Good morning. I'm Serge Belanger, one of the analysts at Needham. I want to welcome you to our 25th Annual Healthcare Conference. To kick us off this morning, we have Pharming Group, a company developing and commercializing products in the rare disease space. From the company, we have the company's CEO, Fabrice Chouraqui, as well as the Chief Medical Officer, Anurag Relan. The company will give us a presentation, and we'll proceed to Q&A. Fabrice, Anurag, welcome. Thanks for joining us this morning, and I'll hand it over to you for the presentation.
Thank you so much, Serge and good morning to every one of you. Just a short disclaimer, as you know, in this call, we'll be making forward-looking statements that are based upon our current insights and plan. As you may know, this may differ from future results. As Serge alluded to, Pharming is a company that has changed very significantly over the past four to five years, moving from a one-asset company to a company with two commercial-stage assets, each growing double-digit, and a high-value pipeline with two programs, with each revenue potential above $1 billion. From a commercial standpoint, we have these two assets on the market. One is a legacy asset, RUCONEST, as a cornerstone treatment in on-demand HAE.
This drug has, over the years, now more than 10 years on the market, carved out a very specific subsegment of the market and is really serving as a reliable and long-term cash generator for the company. Joenja is a drug that we have launched just three years ago now in the U.S. The uptake is accelerating and it's been launched in a ultra-rare primary immunodeficiency, an ultra-rare PID called APDS. There is a number of near-term commercial catalysts. We are also studying this drug in higher prevalent PIDs, so adjacent indications which share a lot of similarities with APDS. We have two phase II trials that are going to read out in the second half of the year.
We have also a second asset in our pipeline, napazimone, which we called KL1333 historically, a drug that came from the acquisition of Abliva, acquisition that we completed about a year ago. The drug is in a registrational phase II. The program is due to read out in the second half of next year. As we'll discuss, this program could be a significant contribution to our growth in the coming years. The objective is clear, to leverage this very significant backbone, both commercially and clinically, to develop a leading global rare disease company. I joined this company a year ago as a CEO, and I was very impressed by the strength of the capabilities that we have developed in clinical development, in supply chain, in commercial.
I really see us leveraging those proven capabilities to take the company to greatest height as we continuously broaden our pipeline and portfolio. If I step backwards for a second, as you probably have seen, we had a very strong 2025, with very significant revenue growth, 27%, revenue growth that was fueled equally by RUCONEST and by Joenja. We also saw during this year an inflection when it comes to our operating profit. You can see that we have generated a very meaningful operating profit and cash flow from operation. Actually, at the end of 2025, our cash flow position was slightly higher than what it was at the beginning of the year before the acquisition of Abliva. That actually shows our ability to generate a meaningful amount of cash and reinvest that cash to broaden our pipeline for future growth and de-risking our operations.
If I now look at 2026 will be another stepping stone in our ability to realize our vision of becoming a leading global ultra-rare, rare disease company. We have signaled the market that our revenue guidance would be between $405 million and $425 million, which means an 8%-13% growth. Our operating expense guidance is between $330 million and $335 million, a 6%-8% growth, despite very significant increase in investment in R&D. There'll be a number of commercial and pipeline milestones. For Joenja, we are expecting regulatory approval for the extension of the APDS indication to children. We received a CRL a few months ago, which I'll elaborate upon in a few minutes. Most recently, we've had two regulatory success.
In Europe, where we received CHMP positive opinion, and in Japan, where we received approval for Joenja, not only for the 12 year old, and older population, as it is currently the case in the US, but also for the 4 - 12 year old, so the so-called pediatric indication. We'll also have a number of pipeline milestone. As I mentioned, we expect to see the readout of our two phase two clinical trials in higher prevalent PIDs in the second half of the year. And we also expect to complete the enrollment of our pivotal FALCON trial for naproxen. So clearly a number of growth catalysts, a number of value creation catalysts this year to make 2026 another important year for Pharming. Let me now elaborate on Ruconest. Ruconest is a legacy drug for Pharming. It's been on the market for more than 10 years.
