PIK3R1

Joenja® is the first and only medicine specifically for APDS to be reimbursed within the NHS Recommended for adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) April 23, 2025: Pharming Group N.V. (“Pharming” or “the Company”) (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces that the National Institute for Health and Care Excellence (NICE) has issued positive final guidance recommending Joenja® (leniolisib) for reimbursement and use within the National Health Service (NHS) in England and Wales for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. The NICE recommendation is based on the totality of the data, including the Phase III clinical trial evaluating leniolisib, an oral selective PI3Kδ inhibitor, in patients with APDS, a rare and progressive primary immunodeficiency. In the primary analysis, treatment with leniolisib led to significant improvements in immune deficiency and immune dysregulation compared to placebo. The Phase III trial demonstrated an improvement in clinical outcomes, which was maintained during longer-term treatment within the open-label extension trial. Fabrice Chouraqui, Chief Executive Officer of Pharming, said: “This positive recommendation for Joenja® from NICE is a significant milestone for patients living with APDS in England and Wales. It underscores Pharming’s commitment to work closely with regulatory and reimbursement authorities, the medical immunology community, and patient associations to bring this first targeted treatment to patients who may benefit.” Professor Sinisa Savic, Professor of Clinical Immunology at St James’s University Hospital, said: “Data from clinical trials demonstrate that leniolisib provides real benefits for patients with APDS, a rare primary immunodeficiency. APDS is a complex and progressive condition that leads to immune dysregulation and recurrent infections, significantly impacting patients' quality of life. The recommendation by NICE, which allows this targeted therapy to be prescribed on the NHS, marks an important step forward in improving treatment options for individuals with this condition.” Dr Susan Walsh, Chief Executive Officer at Immunodeficiency UK, said: “This is a hugely welcomed decision that will make a massive difference to the lives of people with APDS, and their families, by potentially allowing them to have a better quality of life. With leniolisib, we now have a targeted treatment available that addresses the fundamental cause of the immune system problems experienced in APDS. This is a huge leap forward. We are grateful to Pharming for working with NICE to make this drug available via the NHS. Together, they have shown a real commitment to providing people affected by ultra-rare, immune system conditions the treatments they need.” The final NICE recommendation aligns with the U.K. Medicines and Healthcare products Regulatory Authority (MHRA) approval and falls under NICE’s Highly Specialised Technologies (HST) pathway, which evaluates treatments for very rare and severe diseases. Leniolisib is now available for use and funded in England through the Innovative Medicines Fund, ensuring immediate patient access. In Wales, leniolisib is expected to be funded within the next three months through the NHS in specialist centers. APDS is a rare primary immunodeficiency that was first characterized in 2013. APDS is caused by variants in either one of two identified genes known as PIK3CD or PIK3R1, which are vital to the development and function of immune cells in the body. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway, which causes immune cells to fail to mature and function properly, leading to immunodeficiency and dysregulation1,2,3 APDS is characterized by a variety of symptoms, including severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.4,5 Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, it has been reported that people with APDS are frequently misdiagnosed and suffer a median 7-year diagnostic delay.6 As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.4-7 A definitive diagnosis can be made through genetic testing. APDS affects approximately 1 to 2 people per million worldwide. Joenja® (leniolisib) is an oral small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor approved in the U.S., U.K., Australia and Israel as the first and only targeted treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Joenja® inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, which serves as an important cellular messenger and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Results from a randomized, placebo-controlled Phase III clinical trial demonstrated statistically significant improvement in the coprimary endpoints, reflecting a favorable impact on the immune dysregulation and deficiency seen in these patients, and interim open label extension data has supported the safety and tolerability of long-term leniolisib administration.8,9 Leniolisib is currently under regulatory review in the European Economic Area, Canada and several other countries for APDS, with plans to pursue regulatory approval in Japan. Leniolisib is also being evaluated in two Phase III clinical trials in children with APDS and in two Phase II clinical trials in primary immunodeficiencies (PIDs) with immune dysregulation. The safety and efficacy of leniolisib has not been established for PIDs with immune dysregulation beyond APDS. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. We are commercializing and developing a portfolio of innovative medicines, including small molecules and biologics. Pharming is headquartered in Leiden, the Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. References Lucas CL, et al. Nat Immunol. 2014;15(1):88-97. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. Nunes-Santos C, Uzel G, Rosenzweig SD. J Allergy Clin Immunol. 2019;143(5):1676-1687. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606. Maccari ME, et al. Front Immunol. 2018;9:543. Jamee M, et al. Clin Rev Allergy Immunol. 2020 Dec;59(3):323-333. Condliffe AM, Chandra A. Front Immunol. 2018;9:338. Rao VK, et al Blood. 2023 Mar 2;141(9):971-983. Rao VK, et al. J Allergy Clin Immunol 2024;153:265-74. The content above comes from the network. if any infringement, please contact us to modify.

