellow at approximately 4%. I also find those APDS-linked genes, those PI3Kẟ-linked genes. That's about 20% of the patients. But the vast majority of the patients in blue still have no known genetic cause. And we've done a systematic literature review of this. And across all published studies, only about 20% of patients will leave the clinic with a genetic known identity, meaning to treat 80% of individuals with CVID who have these complications, we have to move past this to a functional understanding of how these diseases are similar. Okay. So let's step back.
Do the patients look the same? Well, yes, in fact, they do. Both CVID and APDS will present with frequent infections, a lot of time ear, sinus, lung infections. They as well will have enlarged spleens and enlarged livers. They as well will have autoimmune diseases, very commonly autoimmune cytopenias. They as well will have terrible GI complications and very frequent diarrhea. They as well will have enlarged lymph nodes that can progress to something like lymphoma if it's not caught early and managed appropriately. And they can have non-infectious lung complications such as lymphointerstitial lung diseases or bronchiectasis. So yes, these diseases look very similar when the patients come into the clinic. So Pharming asked us to study this. And these data were presented at an abstract at last year's CIS meeting.
What we did is we took about 1,000 of our patients who we follow at the New England Immune Deficiency Consortium. They asked us, "Of these patients, who looks like APDS, who is with an APDS endotype, if you will?" So it turned out that about 75% of patients with CVID look a whole lot like APDS. We now confirm that APDS disease spectrum does clinically overlap with CVID. Moreover, we now know the end organ manifestations within CVID to go after for a phase II clinical trial. This is critically important. The two diseases share enlarged spleen and large lymph nodes. Splenomegaly and lymphadenopathy look like good endpoints. As well, they share cytopenias, inflammatory lung disease, and inflammatory liver disease. Okay. That's the clinical spectrum. Now let's get into the biology. I am by trade a B-cell biologist.
So can we learn these similar lessons between APDS and expand that into CVID? So I want you to think about APDS like a thermostat in the B cells and the T cells, the lymphocytes of the bodies, your immune cells. And the thermostat is just set too high. So in every single cell, it is on. And this is where we have the improved indication for leniolisib. In the middle column, I want you to think about these PI3Kẟ-linked conditions. And here, the thermostat doesn't start always on. But there's a faulty wire. And so the signals coming in or around it drive it up. And it makes a lot of sense then that we could use a similar drug target in this disease space. And this will be one investigational phase II trial that will be discussed today.
In the last example of CVID, I'm frustratingly not going to come up with a single gene entity in, again, about 80% of the patients that I am treating. But I still need to treat those individuals. They deserve better care. So as well, we're asking, if it looks like APDS and walks like APDS, but we can't find the gene for APDS, can we treat it like APDS? Okay. These are some published data that have just come out in the last year to two years. These data really start to suggest that we can. This is going to be a lot for you who are following along in your screens. I just want you to pay attention to the highlighted boxes that I go through. These are B cells that I've pulled out of your or my blood, healthy controlled blood.
They look fantastic to a clinical immunologist. You see nice maturation. You see no activation. Take my word for it, okay? We then move into CVID. And it is only the patient with CVID who has those end organ complications where you're all of a sudden picking up cells in those blue boxes. These are your activated B cells. And I'll show you in the next slide, these are the B cells that drive autoimmunity and end up causing disease in the end organs of the patients. And lo and behold, as we go through PI3Kẟ-linked B cells and straight into APDS, those B cell plots start to look a whole lot similar. So there is a shared B cell pathology in these patients. Moreover, if we look at the gene signatures that define these pathologic B cells, lo and behold, we PI3K and mTOR signaling.
So these aberrant cells, these cells that we do not want in your or my body and we don't see in healthy controls, are expanded in the patients across CVID, PI3Kẟ-linked conditions, and APDS. And they share an enrichment for PI3K and mTOR signaling. Moreover, these are, in fact, the cells where we see a break in B cell tolerance, meaning these are the cells that are driving autoimmunity in the patients. And you can see that here as that red line expands. These are just the CVID patients who have autoimmunity. And you can beautifully see that expansion of broken tolerance by the accumulation of a B cell receptor that shouldn't be there. Moreover, you can see those really nice dark connections in the APDS patient connecting all those pathologic B cell subsets downstream to that upstream break in tolerance.
So there is one bad player at the very start of B cell development that filters all the way downstream to cause disease. And in the last panel, we're showing you those B cells actually ending up in the lungs of the patients. All of that to say, if we can control that thermostat, that upstream point where these B cells start to go down a bad pathologic pathway, can we prevent, can we roll back that autoimmune disease? And we hope we can. Okay. So finally, if the clinical spectrum looks the same, if the B cell biology looks the same, can we actually use this drug in the CVID disease space? And we have now done this in a couple of cases of compassionate use care. So I'd like to share today a single experience of a patient that I'm managing. This is a 64-year-old female.
She has a diagnosis of CVID but no known gene defects. So she sits in that 80% of patients. When I met her, she had life-threatening comorbidities. So she was getting chronic infections. But she was actually dying of lymphocytes infiltrating into her liver, into her lungs. She had low cell counts. And so she was getting recurrent infections from this as well. She had small fiber polyneuropathy and a lot of dysregulation related to that. And she had a history of cancer as well. She had tried a lot of agents for her autoinflammatory disease. And I'm listing them here. And none of them successfully or sufficiently were controlling her symptoms. And there were a lot of other agents that we did not feel were appropriate to treat her with for risk of furthering her immune suppression and risking life-threatening infections in her case.
So I looked at her B cells. And what I'm showing you across the bottom is PI3K signaling. So to your right is more signaling. And to your left is less signaling. Your or my blood is represented by the dotted line. So this is where our B cells sit. And what I want you to appreciate is the patient in blue had as much or even higher phosphorylation signaling as compared to APDS. And I presented these data to Pharming. And I said, "If she looks like APDS, please, can I treat her like APDS?" And they agreed. So we have now had her on therapy with leniolisib for approximately one year. So these are those bad B cells that I presented to you, okay? So you're seeing her in time across that axis. And you're going to follow her pretreatment in blue, posttreatment in green.
And what we've seen is that she's significantly reduced those bad B cells over the course of her therapy. Now, one further point, and this I have not seen in CVID to date. On a year of therapy, she has done something even more marked, which is that she has actually brought back the production of good B cells. And so in that first CISA I showed you, this is where we are starting to not just replace immune system or suppress immune system. This is where we are starting to balance immune system. And that is our goal in this disease. And I want to finish with her quote. She said, "leniolisib has given me hope that my immunological deficits can be stabilized and ultimately repaired. Dr.
Farmer and her zealousness, which I would agree with, to obtain compassionate use release of leniolisib has renewed my hope for the future and my longevity. Dreams can come true." Thank you. I will now introduce Dr. Rebecca Marsh.