It's a drug that over the years has carved out a very specific subsegment of the HAE on-demand market. It's a drug that is being used mostly for more severe patients. Patients who have more severe attack, more frequent attack, whether they are type one, type two, or normal C1HAE patients. This is due to the very distinctive value proposition of the drug. It is the only recombinant C1 inhibitor protein replacement therapy. It target the root cause of HAE across all pathways, not only one of several pathways like other treatments. It is a drug which is IV administered. It is self-administered by patients. Because of the IV administration and its unique mode of action, it provides patients with the efficacy and the reliability that they need, specifically when they suffer from a severe form of the disease.
That's why we've seen over the year RUCONEST really becoming a cornerstone treatment for this subset of patients, specifically when it has a very distinctive value proposition. Often patients actually have failed other treatments before they come onto RUCONEST. RUCONEST is also manufactured out of the milk of transgenic rabbits, which make its manufacturing process complex and very specific. As such, at this stage, we are not aware of anyone attempting to replicate it. Now to tell you more about RUCONEST's distinctive value proposition, I'd like to ask Anurag to share with you some recent data that we have generated on RUCONEST, in regards to its distinctive value proposition from another treatment that was recently launched.
Thanks Fabrice. While there are no direct head-to-head treatment comparisons of RUCONEST and other therapies such as sebetralstat, there was an indirect treatment comparison performed recently, and this was presented at the American College of Allergy, Asthma, and Immunology in November of last year. These results actually show something that we've heard actually quite commonly when we talk to physicians who treat HAE patients. Specifically, these results showed that patients who were treated with RUCONEST were 4.5 x more likely to achieve complete symptom resolution as compared to sebetralstat. You see that also in the Kaplan-Meier plot on the left, where you see after 24 hours, less than half of the sebetralstat-treated patients achieved complete resolution of the attack, versus more than 90%, specifically more than 93% of the RUCONEST-treated patients.
Really a very different efficacy profile from these drugs, which I think ties back actually to the mechanism of action and the mode of administration that Fabrice mentioned, RUCONEST being an IV replacement, C1 inhibitor therapy with almost immediate bioavailability and as such, being able to produce these types of results. I'll turn it back to you now, Fabrice, to walk us through Joenja. Thank you.
Thank you Anurag. Let's talk about Joenja now. If RUCONEST has been a very significant cash engine for the company and is poised to remain the cornerstone treatment for difficult-to-treat patients, Joenja is a drug which is at the very beginning of its life cycle. Joenja is a PI3K delta inhibitor. Some of you may be familiar with the PI3K delta pathway. PI3K delta is a master regulator of the immune system. Imbalance in this pathway leads to major imbalance in the immune system with immune cells not maturing actually properly, specifically B cells and T cells. That leads to typical immune dysregulation pathologies like lymphoproliferation, autoimmune disease, GI disease, pulmonary disease. There are a number of pathologies that share that pathophysiology.
APDS, which stands for activated PI3K delta syndrome, but also higher prevalent primary immunodeficiencies like genetic PIDs with immune dysregulation linked to PI3K delta and CVID with immune dysregulation. We first actually studied Joenja in APDS. The drug has been approved for APDS in the U.S. for now almost three years. APDS is an ultra-rare disease with a prevalence of about 500 patients in the U.S. 2/3 adult, 12 year and older, 1/3 pediatric, 12 year and below. The drug uptake has been accelerating in the adult segment. We've seen actually very significant growth throughout last year. There is still considerable amount of patients actually to put on drug. At the end of last year, we had 120 patients in the U.S. on Joenja. Clearly, a potential to easily double that number based on prevalence only in adult.
There are now in APDS other growth opportunities to unlock, pediatric, 1/3 of the patient population. As I mentioned earlier, we were expecting to receive approval for the expansion of the indication to the pediatric indication, but we received a CRL from FDA at the end of January. Obviously, we were unhappy about it, but we had the opportunity at the end of March to engage with the FDA face-to-face during a Type A meeting. We are waiting for the minutes of that meeting to update investors on the path forward. We are clearly committed to bringing this drug to pediatric patients, knowing the value this drug has not only for pediatric, but for adult patients. I've personally met a few patients just in the past few weeks. One told me that after being on a Joenja treatment, she feels someone else. This is very powerful testimony.