导读前几节我们介绍了RTKs（第一、二期）、MAPK通路（第三期），今天我们介绍另一个在RTKs下游、与MAPK平行的另一个重要通路—PI3K通路。01PI3K的组成与激活方式磷脂酰肌醇3-激酶（Phosphatidylinositide 3-kinases，PI3K）是一种胞内磷脂酰肌醇激酶，具有磷脂酰肌醇激酶活性的同时，也具有丝氨酸/苏氨酸(Ser/Thr)激酶活性。PI3K可分为3类，其中研究最广泛的为I类PI3K, 此类PI3K为异源二聚体，由一个调节亚基p85（由PIK3R1基因编码）和一个催化亚基p110（由PIK3CA基因编码）组成。催化亚基共有α、β、δ、γ四种类型，其中，α、β、δ类对应p85α, p85β或p55调节亚基；而γ类对应p101和p84/87调节亚基。调节亚基具有SH2结构域，能够识别RTKs的胞内激酶结构域（TK），并引发催化亚基p110的激活。图 1. PI3K的激活方式PI3K的激活方式一共有4种。如上图所示，当胰岛素家族生长因子激活相应的RTKs时，p85可以通过IRS1等接头蛋白（Adapter Protein）间接被接活（a）；此外，其他家族生长因子及RTKs结合时，p85也可以直接识别TK结构域（b）；上一期中我们提到的RAS蛋白在RAS-GTP的形式下，也可以直接活化PI3K 的催化亚基p110（c）。Raf和PI3K均可被RAS调节是MAPK通路与PI3K通路存在交叉的主要原因；此外，γ型PI3K催化亚基还可以被某些G蛋白偶联受体激活（d）。02P13K催化功能图 2. PI3K催化的反应PI3K激活后能够催化PIP2的3位羟基磷酸化生成PIP3，从而进一步促进下游通路；恰恰相反，细胞中另一种酶PTEN则能催化这个反应的逆过程，并对PI3K下游的通路产生抑制作用。PIP3生成后，可以充当第二信使，同时招募PDK1和AKT蛋白到质膜上，使PDK1磷酸化AKT蛋白的308号位的苏氨酸（T308），导致AKT部分活化。被活化的AKT将进一步激活下游调控通路。03PI3k-AKT 通路图 3. PI3K-AKT及下游蛋白AKT 是一类 AGC 家族的丝氨酸/苏氨酸激酶，主要包含3 个结构域：PH 结构域（对 PIP3 有亲和力，对与胞膜的结合至关重要）、催化结构域、调节结构域。AKT作为一种原癌基因，在多种细胞过程中发挥关键作用，如葡萄糖代谢，细胞凋亡，细胞增殖，转录和细胞迁移；PI3K/AKT 信号通路失调见于多种人类疾病，包括癌症、糖尿病、心血管疾病和神经疾病。 AKT下游作用的底物分类繁多，结合上图我们对主要的底物进行概述：1、TSC2TSC复合体（结节性硬化症复合体）包含三个亚基：TSC1，TSC2以及TBC1D7，能够负调控mTORC1复合体的活性，起到肿瘤抑制的作用。产生这种作用的主要原理是：TSC2包含的GTP酶活化蛋白（GTPase activating protein，简称GAP）结构域，将GTP形式的RHEB（RAS家族的一种小G蛋白）水解为GDP形式的RHEB，导致RHEB失活，不能激活mTORC1的激酶活性，从而抑制细胞生长。而AKT诱导TSC2蛋白(tuberin) 的939位Ser和 1462位Thr磷酸化后，活性抑制，导致mTOR通路反而被激活；2、BADBAD（Bcl2相关的细胞死亡激动剂）能够正向调节线粒体的凋亡，AKT磷酸化该蛋白后，BAD活性抑制；3、MDM2AKT能够通过磷酸化p53的泛素连接酶—MDM2而使其激活，从而抑制p53产生的细胞周期阻滞与凋亡。4、p21 和 p27    CDK抑制因子p21和p27是两个重要的细胞周期调节因子，在正常细胞 DNA受损伤时 , 被P53诱导产生，抑制DNA复制，增强DNA修复，起到抑癌作用。而AKT磷酸化抑制这些CDK抑制因子后能够抑制其活性。5、GSK3βGSK3β（糖原合成酶激酶3β）是一种在进化上非常保守的丝氨酸/苏氨酸激酶，参与肝糖代谢，在Wnt 通路中扮演重要的角色。正常情况下GSK3β可以磷酸化β-catenin使其经蛋白酶体降解， AKT磷酸化GSK3β后，导致GSK3β失活，不能再磷酸化β-catenin，致使β-Catenin在胞浆内大量聚集，从而进入细胞核并激活与细胞分裂和生长调控相关的基因（如c-myc和Cyclin D1等）。6、IKK ( IκB kinase )IKK ( IκB kinase ) 被AKT磷酸化激活，IKK 进一步磷酸化抑制能够抑制NF-kβ途径的转录因子IκB（注意断句....），最终结果是：AKT正向调控了NF-kβ途径，从而对细胞生存、增殖、侵袭、血管生成和化疗耐药产生影响。 7、WEE1    CDK1抑制激酶—WEE1能够被磷酸化抑制，对有丝分裂产生影响。8、ASK1ASK1 （凋亡信号调节激酶1）是一种能够激活JNK信号通路（MAPK通路的一种，详情见第二期）的MAPKKK，与凋亡诱导，促凋亡和内皮网应激(ERS)有关，AKT磷酸化ASK1后，导致其活性抑制。9、FOXOFOXO是一种凋亡诱导转录因子，AKT磷酸化FOXO后导致其在细胞内重新定位并失去转录活性。综上所述，我们可以看出：AKT所产生的效应最终结果大多引起细胞增殖及避免凋亡。04PI3K-AKT-mTOR 通路及TORC复合物前面我们已经说过了，AKT能够通过抑制TSC2，间接导致RHEB激活mTOR增强。mTOR全称叫做哺乳动物雷帕霉素靶点（mammalian target of rapamycin， mTOR）。mTOR是一类丝/苏氨酸激酶，C端与磷脂酰肌醇激酶（PI3K）催化域同源，但是却不具备酯酶激酶的活性，而具有Ser/Thr蛋白激酶活性。