Thank you, Jocelyn. That was an amazing presentation. I'm so thrilled that you were able to take time to be with us today for Research and Development Day. My name is Rebecca Marsh. I'm a medical director at Pharming. I will be speaking today about Pharming and how we are acting with urgency to unlock the full potential of leniolisib to transform care for immune dysregulation and primary immunodeficiencies. I will say that even though I am speaking here today, I am presenting on behalf of Kevin Thorneloe and our entire immunology development core team. This is a required disclaimer.
Leniolisib is being investigated for a new indication that has not been approved by the FDA or any other regulatory authorities. The safety, efficacy, and appropriate use of leniolisib have not been established for this indication. There is no guarantee that this product will successfully complete clinical development or receive regulatory approval for any new indication. I really wanted to open this part of the presentation by talking about our mission at Pharming. That mission really is to transform the care of additional PID patients with immune dysregulation. I'm a clinical immunologist and a bone marrow transplant physician. My entire clinical practice centers around caring for patients with only primary immune deficiency disorders. This is an area that's very close to my heart. Our mission to transform the care of additional PID patients is very well-founded.
It is supported by clear and significant patient need, as you just heard from Dr. Farmer. It is supported by a very strong scientific rationale. We don't have time to talk about it today due to time restrictions. We do have additional clinical experience from healthcare providers like Dr. Farmer who have requested single patient IND treatment access to leniolisib. We've actually treated five patients with CVID to date, most of them who have been on treatment now for over 1 years-2 years. The clinical trials that we've developed at Pharming really target PID disorders with immune dysregulation that's under the influence of PI3Kẟ. We don't have time to discuss all of the disorders that we're studying at Pharming today. We really are focused on those that share a common pathophysiologic disease mechanism or an endotype that you heard Dr.
Farmer speaks to and falls under the rubric of a CVID diagnosis. Those groupings of disorders you can see here include APDS, genetic PIDs linked to PI3K kinase delta signaling, and CVID with immune dysregulation. When thinking about these disorders, it's really important to think PI3Kδ is really a master regulator of the immune system. Sometimes we talk about PI3Kẟ signaling in a very simplistic manner. But it's actually really important to PI3Kδ is not only functioning in B cells. It's actually playing a big role throughout the immune system and regulates signaling of T cells, natural killer cells, macrophages, dendritic cells, also eosinophils and basophils. I could go on, but you get the point. It's also orchestrating the function within individual cells on a very large basis.
So PI3Kδ is sitting at the plasma membrane of immune cells and regulating or tuning the signaling of a whole host of immunoreceptors. These include not only important B cell molecules like the B cell receptor, but also the T cell receptor, co-stimulatory receptors like CD28. It's regulating trafficking receptors. It's regulating cytokine receptors like a JAK inhibitor would. And because of the big role that PI3Kδ is playing throughout the immune system, it's regulating a whole host of different functions, including cell trafficking, cell growth, cell proliferation, cell differentiation and function, apoptosis and survival, cytokine receptor signaling and cytokine production.
And so when you think about all of the roles that PI3Kδ is playing in the immune system, it becomes really easy to understand how any little bit of dysregulation or overuse and activity of pathways that involve PI3Kδ can lead to immune dysregulation pathology. And here we're specifically talking about the manifestations that Dr. Farmer already spoke to. So things like lymphoproliferation. So here we're talking about patients with big spleens, big lymph nodes, patients with autoimmunity, things in particular like autoimmune cytopenias, which can be life-threatening, gastrointestinal disease, of which there are many different flavors, pulmonary disease, particularly interstitial lung disease, which can be progressive and really convey a lot of morbidity and mortality risk.
Because we're focused today on these disorders that are grouped under this shared rubric of immune dysregulation that's under the PI3Kδ, I'm going to speak now to the clinical trials that we've developed in this space. All of you are very well aware that we've previously completed a phase III study in APDS, which led to the approval of leniolisib in APDS patients 12 years of age and older. That's important because, as you heard, APDS exemplifies a PID that's characterized by immune dysregulation. It really serves as a proof of concept model for understanding related disorders that we're studying. This is just to remind you about some of our data. Leniolisib is a first-in-class medicine in APDS. It really modulates or tunes down the activity of PI3Kδ.
What you can see here in the blue bar is a very beautiful reduction in the total sort of lymph node lesion burden in patients with APDS who are treated with leniolisib compared to placebo there in the small gray bar. A picture is always worth a thousand words. So you can also see in the two images shown here, very nice reduction in lymph node size from prior to treatment to after 12 weeks of treatment in a patient with APDS treated with leniolisib.
And because we've seen such a good efficacy in APDS, and remember that in APDS, it's caused by genetic variants that cause upregulation of function of the PI3Kδ enzyme itself, if we can have such a good effect in patients with constitutive activity, it stands to reason very logically that we can also address immune dysregulation in other patients who have pathophysiologic deficits in the way that the pathways are all regulated. And so we've developed two phase II trials in these two different disorder groups. So again, PI3Kδ linked disorders and CVID with immune dysregulation. And really, our phase II trials are designed to, number one, evaluate safety. Number two, evaluate optimal dosing.
Number three, of course, we're interested in generating preliminary data about the impact of leniolisib on common and serious clinical manifestations because it is our mission to really transform care for these patients and make an impact in their daily lives. You can see here on the left, in blue bars are rates of various complications in patients with CVID compared to rates in the general population shown in orange. So you can see that digestive system disorders, autoimmune cytopenias, interstitial lung disease, all occur at a much higher frequency in patients with CVID. On the right, as Dr. Farmer spoke to, you can see the tremendous negative impact of complications of immune dysregulation on mortality.
As she mentioned, you can see in the top bar there that patients with CVID who develop immune dysregulation have an 11x higher risk of death compared to CVID patients who never develop complications of immune dysregulation. Then you can easily observe the negative impact of individual manifestations like splenomegaly, interstitial lung disease, GI disease, liver disease. Now, the first trial that we opened was a phase II proof of concept trial in genetic PIDs linked to PI3K signaling. This study was developed in very close collaboration with Dr. Gulbu Uzel at the National Institutes of Health. Unfortunately, due to time, we do not have the ability to go into all of the disorders that are shown here. Several of them you heard about from Dr. Farmer.
But I will just point out that there are a couple of additional disorders that don't fall under a CVID diagnosis rubric. These are ALPS or autoimmune lymphoproliferative syndrome and also RALD or RAS-associated leukoproliferative disorder. And these are included in this trial because genetic lesions in these patients result in overuse of the PI3Kδ pathway. And we're happy to talk about that offline with anyone who has additional questions. This first phase II proof of concept trial, again, was set up, number one, to evaluate safety and optimal dosing. And for that reason, you can see that it is a dose escalation study. So patients start out at 10 mg for a month. They then escalate to 30 mg for another month. And then they escalate to 70 mg for 12 more weeks. It is a single-arm, open-label study, 12 patients.