A younger patient actually told me that since she's been diagnosed and treated with Joenja, her level of happiness has changed tremendously. Joenja is clearly a drug that works, that really transformed the lives of these patients. There are also other very clearly laid out growth opportunities in APDS with the reclassification of so-called VUS patients, VUS standing for variant of uncertain significance. These are patients that have an anomaly on the two gene coding for APDS, but there's not enough data in the literature for a test lab to say for sure whether actually those patients have APDS. We have already identified close to 1,800 of those VUS patients, and we know that possibly about 20% or so could be reclassified as APDS. That could actually increase the total pool of APDS patients by an additional 50%.
This is very meaningful, and we are working actually to generate the data so genetic lab could reclassify those patients. There was also a publication in Cell in June last year that suggests that the prevalence of APDS could be far larger than what we think it is today. The article actually concludes that the prevalence of APDS could be up to 100 x higher. This is very significant. We are working actually to understand this statement and the data. We see that as an upside, not yet as an opportunity. We'll update, obviously, investors as soon as we have gathered enough data and see where this could take APDS. APDS also is a great platform for us to expand geographically.
We have already launched a drug in the U.K., and as I told you, we received recently a positive CHMP opinion from E.U. and approval in Japan. We have targeted eight countries outside of the U.S. where we believe we can develop a significant business with Joenja, and that could create actually a platform for the future expansion of our portfolio. Now, obviously, APDS is the first indication. Yes, there are a number of commercial opportunities to unlock in the coming months and years, but there are also very significant potential opportunity to take Joenja to a whole different level by expanding the addressable patient population in higher prevalent primary immunodeficiencies. This is actually what you see on the right side of that slide.
To talk about our ongoing plans in this setting, I'll ask Anurag to tell you more about the progress of our clinical program, our two phase II's in genetic PIDs with immune dysregulation linked to PI3K-delta and in CVID with immune dysregulation.
Thanks Fabrice. It's really that understanding of APDS and how Joenja has been able to influence and improve the lives of APDS patients that led us to start thinking about other primary immune deficiencies that share this similar pathophysiology with APDS. In fact, many of the patients with APDS are initially diagnosed with CVID. As you see here, CVID is this umbrella diagnosis that covers all of these three conditions that we're looking into now. Going on further, when we think about this experience, you can go to the next slide. Thanks. What we see is that APDS, again, shares this similar pathophysiology and shares many of the same features as these other conditions that we're studying. You can see, again, the prevalence is significantly higher for these other two conditions in the second and third columns.
APDS, of course, is genetically defined. In the middle column, you can see that some genes define this genetic PIDs linked to PI3K-delta. With CVID, it's really a clinical diagnosis where most patients don't have a known genetic factor. Really, though, what ties all of this together is this imbalance in this PI3K pathway that Fabrice mentioned, and that imbalance leads to actually the common cluster of problems that these patients face, including recurrent infections, the autoimmune complications, the lymphoproliferation, and all of the end organ damage. Not to mention that all of these patients often develop malignancies, specifically lymphomas, due to this unchecked lymphoproliferation. On that basis now, we've actually started two phase II studies, and you see that both of those phase II studies, these proof of concept studies, are expected to read out in the second half of this year.
We're very excited about the prospects here because we have a clear understanding of how Joenja works in APDS and how it could potentially work here in these other much larger primary immune deficiencies. In fact, we have some experience already in these other primary immune deficiencies because clinicians came to us after they saw the results in APDS and said, "Look, we have other patients with a very similar clinical presentation." Now we've treated six of these patients as part of an Expanded Access Program. In general, we've seen that leniolisib has been well-tolerated. We've seen improvements in biomarkers. We've seen their lymph nodes and spleen shrink, and we've seen some other improvements, including in patient-reported outcomes such as fatigue and sense of well-being. These are patients now that have been treated for a median duration of 1.4 years.
In fact, we'll be presenting these results at the upcoming Clinical Immunology Society conference in May in New Orleans to share more details about the patients who were treated as part of this Expanded Access Program. Overall, again, we're very excited about the prospect here to be able to help a much larger group of patients and help them in the same way that we've been able to help APDS patients with Joenja. Now turning to our third program, napazimone, or formerly known as KL1333. This is being developed for primary mitochondrial disease due to genetic defects in the mitochondrial DNA. We're excited about this program really for three reasons. The first is there's a significant unmet need.