mTOR 能够形成两种复合物：TORC1和TORC2。图 4. PI3K-AKT-mTOR通路除了能被AKT激活外，mTOR还能根据细胞环境的能量与营养情况被激活或抑制。如上图所示，当能量不足（AMP/ATP 比例增高）、缺氧时， TSC2、TSC1形成复合体增强，抑制mTOR复合物形成。当溶酶体氨基酸过量时，H+-vATP酶能够激活带有鸟嘌呤核苷酸交换因子（GEFs)的蛋白复合物Ragulator，从而促进TORC1的形成。图 5. TORC1与TORC2前面已经提到，mTOR有两种复合物：mTORC1 和mTORC2。mTORC1 由 mTOR、mTOR 调节相关蛋白 Raptor、MLST8 和非核心组分 PRAS40、DEPTOR 组成。mTORC2 由 mTOR、mTOR 帕霉素不敏感伴侣 RICTOR、MLST8 和 mSIN1 组成。这两种复合物的主要区别就在于：结合蛋白是Raptor还是Rictor以及相关蛋白是PRAS40还是mSIN1。其中，前者的区别主要决定TORC1对雷帕霉素敏感，而TORC2对雷帕霉素不敏感；而后者的区别则在于：PRAS40是AKT的底物，而mSIN1是MAPK的底物。从功能上来说，TORC2功能较为简单，它能够磷酸化AKT从而对mTOR产生正反馈，促进mTOR进一步活化（与前面PDK1的部分活化呼应）。TORC1则不同，能够继续磷酸化下游多种底物，调控细胞生存、增殖、蛋白质合成、脂质生成、血管生成和自噬等生物过程。05TORC1 下游底物与效应图 6. TORC1下游底物及效应TORC1 与蛋白质合成真核起始因子4E（eIF4E） 是一种帽结合蛋白，可以特异性地识别mRNA的5'端的帽子结构，在真核翻译的起始过程中发挥重要作用。其阻遏蛋白4EBP1磷酸化缺失时，eIF4E 不能被释放出来用于招募核糖体用于激活翻译过程。mTOR通过磷酸化4EBP1，解除其对EIF4E的抑制作用，从而促进翻译和蛋白质的合成。TORC1还可以先磷酸化激活下游AGC家族核糖体S6激酶（S6K1），S6K1可以磷酸化激活核糖体S6蛋白（RPS6）、PDK1（AKT上游激动蛋白）、MDM2（p53抑制因子）、转录调节因子EEF2、接头蛋白IRS等，磷酸化抑制促凋亡蛋白BAD。最终的效应就是：避免细胞凋亡、促进蛋白质合成。TORC1 与脂质合成TORC1除了促进蛋白质合成外，还可以磷酸化激活STAT3 (信号转导与转录激活因子3)促进细胞增殖；激活SREBPs(固醇调节元件结合蛋白)和PPARα和γ(过氧化物酶体增殖物激活受体) 促进脂质合成。TORC1 与血管生成TORC1能够通过激活HIF1α促进血管生成，而HIF1α也可以间接地激活TSC2，从而对TORC产生负调控作用。TORC1与自噬TORC1通过磷酸化抑制下游底物ULK1等自噬相关蛋白，抑制自噬过程。综上所述，TORC1通过磷酸化激活/抑制一系列底物，直接/间接提高了蛋白质和脂质的合成、促进细胞增殖，引起细胞和组织的生长。06PI3K-AKT-mTOR 与肿瘤从上文我们可知，PI3K 通路可以通过多种途径避免细胞凋亡，促进其存活及增殖。PI3K/AKT信号通路在肿瘤发生中广泛的激活，尤其是PIK3CA，PIK3R1，PTEN，AKT等基因存在高频突变（其中PIK3CA基因在大约36%的乳腺癌中存在突变），与肿瘤发生、发展以及耐药密切相关。目前该通路的主要涉及的突变有：1、PIK3CA突变PIK3CA是肿瘤中编码 PI3K 蛋白 P110 亚基的基因，具有较高的突变比例。在前列腺癌、乳腺癌等多种癌症中，超过 10%以上的病例存在PIK3CA 突变。其中，激活型突变占80%以上。激活点突变可以让 PI3K 蛋白不依赖上游信号，而持续保持激活状态。PIK3CA 突变被认为是 EGFR-TKI 治疗产生耐药的潜在原因之一。2、PTEN突变前文我们提到， 抑癌基因PTEN能够产生与PI3K相反的效应，因此其突变也导致癌症发展。在子宫内膜癌、脑癌、皮肤癌和前列腺癌中， 10%以上的病例存在 PTEN 基因突变。3、AKT突变AKT基因家族包括：AKT1，AKT2，AKT3。AKT 在肿瘤中最常见的突变形式，是激活点突变和基因拷贝数异常增加。在乳腺癌、结直肠癌、卵巢癌和膀胱癌中，有相当高比例的病例。图 7. 针对PI3K-AKT-mTOR通路设计的药物如上图所示，目前针对PI3K、AKT以及mTORC靶点的药物研发均有一些进展。参考文献：[1] Robert, Jacques. Textbook of Cell Signalling in Cancer [M]. Springer International Publishing, 2015.[2]  Wagener C , Stocking C , O. Müller. Cancer Signaling - From Molecular Biology to Targeted Therapy[M]. 2017.[3] Amanda H . Cancer cell signalling[M]. Wiley Blackwell, 2014.部分素材来源于网络，侵删。预告第五期：细胞因子通路；第六期：TGFβ通路；原创不易，欢迎发现“分享”和“点赞”