Key inclusions you can see here need to be an appropriate age, need to have a pathogenic or likely pathogenic variant in any of the genes that are shown. They need to have clinical manifestations that we're targeting and have likelihood to treat, so cytopenias, lymphoproliferation in the form of either splenomegaly and/or lymphadenopathy or interstitial lung disease. Key exclusions are shown. Patients cannot have had a stem cell transplant. And they can't be on really immunosuppressive medications other than we do allow just a little bit of steroid. Notably, after completion of the phase II trial, all patients do have the option to continue into a separate 3-year open-label extension study. And most patients do choose to move on because they're perceiving some benefit. Now, the next study that we designed was in very close collaboration with Dr. Jocelyn Farmer, who you heard from earlier.
You'll note that I intentionally overlaid these two slides so that you can see how similar they are because there is a lot of overlap in some of the disorders that are included in that first study, namely CTLA-4 and FKBP10. So again, patients are escalating dosing over the course of the trial. There is an extra month of treatment in the CVID study to really allow us more time to estimate efficacy in terms of liver disease. Key inclusions are similar except that patients do not have to have a genetic diagnosis. They really just have to have a clinical diagnosis of CVID. And then they need to have disease manifestations that we're targeting and have high likelihood to impact. We have a few more exclusion criteria really designed for safety. So patients cannot have severely low T cells or NK cells.
These are the shared phase II objectives and endpoints that are really geared to support pivotal trial design. So you can see here again, the first objective is really safety. So we're assessing safety through standard AE monitoring. We're also looking for tolerability. And we're working hard to confirm the dosing strategy in these populations so that we're best positioned in the phase III program to be successful. And so we've got very detailed PK and PD assessments that are part of both of these phase II studies. We're also estimating the clinical efficacy of leniolisib for immune dysregulation. So based on the clinical manifestations that Dr. Farmer outlined, we're paying very close attention to changes in lymph node and spleen size changes. We're looking very closely at improvements in blood cell counts.
We're using very detailed CT scoring of lung disease to really analyze the impact on interstitial lung disease. We're looking at typical pulmonary function tests. Then we've got some other readouts that I don't have time to talk about today. We are also working very hard to evaluate the mechanistic impact of leniolisib and then to also pilot correlative biomarkers scoring systems to help us in our phase III effort. For the mechanistic impact, we're doing some very detailed phenotypic evaluation of B cells by flow cytometry. We're also looking at detailed phenotypic changes in T cells. We're correlating biomarkers that really play into the mechanism of disease in CVID with immune dysregulation, so things like CXCL13, interferon gamma, soluble IL-2 receptor. Then we're actually piloting a modified scoring system that's used in the immunology space to help grade disease for patients with immune dysregulation.
Then we've developed several custom patient-reported outcome tools to really capture how patients are feeling in their day-to-day lives. Now, this is just a little bit of quick epidemiology to help you understand the impact that we are hoping to be able to make. We did a really good job taking a deep dive into many different sources of epidemiology. So we spent a lot of time with our colleagues at the ESID registry. We worked with the USIDNET registry in North America. We did a comprehensive literature review. We've also talked with many primary immune deficiency key opinion leaders. As you can see here in the second column, these are their references. These are the estimates from those.
So at the end of the day, the diagnosed targeted population per million for the genetic PIDs linked to PI3K signaling is about 7.5 per million. Now, it's important to remember that CTLA-4 and NF-κB1 and FKBP10 are also included in the estimates for epidemiology for CVID. Again, these are the references shown here where we're basing our numbers. You can see that overall, we're estimating the total CVID population to be about 106 per million. Those who develop immune dysregulation is about 50%. So that gets us to 53. Then based on Dr. Farmer's work, we estimate that about 75% of those patients have an APDS-like endotype, which brings us to 39.
When you put everything together, we really have a tremendous opportunity to be able to transform the care of PID patients with immune dysregulation at a population estimate of about 44 per million. We are all extremely hopeful and excited and looking forward to bringing forth transformative care for these patients. With that, I will close and say simply that leniolisib for PIDs with immune dysregulation has the real potential to bring unmet need patients a good treatment. PI3Kδ, as a master regulator of the immune system and targeting PI3Kδ, can hopefully modulate the underlying immune dysregulation in PID patients. We are on track, as Anurag mentioned, to deliver top-line data in the second half of this year showing the impact that we are hopefully making for these patients. Thank you.
We'll be happy to take some questions and have some conversations.
Thank you, Rebecca. As a reminder, covering analysts, you can raise your hand to ask a question. Investors and analysts, please use the Q&A button to type your question. First question comes from the line of Joe Pantginis at H.C. Wainwright. Joe, go ahead.
Hi. Thank you for the follow-up. My first question is for Dr. Farmer, if you don't mind. And maybe Anurag would like to chime in as well. So Dr. Farmer, you said that there's really a dearth, essentially zero compounds, being developed for these indications outside of leniolisib. So why do you feel, either from a scientific MOA or clinically, there is such a dearth of pipeline assets? And then do you see any potential impact or even off-label use for other B cell targeting assets, say, for APDS or what have you?
Yeah. Great questions all around. So in the data I showed with the mortality, that was really a landmark study. And the follow-up study in Germany was just published last year. So I think for a long time, we were just kind of patting ourselves on the back as clinical immunologists that we fixed the infections. And it really took those decades of epidemiologic data saying we weren't doing enough to really unearth that this clinical problem existed. So I think that's part of the delay. I think the second has been the concept that you could come into a patient with a low immune system and use what's classically thought of as an immune suppressive agent. So we do use off-label B cell targeting. We use rituximab. We use agents. It takes me about 6 months-12 months to get them approved, a lot of my time.
There are patients, right? If I give rituximab, I take away the bad B cells. COVID was very humbling during that time, right? I wasn't able to immunize those patients to new pathogens once I take the B cells out. There are risks to those therapies. I think what's so exciting to me here is that there is the opportunity to immune modulate without overtly immune suppressing. In that patient example that I showed you, actually, I reconstituted. I brought back B cells that are able to make, hopefully, a functional antibody for the patient in time. My hope is that's our future, that we're able to modulate more than suppress. Yes, we do use agents off-label, not to the point where I think I can sustain that in routine clinical practice.
Certainly, we would welcome FDA-approved therapies that we could routinely get through for these patients in a much more expedited fashion, and again, focusing on ones where we don't see an increase in infection risk.
No, thank you for that. Just a quick question, if you don't mind, for this PID genetic study. Can you discuss the variability of steroid use and how you're controlling for that?
Yeah. So the patients are allowed to stay up to 25 mg a day of prednisone. That's really just for safety reasons. So that if they need a little background steroid to make it into coming into study, we do allow that to come in. So it's not a significant amount of steroid, but we do allow a little bit of background.
Great. Thank you, Joe. Our next question comes from Jeff Jones at Oppenheimer. Jeff, go ahead.
Good morning.
Good morning. I think we lost you, Jeff. Come back.
As you're looking at patient selection across the various phenotypes, is there a way to look directly or more directly at PI3Kẟ activity and pathways to try for patient selection? And then maybe to expand on some of the commentary on RITUXAN and some of the off-label, thinking about BTK inhibitors and things like that, how all of these either play a role today or might play a role as we look at patient population selection here, both for the trial and beyond. Thank you.