The second is we understand how the drug actually works in targeting that underlying pathology in these patients, and I'll walk you through some of the data that we have. Third, and probably most importantly, that this program is in a pivotal study that's undergone a positive or interim futility analysis and shown that both endpoints cleared detailed, and I'll talk to you a little bit about that too. Again, what we see in these patients who have these genetic defects in their mitochondrial DNA is that their mitochondria are not functioning properly. As you can imagine, because of that, they actually have significant symptoms of fatigue and muscle weakness that impair their ability to even do normal activities. KL1333 or napazimone normalizes the NAD+/NADH ratio that's abnormal in these patients.
We have data, in vitro data, we have data from animal models, and in fact, data from patients treated with the drug showing improvements. There's more than 30,000 diagnosed patients in the U.S. and the E.U.5, and we're using a number of clinically validated, clinically relevant endpoints that have been supported by FDA for the pivotal study. We have more than 25 sites now actively recruiting patients, and we're on track to complete enrollment later this year to enable a readout by the end of 2027. Let's talk a little bit about some of the data that we've seen already. This is from the phase I-A/I-B study, where we saw improvements in fatigue and muscle function, but also we saw evidence of target engagement.
Because what we see is an improvement in the lactate to pyruvate ratio, which becomes abnormally high in these patients because of the inability for those mitochondria to properly function. This is the type of data that we're going to be also collecting in the pivotal study, in the phase II pivotal program, looking specifically at fatigue, looking at muscle function, and then being able to correlate that with patient outcomes. As I mentioned, the program has already undergone a positive interim analysis, and this was a key step in the program's development. What was done was that after 40 patients were recruited and treated for six months, an interim analysis was conducted.
What was found, and this was a interim analysis that was pre-specified, and what was found was that there were differences both in the primary efficacy endpoints for fatigue as well as for muscle weakness, suggesting improvements in patients treated with napazimone. In fact, based on this interim analysis, if the trends continue consistently, we expect a successful result at the completion of the study. The Data Monitoring Safety Committee concluded that the safety profile was acceptable, there was no changes to the study design required, and the total sample size was re-estimated for 180 patients. That's really what we're focused on right now, is enrolling the remaining of those 180 patients. The first 40 are already included, and now we're including the remaining 140.
As I mentioned, we have more than 25 active sites, and we're planning a significant increase in that number, including in the U.S., that will enable us to read out the study next year. I'll turn it back over to you, Fabrice, to walk us through the outlook.
Thank you very much, Anurag Relan. As you can see clearly, the company that is shaping with a very solid commercial pipeline, made of two very distinctive asset. A cash generator with RUCONEST that has really long-term potential. A drug like Joenja, which is early in its life cycle with very significant milestone ahead, and then a high-value pipeline. That led us to provide the market with some clear financial guidance for 2026. From a revenue perspective, as I said earlier, we are expecting revenue between $405 million and $425 million, which is an 8%-13% growth. This guidance means very significant and accelerating Joenja growth, and continued RUCONEST growth. Given obviously the change that we see in the market, we don't expect RUCONEST to grow at the same level as last year.
Just to give you an idea, at the midpoint of that guidance, we expect to see RUCONEST to grow a mid-single-digit. We expect the market to be very dynamic and see volatility quarter after quarter. Clearly, RUCONEST is poised to remain a cornerstone treatment in those difficult-to-treat patients and, as such, remain a very strong cash engine for the company. From an operating expenses, we have signaled the market that we expect to spend between $330 million and $335 million. That includes an additional $60 million in incremental R&D investments to advance our pipeline and $9 million of structural G&A cost reduction, as we've announced last year. We've announced last year a decrease of our G&A headcount by 20%. We felt that when we have that many growth opportunities, we must be extremely diligent in the way we allocate our capital.
That's why we felt that there was opportunities to be much more efficient when it comes to our G&A accounts, so we can reinvest that money in areas that would yield much higher return on investments and value for shareholders. We expect that our available cash and the future cash flows that we generate to cover our current pipeline needs and pre-launch cost, as well as allow us to envisage potential future expansion of our pipeline. Overall, as you can see, Pharming is having a very strong momentum. I think that the result of 2025 is a good proof. It's a tangible proof of this very healthy momentum driven by both RUCONEST and Joenja's growth. We've shown that we are setting a renewed financial discipline, so we can run our operation very efficiently, maintain the company profitable whilst investing significantly in our future growth and in our pipeline.