Full year 2024 total revenues increased by 21% to US$297.2 million and exceeded our guidance, driven by record RUCONEST® revenue and strong Joenja® (leniolisib) growth Fourth quarter 2024 total revenues increased by 14% to US$92.7 million, compared to the fourth quarter 2023RUCONEST® full year revenue increased by 11% to US$252.2 million and fourth quarter revenue increased by 9% to US$79.6 million, compared to the fourth quarter 2023Joenja® revenue increased by 147% to US$45.0 million in the first full year post-launch and fourth quarter revenue increased by 66% to US$13.1 million, compared to the fourth quarter 2023Fourth quarter operating profit increased to US$6.7 million from US$1.1 million in the fourth quarter 2023Generated operating profit and positive net cash flows from operations for the second quarter in a rowTwo ongoing Phase II clinical trials of leniolisib for additional primary immunodeficiencies (PIDs) with immune dysregulation, including common variable immunodeficiency (CVID)Completed the acquisition of Abliva AB, adding KL1333 for mitochondrial DNA-driven primary mitochondrial diseases to Pharming’s late-stage clinical pipeline, in line with our vision to become a leading global rare disease companyFabrice Chouraqui appointed as Chief Executive Officer and Executive Director at EGM held on March 4, 20252025 total revenue guidance of US$315 million – US$335 millionPharming to host a conference call today at 13:30 CET (8:30 am EDT) Leiden, the Netherlands, March 13, 2025: Pharming Group N.V. (“Pharming” or “the Company”) (Euronext Amsterdam: PHARM / Nasdaq: PHAR) presents its preliminary (unaudited) financial report for the three months and full year ended December 31, 2024. Chief Executive Officer, Fabrice Chouraqui commented: “I am delighted to have been appointed as CEO of Pharming and am deeply excited for the opportunities that lie ahead. The strength of the results presented today, with record RUCONEST® revenue and strong Joenja® growth, is testament to Pharming’s momentum. We ended 2024 on a strong note, growing total revenues by 21% to US$297.2 million and exceeding our revenue guidance range of US$280-$295 million. This achievement underscores the continued importance of RUCONEST® in the HAE treatment landscape as well as the strong commercial performance of Joenja® in just its first full year of sales. We enter 2025 with a number of regulatory reviews for leniolisib ongoing as we prepare for launches in key markets and for pediatrics. We also advanced our efforts to expand the addressable patient population for