Yeah. Pharming pushed me up very hard to look at the [audio distortion] signaling, which I can certainly do. It's an assay I've done for years. It's a tough assay. It's one that's really tough to bring to kind of clinical development because it's so varied. What I've nicely shown you in that second-to-last slide is that that pathway activity links with the proportion of atypical B cells. So over time, you can start to use that more functional second assay, which is much more feasible. We already do that in routine clinical care to start to pick out these patient populations. And so you are 100% correct.
What's convergent across all three of those arms, APDS, PI3Kẟ linked disorders, and CTLA-4 that get the non-infectious manifestations that we think about bringing on to trial, is that they absolutely share those expansion of cells that are high in PI3K signaling. And we will show it in the preliminary work, of course. My hope is over time, we can divorce ourselves from having to do the complicated assay and move into those readily available clinical assays. In terms of your second question, it's great. That question gets brought to me a lot with the BTK inhibitors. So as Dr. Marsh mentioned, we have dysregulation of both the B cells and the T cells in this condition. So leniolisib is really fortunate, and then it crosses over both of those.
So when I use rituximab, it benefits the debulking of the bad B cells, but I can't hold the patient at bay for long periods of time. I have to use a concomitant T cell inhibitor to do that. So with the BTK, you're going to hit B cells. You're going to hit innate immune cells. You hit macrophages. You leave the T cells uninhibited. And I think we will have to see if that isolated B cell targeting approach is enough to get us there, right? I think it's yet to be determined. I like the fact that we have a long experience of using off-label both B cell and T cell targeted agents in this disease. And that has seemed to work over longer periods of time.
I like leniolisib in that it's not single lineage specific because this disease looks to be across multiple different lineage of lymphocytes.
Yes.
As part of the clinical trials, we do look at phospho-AKT and phospho-S6 so that we can really correlate the impact of various levels of baseline pathway activity with clinical trial response outcomes. But we actually are not expecting that to necessarily be a prerequisite for what Jocelyn's mentioned and what I mentioned, that really the ubiquitous nature of involvement in PI3K and various pathways that are involved in the pathophysiology of immune dysregulation, it's really going to be acting in multiple ways, probably.
Okay. Great. Thank you, Jeff. Next question will come from the line of Lucy Codrington at Jefferies. Lucy, please go ahead.
Hi. Thank you for taking my questions. I think you may have actually ended up answering one of them in the subsequent presentation. But in terms of the proportion of CVID patients that do have the immune dysregulation or the non-infectious complications, I think it was subsequently said to be 50%, but if we could just confirm that. And then in the compassionate use patient that you talked about, you showed the kind of change in the B cell profile. But I guess and sorry if I missed it. Were there any clinical benefits seen in her symptomology in that one year? And then my final question, I guess, what constitutes success in the phase II trials?
For example, if we weren't to see any signs of clinical efficacy, but you did see the mechanistic impact that you were looking for, would that still be enough to drive you to go into phase III? Thank you.
general which was related to the proportion of CVID patients that have symptoms of immune dysregulation also. And we did mention that that was approximately 50%. And then Dr. Farmer, I don't know if you want to answer the second question.
Yeah. Yeah. I'm sorry, not having a special slide for that. I was kind of letting the patient speak for herself. But yes. So especially the liver disease, the natural history of that is progression over each subsequent year. And so we've held the liver disease stable, given this woman essentially a year of her life back. Spleen has held stable. Lungs have had no advancement during that time. I think it's yet to be determined whether that will be the single agent forevermore in her condition. Her T cells doubled. She cleared long COVID for the first time. She was antigen positive for, I think, over a year. So she was able to do things like attend her children's white coat ceremony and be outside of the house more. And so all of those were huge wins.
I think, can we hit the next benchmark to say we've completely restored? She can respond to vaccines. No, I don't think we've hit that yet. But I am encouraged with the data I see so far. And again, this is a progressive disease. So I usually say to my patients, "If we can hold it in its tracks, I've saved your life. We've won." If I can reverse it, icing on the cake. But I think first goal is, can we start to hold patients where otherwise she'd be listed essentially for a liver transplant? So that would be the win.
I think, Lucy, your third question related to what constitutes a win in the overall program. Really, what we're looking for is improvements in the hallmarks of the disease. I think you heard clearly from Dr. Farmer and Dr. Marsh what those disease manifestations are, both from a B cell perspective, but also from a clinical perspective. We really are looking for improvements in lymphoproliferation, the types of things that we've seen in APDS patients, improvements in their cytopenias, improvements in some of the other end-organ damage manifestations, whether it's the lung disease or the liver disease. Those are the types of things that we'll be looking for in this study, and they'll be able to guide us further.
Thank you.
Great. Thank you, Lucy. I think we have time for two more questions. First one comes in from Chiara Montanari on behalf of Sushila Hernandez at Van Lanschot Kempen. It's a question for Dr. Farmer. Within the PIDs linked to PI3Kẟ and CVID, can you comment on how many patients have symptoms so severe that they actually need treatment?
Yeah. So, I think Dr. Marsh did a nice job of laying out kind of, and I was trying to with the shading on that slide. So when you think about APDS, again, that's your thermostat always on. Those patients uniformly need treatment when they have that genetic diagnosis. When you move into patients with CTLA-4 deficiency with NF-κB1, NF-κB is a bad gene to have if you are a CVID patient. The vast majority of those patients will need to go on to therapy. And then when you move into CVID, if you sit at a large academic tertiary care center, it's approximately two-thirds of the patients we see with CVID that actually need this therapy. But across all-comers, yes, 50%.
That's kind of the breakdown, if that makes sense, from absolutely every patient with APDS needing it down to what you've been quoted as the 50% in CVID.
And then final question from the chat. In the absence of an increase in PI3Kẟ signaling, what is the mechanistic rationale to support leniolisib will provide benefits?
So, oh, I can answer. So to be clear, they do have increased PI3K signaling. So that was the phosphoflow I showed you. It's just hard to make that your metric. It's very variable. If you take my B cells on a I've done this assay for years. It's a very variable assay. It depends on the stimulation of the B cells. It's better to do fresh than frozen. So you can picture how difficult that can be. So the pathway activation is there. That is what is there. In CVID, it is there in the cells that I showed you on that last slide that are atypical. They're going down that bad pathway. And so I think the larger question is, are we beholden to always doing this complicated assay?
Or can we move one step above that and say, if we define these pathologic B cells as inherently having this high PI3K signaling, can we start to just take that as a firm known entity? And then can we start to treat all patients that have these convergent B cells with a drug that beautifully targets these pathologic B cells? And I think probably and hopefully, we can. But just to be absolutely clear, we do see the increased activation of the pathway in the patients that we're targeting on these trials. Is that correct? Yeah.
Yeah. And Dr. Marsh.