We have very clear strategic growth priorities. With Joenja specifically, we are very fortunate to have a high-value pipeline with near-term value inflection point in the second half of this year with the two phase II readout on higher prevalent PIDs on Joenja, and at the end of next year with the expected readout of the pivotal trial for napazimone. We are clearly building a future-ready company that is able to scale and is able to leverage the, in my opinion, world-class capabilities that we have developed in rare and ultra-rare disease. We have made some changes to the leadership team to make sure that we have a fit-for-purpose team that can really embrace those opportunities and take the company to a whole new level. Clearly the goal is to deliver on our vision by building a scalable organization.
I hope that the presentation that Anurag Relan and I just delivered give you a good overview of where Pharming is coming, what are our current priorities, and what are the very significant potential in the years to come. I personally joined Pharming a year ago, as I could see the opportunity to apply a 5x mindset to a commercial-stage company, which is not often the case. Clearly, we've been very encouraged with how things have developed, and we are clearly determined to redeliver on our ambition. Thank you very much, and we'll be very happy to take any questions.
Well, thank you both for the overview on Pharming. Obviously exciting setup here with both some top-line growth as well as some extensive clinical activity. Maybe to start off with on RUCONEST, there's been the last two years, three new prophylactic HAE products were approved, one in the acute HAE segment. Yet last year you were able to show, I forget, 25% or 26% year-over-year growth. Pretty impressive for a product that's been on the market for 10 years. Maybe just highlight what drove that growth in 2025.
Absolutely. It's true that the drug actually grew very significantly last year. I think as I said earlier, this is a drug that has carved out a very specific sub-segment of the on-demand market, about 20%, because it has a very specific value proposition for that sub-segment. Given its unique mechanism of action and unique mode of administration, the drug allows those difficult-to-treat patients to have the level of efficacy and reliability that they need. These patients, unfortunately, do not take RUCONEST by choice. They take RUCONEST because they need RUCONEST. We see actually a very strong emotional connection between the treatment, RUCONEST, and themselves because often these patients have failed so many treatments that finally they were able to get their life back, and this is the type of things that we hear, and that triggered that emotional connection.
Over the past couple of years, a lot of the RUCONEST growth has been driven by the new guidelines for C1 normal. C1 normal patients are often most severe patients and naturally, RUCONEST obviously has been able to carve out a disproportionate share of these patients. Overall, the drug obviously is being used by all type of patients, Type one, Type two, and C1 normal.
Got it. On Joenja, sounds like you have some clarity regarding the CRL and you're getting ready to refile. How many pediatric patients do you think are warehoused and waiting for approval here, and could get on the product upon approval?
Which is true that we've had that Type A meeting two weeks ago with the FDA, and we're waiting for the minutes to share more with the investor community. We have already identified more than 50 pediatric patients in the U.S. About a third of them are already on Joenja through access programs. We expect to identify many more, obviously. As I said, the prevalence indicates about 150 pediatric patients 12 years and younger in the U.S., 50 of them identified, so clearly a very significant opportunity. What's important to note is as we continue to grow in the adult segment, by unlocking this new pediatric opportunity will allow actually to accelerate the growth because we're going to continue to identify adult patients and will be able to add as well those pediatric patients.
This is actually what's really attractive, because clearly we see a number of growth opportunities with Joenja in the near term.
Okay. Maybe one last one since we're coming up on time. Regarding the VUS reclassification, who is this driven by? Are the regulators involved or it's mostly an academic exercise?
No regulatory involvement, really. Really, what it is is an academic exercise combined with the genetic testing labs that review the information that's published by the academics. The labs take all of the information that's known about a given variant and then analyze that and then determine if there's enough information to be able to classify a variant as disease-causing or not. Once it's classified as disease-causing, then there really isn't any need for any further work to be done.
Got it. Okay. Well, gentlemen, thank you for joining us this morning. We appreciate you giving us an overview in Pharming. Have a great rest of the week.
Thank you.
Thanks.
Have a great conference.
Thank you.