Thank you.
We'll now be turning to our next agenda item on today's schedule. That's to discuss napazimone or KL1333, which is being developed for primary mitochondrial diseases. Again, these are rare disorders with significant unmet need. napazimone is really positioned to become the first standard of care for this disease. There is a pivotal study ongoing. You'll hear more about that study and what the opportunity really represents for Pharming. With that, I'd like to now introduce Dr. Amel Karaa. Dr. Karaa is an internist and clinical geneticist by training, currently the director of the Mitochondrial Disease Program at Mass General Hospital in Boston, where she oversees clinical care, clinical research, and trials for patients with mitochondrial disease. She is the recipient of the United Mitochondrial Disease Foundation Fellowship.
She is the former past president of the Mitochondrial Medicine Society, past chair of the United Mitochondrial Disease Foundation Scientific and Medical Advisory Board. She is also a founder and a board member of the Mitochondrial Care Network, a U.S.-wide network overseeing expert centers for patients with mitochondrial disease, and the founder of TREAT MITO, a clinical trial and research consortium for patients with mitochondrial diseases. Dr. Karaa.
Thank you very much. Good morning, everyone. I just wanted to start by disclosing that I am a consultant for Pharming, and I do receive a clinical research grant as well. What I'll share with you today reflects my own opinion as an expert in clinical and research with patients with mitochondrial disease and do not reflect at all my institution or my university. My goal today is to frame primary mitochondrial disease as a serious, genetically defined metabolic space with real unmet needs, measurable endpoints, and a growing therapeutic momentum. Mitochondrial diseases are not neurological curiosities. They are a distinct class of inherited metabolic diseases formally recognized within the International Disease Classification of Inherited Metabolic Disorders.
What makes them unique is that the genetic mitochondrial dysfunction sits across multiple organs and causes a systemic presentation that is broad in clinical impact and not a narrow niche, sorry, and not a narrow niche indication. While genetic mitochondrial dysfunction is cross- and multisystemic, secondary mitochondrial dysfunction caused by other rare genetic conditions and other environmental and toxic factors are also primary mechanisms in multiple other diseases. So therapies for primary mitochondrial disease can potentially benefit other conditions where a mitochondrial dysfunction is present and vice versa. So what makes mitochondrial diseases a bit unique is this dual genome input that they have. They can be caused by mutation in either the mitochondrial DNA or the nuclear DNA. Mitochondrial DNA disorders typically cause adult-onset disease and are maternally inherited, whereas nuclear gene defects are typically causing pediatric cases that are Mendelian inheritance and recessive in nature.
There are about 37 mitochondrial genes that can cause disease and about 400 nuclear DNA genes that can cause mitochondrial disease. So as you can see, this is a hugely heterogeneous genetic condition. This also naturally segments the disease within the market by gene inheritance pattern, age of onset, and trajectory, which is highly favorable for drug development and orphan strategies as well as lifecycle expansion. I now want to ground this a little bit in a real patient. I invite you to meet Regina, one of my patients. Regina has a mitochondrial myopathy caused by the mutation 8344A>G. Regina has a strong family history of other members also affected by the disease, given that this is a mitochondrially inherited disorder.
Over the years, the disease had affected Regina's movement, hearing, speech, and all functions that allow her to socially interact, leading her, despite supportive care, to lose independence, employment, and the ability to socialize, including with her own family. This is not a unique story to Regina. Most of our patients do have similar disease burden and have a lot of morbidity and mortality. I will invite you to listen in her own words to what Regina has experienced.
So what led you to go to the doctors and to seek a diagnosis? What kind of symptoms were you experiencing 20 years ago?
Well, it wasn't so much the symptoms that I had. I had a brother who was diagnosed with the disease. At that point, I was made aware that all of his siblings had the gene. Looking at what he was dealing with and what I had experienced all my life, I realized I really should be checked for it because all my life, I had been tired all the time. I couldn't do things other people did. I couldn't compete. I couldn't play sports because I just didn't have the energy. I always wondered why they could do it and why I couldn't do it. Even when I had my children, I felt the same way. Why am I having such a hard time taking care of these children when other people can do it with such ease?
Now we are going to hear the impact that mitochondrial disease has on Regina's day-to-day life.
I have three brothers. I have three brothers and a son. My three brothers will never have children. They will never have children because they don't want to be fighting to this world if they're not going to have any quality of life. That's exactly what mitochondria is. It takes all your quality of life away. The only grandchildren I have are from my son. I have a little boy and a little girl. They won't let me take care of them. They won't let me spend time with them because of my condition right now.
So as you can see, what comes across from these two short videos is, one, the delayed diagnosis. This is not uncommon but is improving tremendously in 2026 and in the past 10 years due to the advent of more genetic testing. It also highlights the cumulative disability. By the time these patients are diagnosed, the disease burden is already very high. It creates urgency for disease-modifying therapies. So how do we diagnose these disorders that are so heterogeneous and so complex? Well, to this day, we don't really have a good biomarker to diagnose mitochondrial diseases. We heavily rely on genetic testing. This has been the gold standard for the last 10 years, 14 years. The recommendation as of 2026 is that whole exome sequencing with mitochondrial DNA sequencing or whole genome sequencing be the first-tier testing.
However, utilization of these sequencing methods can be hindered by insurance coverage, at least in the U.S. Despite the use of these large-scale genetic testing, there do remain cases who remain molecularly undiagnosed, owing to the fact that there are probably many more genes to be discovered that cause mitochondrial disease. After the diagnosis and during the process of the diagnosis, we do rely on other measures that look at the mitochondrial dysfunction biochemically. In the last five years, GDF15 and FGF21 have emerged as potential biomarkers. They do lack sensitivity and specificity, unfortunately. Then we do rely on tissue pathology, which primarily includes muscle biopsies, specifically for a subtype of mitochondrial DNA disorder called mitochondrial DNA deletion syndrome, where the deletion of the mitochondrial DNA can sometimes only be detected on muscle tissue.
We also rely on tissue pathology when we discover a new variant of uncertain significance where we need more functional assessment to better interpret the pathogenicity of the variant. Obviously, due to the multisystemic nature of the disease, a full survey of all end organs has to be done, which includes major organs like the brain, the heart, the kidneys, the eyes, and so forth and so on. So patients need to undergo a very comprehensive assessment. Mitochondrial disease are relentless. They are progressive and impact mortality over the course of the lifespan. A published paper from the Mitochondrial Medicine Society did show that mortality in primary mitochondrial disease patients is very high compared to age and sex-matched individuals.
It is constant across the subgroups of mitochondrial disease, with a bimodal distribution affecting early mortality for the pediatric cases as well as mortality in the mid-20s to mid-50s for the adult patient. Mortality increases over time, and progression remains heterogeneous but measurable. We now do have natural history studies that can support this data. On the cellular level, the biology is well characterized now. Primary mitochondrial disease disrupts multiple cell functions, including dysfunction of the OXPHOS metabolism, leading to low ATP production and energy failure, increased mitochondrial oxidative stress, impaired mitochondrial trafficking, biogenesis, dynamics, and includes defective mitophagy. These are all druggable. We're no longer asking whether mitochondria matters but deciding which lever to pull. The result of this dysfunction is that the same energy failure manifests differently across organs.
But the underlying driver remains a shared one, causing organs of highest energy demand to be first affected and to cause severe central nervous system, heart, muscle, eye, GI, and kidney problems. Any symptom that you can think of in any organ that you can think of can be affected by mitochondrial disease in one way or another. Studies have actually shown that, on average, a mitochondrial disease patient has 16 different symptoms at any given time. So there's a huge morbidity from this disease. These are some illustrations of more typical red flag symptoms that we do see in our patients. The first panel represents a brain MRI from a pediatric patient with Leigh syndrome, showing typical bilateral lesions in the basal ganglia.
The second picture is the retina of a patient with Leber hereditary optic neuropathy, a mitochondrial DNA patient with hyperemia of the vessels and atrophy of the optic nerve. The third panel shows a muscle fiber with red rimming that represents proliferation of mitochondria called ragged red fiber, which is pathognomonic for mitochondrial disease when present at high percentage for age. Then you see ringed erythrocyte precursor cells filled with iron-laden mitochondria, showcasing the sideroblastic anemia that some patients have. The middle panel shows a very dilated colon of a patient who has severe GI dysmotility. This pseudo-obstruction happens without any anatomical obstacle. Then finally, a cardiomyopathy with a thickened heart, as you can see here, within the septum and the left ventricle. So what are the symptoms that are most meaningful to patients? We asked this question several times as drug development efforts started.
We wanted to really understand what was most meaningful to patients to treat if we had a drug that could solve it all. Consistently, across all the registry information that we have access to and the studies that we have done, muscle weakness and fatigue come at the top of these complaints. Patients want to have their fatigue and their muscle weakness fixed because that is what is most impactful for their day-to-day lives. These are now measurable and reproducible and have some validated outcome measures and strongly limit the daily function and are well correlated with day-to-day activity of the patients. What has been achieved since drug development has taken off in primary mitochondrial disease? We now better understand what this fatigue looks like in patients with mitochondrial disease.
This is a well-run study that was done in the context of the FALCON study, where patients clearly characterized their fatigue that can be multimodal, affecting the brain, affecting physical fatigue, energy, and muscle fatigue as well. These have very different impacts on day-to-day life, including effects on schooling, effect on work, effect on housework, effect on relationship and social interactions. This creates a vicious circle where these impacts further impair and heighten the fatigue perception and vice versa. In the setting of the FALCON study, multiple fatigue questionnaires were reviewed. The PROMIS Fatigue Mitochondrial Disease short form was created and was not created, validated, because it's a PROMIS tool that has been already in existence, developed by the NIH. It has been validated in this specific patient population.
After cognitive debriefing, we do feel that it strongly captures the fatigue experience of patients with primary mitochondrial disease and hopefully can show meaningful change over time. Now we do have validated disease-specific outcome measures for fatigue, which is the most common complaint for these patients. How common is mitochondrial disease? It's actually more common than people think. Population studies show prevalence higher than many assume. In studies, pathogenic mitochondrial DNA variants are present in about 32 million-40 million people worldwide. These are people living with these variants with or without symptoms developed from these variants. Of those, about 1 million-2 million will go on and develop full-blown mitochondrial disease of different severity and different organ involvement.
When we dig deeper into these mtDNA disorders, the mitochondrial DNA mutation 3243, which is the most common mitochondrial DNA mutation, represents about 300,000-400,000 patients within that group, followed by the single large-scale deletion, which represents about 100,000-150,000 patients carrying disease caused by this deletion. Together, they represent the majority of mitochondrial DNA disorders. They also represent the targeted population by the FALCON study. How do we manage and treat our mitochondrial disease patients? Despite decades of research, no approved therapy is available. The recently approved drugs have extremely limited indication and are not able to support the broader group of primary mitochondrial disease.
So treatment remains largely supportive, trying to minimize energy losses and optimize energy gains by recommending that patients eat healthy, sleep well, keep themselves hydrated, and exercise, which exercise is very important because it's the only intervention that has scientifically been proven to improve OXPHOS and mitochondrial biogenesis within organ tissues. So what is the therapeutic landscape looking like these days? It is exciting because there's diversity of approaches now in the development targeting multiple different cellular mechanisms, including antioxidant targeting biogenesis, nitric oxide modulator targeting mitophagy, membrane stabilizer, and even gene therapy for certain mitochondrial DNA disorders. The red boxes highlight the active programs as of 2026. There aren't as many as there used to be. But these remain active programs that have high excitement for the community. And we're hoping that we will get more and more drugs approved over time.
In the last five months, we had two recent approvals in ultra-rare subsets of mitochondrial diseases. We have Forzinity that was approved for Barth syndrome and Kygevvi that was approved for TK2 deficiency. Both these are ultra-rare subgroups of primary mitochondrial diseases that will target very, very small numbers of patients. But these two approvals are very exciting because they are not just important clinically but as precedent-setting, signaling for the field, showcasing that regulators are open to engage and willing to approve drugs when endpoints and unmet needs cross path. So what does the ecosystem of mitochondrial medicine look like in the U.S. and worldwide? We have a well-organized ecosystem in the U.S. We have centers of excellence and expert networks that oversee the majority of our patients with mitochondrial disease.
We have a Mitochondrial Medicine Society that is very active, putting forth guidelines for diagnosis and management, acute and chronic, for primary mitochondrial disease. We had a North American Mitochondrial Disease Consortium with an 11-year registry for mitochondrial disease. More recently, TREAT MITO, which is the consortium for clinical trial readiness, that has started a large-scale prospective natural history study that is FDA-compliant to serve as external arms and to better understand the natural history of the disease as well as to help support endpoint development. This is coupled with patient organizations that are sophisticated partners for academia and industry. They drive awareness through education. They have registries sometimes of their own. They have annual disease conferences. They run a lot of successful patient support programs. We have a landscape that is ready for trial execution, which lowers the risk for patient enrollment and is ready to go.
With that, I would like to leave you with this message: Primary mitochondrial diseases are not a single problem with a single solution but are no longer an intractable one. The science is real. The patients are ready. And we are all here ready to make this work. Thank you.
Thank you so much, Amel. That was an excellent introduction and overview of mitochondrial disease. I'm Magnus Hansson. I'm a Medical Director at Pharming. I'm heading up the napazimone program. The first time I learned about mitochondrial disease was actually 21 years ago in a very odd location, a very remote village in the Austrian Alps. I was there to pick up a technique for my PhD thesis on mitochondria. I'd never heard about mitochondrial disease during med school. But at this small conference, there were actually two physicians working on mitochondrial disease, one diagnosing--this was before genetic testing was widely available--and one treating patients. He's actually taught a lot of the physicians we now work on and is soon an active investigator in our study. So that's a nice connection.
But already then, I learned how devastating, when the mitochondrial energy production is insufficient, how devastating diseases can follow. So several years later, when I first encountered KL1333, which we now have a nice name for, napazimone, I was super excited about the mechanism of action because I saw in that compound and that mechanism the potential to actually have a true, meaningful impact on people with mitochondrial disease. So I will speak today about the drug development program for napazimone. So napazimone is an investigational drug that has not yet been approved or has not been approved. And we are right now doing the clinical trials to establish safety and efficacy.
So I will talk about those components, first with the mechanism of action, the basis for how we have targeted the program, but then how we have been very careful in selecting a targeted disease population, fit-for-purpose clinical outcome assessments, and then built-in de-risking strategies for the program. So the reason I was excited about napazimone was that it specifically targeted something that is key to the energy deficiency in mitochondrial disease. And that is the low and disrupted NAD+/NADH balance. In the leniolisib program, we target the balance of the immune cells. Here, we target the balance of what regulates energy in the cell. So with the mutations that cause a large subset of mitochondrial disease, mtDNA mutation affecting the OXPHOS system in mitochondria, that leads to this low NAD+/NADH ratio.
That drives a decrease, puts a stop to the energy production, and also inhibits the endogenous compensating mechanism, the so-called mitochondrial biogenesis pathways. That leads to these debilitating symptoms that we focus on, such as fatigue and the progressive organ dysfunction. Very commonly, as you heard from Dr. Karaa, is the muscle weakness. This significantly impacts the activities of daily living. Digging a bit further on that mechanism of action and why I'm excited about it is that you can see from these illustrations how central NADH and NAD+, the two versions of NAD, are in energy metabolism. It both mediates the energy production and regulates it. In the central image there, we have OXPHOS dysfunction caused by these mutations causing mitochondrial disease. That creates a block in this pathway.
So it leads to kind of a halt of this energy production system where we see an accumulation of NADH and a relative deficiency of NAD+. Now, what is really a hallmark of mitochondrial dysfunction in general is that we see an increase in lactate. So the cells have a small rescue system where they can produce lactate from pyruvate. So that's also a hallmark of mitochondrial disease and a hallmark of the dysregulated NADH/NAD+ balance. Napazimone has been designed to restore that balance. So it provides an alternative pathway to convert NADH to NAD+. And that is done by redox cycling of the compound. And that also directly feeds into the OXPHOS system. So in vitro, when we look at patient cells, we see activation of the mitochondrial biogenesis or restoration of the mitochondrial biogenesis pathways.
As you can see from this published paper, when we explore this in patient cells and compare that to wild-type cells, you see here four different graphs. First, how the patient cells, in this case from MELAS patients, that's syndrome associated with the most common genetic mutation for mitochondrial disease. We see how the NAD+/NADH ratio is decreased and how that then leads to a decreased mitochondrial mass, a decrease in those components of the electron transport chain, the OXPHOS system that is coded or affected by that mutation, and then an overall decrease in the energy production. After treatment with KL1333, napazimone, we see a restoration of the NAD+/NADH ratio, leading to an increased mitochondrial mass, a specific increase of those proteins that were downregulated or decreased, and then an overall increase in energy production.
How do we then translate that benefit at the cellular level to a benefit for patients? As we heard early in the program and which Dr. Karaa referred to, from the patient perspective, subjective and debilitating fatigue and muscle weakness are really the two most common and highly highlighted symptoms of mitochondrial disease. We decided to explore those already in phase I. We saw promising differences between the active arms and the placebo arms, both with reduction of fatigue and a signal of improvement of muscle function. We also looked at biomarkers. As I mentioned, lactate pyruvate is a marker of that NAD+/NADH dysfunction that is a consequence of mitochondrial dysfunction. We decided then to look more recently closely at this. A couple of weeks ago, we presented this data in Italy.
Based on the phase I data, we took the samples we had from all time points and built a pharmacokinetic model. We used that model and compared it to all the lactate pyruvate samples from phase I. We see from that data a clear exposure-response relationship. That is a nice confirmation of target engagement by the drug. OK, but moving over, as Dr. Karaa also told you, a lot of the treatment remains supportive. To that extent, it hasn't changed that much from 21 years ago. Your diagnosis has certainly improved. But still, a lot of the treatment remains supportive. We also see the same picture when we interview health care providers, that most patients, unfortunately, need to find a way to deal with the condition and the high unmet need.
Here, scored on a scale, it's really scored really towards the top of the scale. So moving over to our drug development program, so we have been really careful in selecting the target population and then matching endpoints to that. And as I said, tried to de-risk the program as far as possible. So if we first look at the patient population, you recognize the same image here where we have a subset of mitochondrial disease. So this is category six, mitochondrial DNA-related disorders. And the reason we specifically focus on them is that they impair OXPHOS function. So they are a good match to the mechanism of action of napazimone. We also focus on those mutations causing multisystemic disease. And you can see in the table here that we listed the three most common, but also include very similar types of mutations that are less common.
If we look further at those three mutations alone, we can see that the prevalence of those, they account for more than half of the total adult patient pool. They're associated with different symptoms and syndromes. But what they all have in common is that both fatigue and muscle weakness, myopathy, is very common in all. This slide summarizes the clinical trial program for napazimone. In the center of this program is, of course, the ongoing FALCON study. So this is a randomized, blinded, placebo-controlled study. And we work closely with the regulatory authorities to make sure that this has a pivotal study design. This study will be followed by an open-label extension that will open the second quarter of this year. And that will ensure that all patients who complete the FALCON study will have access to continued drug treatment.
Looking more specifically at the de-risking components we built into the FALCON study, we knew that it was really important to carefully select, not only based on the genotype but also on the symptoms the patients experience, to make them fit for purpose for the two study endpoints, the two primary endpoints we have in the study that reflect fatigue and myopathy in the lower extremities. We have an extended run-in period, an extended screening period. Both at the beginning and the end of that period, the patient has to meet certain thresholds for symptom severity. An important other component of the de-risking strategy is that we have separated myopathy and fatigue evaluations. We have two alternative primary endpoints. The study will be positive and demonstrate benefit if either of those demonstrates a statistically significant difference compared to the placebo arm.
Then we had an opportunity to have an interim analysis, which was an important milestone from the program, and a bit more details on that. That was performed by a fully independent data monitoring committee. They evaluated safety. But they also evaluated efficacy. We didn't test for efficacy. But we did do a futility analysis of both endpoints. And what was really encouraging was that both of the primary endpoints passed this futility threshold. And we are therefore very confident that as this study continues, the treatment duration, and we increase the study size from 40, that led to the interim analysis, to 118 total, we will have a really strong data set. So they recommended us to continue the study as planned. The safety and tolerability profile was acceptable.
If we look overall at the safety from the completed studies, three phase I studies and the first part of the FALCON study, we see a beneficial and benign safety profile. Looking at the full FALCON Wave 1 data, week 48 confirms that information from the phase I studies. Of course, we had the opportunity to learn from previous studies that were completed in the field. Most importantly, the mechanism of action to target the underlying pathology is critical. But we also learned a lot about how to target the disease population and how to match specific endpoints to that. When we designed the program, we had in mind, of course, that the target product profile would be attractive to both patients and also prescribers. Now, when we interview these two groups, we also see that pans out.
So we get very good feedback from both groups, highlighting that it's a very promising mechanism and that the endpoints we study are meaningful for the patients. Going back to the prevalence of the population. So as Amel indicated, for being a rare disease, this is a relatively common rare disease. If we just look at our subsegment, the FALCON trial inclusion criteria, that's more than half of the entire adult population. And that corresponds to more than 30,000 diagnosed patients with these mutations, so the addressable patient populations in the U.S. and the major European markets. In summary, our program for mitochondrial disease targets conditions with significant unmet medical need. As Anurag mentioned, we are positioned to become the first standard of care in mitochondrial mtDNA-related disease. We're super excited about the pivotal study. It's ongoing. We passed a positive interim analysis.
And we've had that aligned with the regulatory authorities. So we believe this program is a significant value creation for patients with mitochondrial disease as well as Pharming. Thank you.
Thank you. I see some questions have come in. Just a reminder to use the Q&A button to ask questions. Analysts, feel free to raise your hand to ask a question. The first question we have comes from Chiara Montanari on behalf of Sushila Hernandez at Van Lanschot Kempen. Can you any more color on the status of recruitment on the FALCON study?
The recruitment is going according to projections. So our target is to complete the recruitment by the end of the year and to have the study read out one year after the placebo control phase is completed.
Next question from Jeff Jones at Oppenheimer. Jeff, please go ahead.
Thanks, guys. Really appreciate the detailed presentation.
Could you speak a little bit more on the PROMIS score and what is a clinically meaningful change and what you're hoping to show there? And maybe a little bit the same question on the sit-stand score, the degree of change you need to see there. Thank you.
I'd like to begin. And then Dr. Karaa? Yes. So what is inherently good with the PROMIS fatigue questions is that each question has an inherent meaningfulness to the patients. And that's what we established when we developed the short form and also then cognitively debriefed it. So what we've said, the threshold for inclusion in this study is about one standard deviation worse than the average population. And I mean, the study is fully blinded. But we see really interesting trends in the blinded data.
The specific number for what is clinically meaningful in a regulatory setting, that is something that we will use the data and make correlations with kind of global assessments to discuss with the FDA. So that question, what is clinically meaningful, has several nuances to it. It, of course, has to reflect what is meaningful from the patient perspective. And a lot of the exploratory endpoints we have in this study, as well as exit interviews, have the purpose to establish that number. Yeah, and the same is true for 30 seconds sit-to-stand. So what is good with that endpoint is that it reflects a type of movement, which is very functional for many activities of daily living. And we will do the same process for that endpoint, correlate it with other exploratory endpoints, and use the study data to show that.
I would add to that that it was specifically the PROMIS Fatigue score was specifically selected because that is a tool that the FDA knows well, that has a long history of standardized measurements in other diseases and meaningful change in other diseases, including neurological diseases that are very similar to mitochondrial disease, which will be used to extrapolate at some point. And then, like Magnus said, the anchoring within the clinical trial is going to help support what meaningful change looks like at the end of the trial. And what I wanted to add is that in parallel to the FALCON study, we are conducting a natural history study through mitoSHARE, the patient registry, and collecting PROMIS Fatigue scores on patients every three months also. And that is also going to help us identify what a meaningful change is. Same is true for the 30 seconds sit-to-stand.
We do now have cohorts of primary mitochondrial diseases that have been doing the 30 seconds sit-to-stand for five years. We do have more standardized values of what the deviations are within this patient population. We're also doing that within our parallel natural history study, where we are asking patients to do the 30 seconds sit-to-stand at home. So we're cross-validating these two endpoints, not only within the trial but also in a parallel, separate natural history study, using the exact same criteria for patient selection as the FALCON trial.
Magnus, I think you partially addressed it. Maybe also just comment on the degree of impairment that these patients have at baseline with both of these measures.
Yeah. That's one of the critical components of the study design, that we have thresholds for inclusion.
We've set them to be a standard deviation worse than the population mean. That has, of course, two reasons: to ensure that the patients really have an appropriate severity of those symptoms, but also to make the scales in themselves sensitive to change. Because I think that's often been a problem in previous studies, that you apply different questionnaires, different assessments, but you really don't know if you are in a range where you will have sensitivity to change. We thought about that process really carefully.
OK.
One more question from Lucy Codrington at Jefferies. Then there's one final question after that.
Hi. Thank you. Just wondering if you could remind us, in terms of the FDA involvement in the design of the study and any risk, potential risk, in terms of the endpoints and/or this being considered a pivotal study?
And then just secondly, and again, apologies if I've missed this, but with regards to the endpoints and kind of relates to my earlier question for the other sorry, I've lost my mind. In terms of, is stabilization considered success, or do you need to see improvement here? Thank you. Sorry about that.
Thank you. Great questions. If I start with the FDA involvement. So throughout the development of the protocol, we had very close interaction with the FDA. And one of the first interactions was the concepts of the disease to study. So the concept is the regulatory language for which symptoms are meaningful to the patient. I think the first important agreement was that fatigue in itself is sufficiently important to have as a primary endpoint. Then we added the sit-to-stand test as another independent endpoint and also aligned that with the FDA.
But it also, of course, included the appropriate sample size, the duration of the study, the validation plan. Before we embarked on the initial validation of the PROMIS fatigue scale, we submitted the whole interview guidance to the FDA. So they've been heavily involved in the whole design of all components of the study.
Thank you. I think that largely addresses the next questions, which were the FDA views on the endpoints and also what the patients think. So at that, I think I'd like to turn it over to Fabrice for some closing comments.
Thank you, Michael. So as this meeting comes to an end, I'd like to thank you all for your attention today.
Coming off strong growth momentum and financial performance in 2025, we were pleased to share with you our initial 2026 financial guidance, including, as you saw, a meaningful increase in revenues driven by the anticipated accelerating Joenja growth and the continued RUCONEST growth. We have clear and significant revenue catalysts ahead for Joenja. Our renewed discipline in capital allocation will help drive the bottom line. I hope that you got deeper insights into our high-value pipeline today, with the opportunity for you to hear directly from Dr. Farmer and Dr. Karaa, who are world-renowned clinical experts in their respective fields.
We have two important clinical data readouts in the near term, starting with the two leniolisib phase II readouts in the second half of this year and the readout of the napazimone pivotal study by the end of next year, each having the potential to unlock significant value. With our proven commercial and development capabilities, a fit-for-purpose growth-oriented leadership team, and a scalable organization, I truly believe that Pharming is more than ever poised to achieve its vision of being a leading global rare disease company. Thank you for your attention. We can now close this Investor Day.