leniolisib, with two Phase II trials in additional PIDs now underway. The genetically identifiable PIDs indication and the CVID indication first announced today represent significantly larger market opportunities than APDS, with blockbuster revenue potential. We are also strengthening our clinical pipeline with the acquisition of Abliva, which has now been completed. This adds a potential first-in-disease treatment for primary mitochondrial diseases, KL1333, which has the opportunity to further transform Pharming’s growth trajectory as it too has blockbuster potential. The acquisition aligns with our vision to become a leading global rare disease company and is well aligned with our operational capabilities. We are now moving to start the second wave of patient recruitment for the pivotal FALCON clinical trial as soon as possible. Pharming’s 2024 financial performance was also noteworthy, with the company generating an operating profit and positive net cash flows from operations in the last two quarters of the year. This performance highlights the financial strength of our core commercial business. Looking to 2025, we will continue to invest diligently to grow our portfolio in the U.S. and Joenja® in key countries, to reach more patients with APDS, and to progress the significant opportunities in our R&D pipeline for PIDs and primary mitochondrial diseases. I firmly believe that Pharming is well-positioned to build on this positive momentum and embrace a new cycle of growth, delivering strong long-term value creation for all stakeholders and continuing our mission to serve the unserved rare disease patients. I look forward to working with the Pharming team to make this a reality.” Fourth quarter and full year 2024 highlights Commercialized productsRUCONEST® marketed for the treatment of acute HAE attacks RUCONEST® demonstrated significant strength in the fourth quarter of 2024, with record revenues of US$79.6 million, a 9% increase compared to the fourth quarter of 2023. RUCONEST® revenues for the full year 2024 were a record US$252.2 million, an 11% increase compared to 2023, significantly above our expectation for mid single digit percentage growth. The U.S. market contributed 98% of 2024 revenues, while the EU and Rest of World contributed 2%. The strong RUCONEST® revenue growth in 2024 can be attributed to strong performance in new physicians prescribing RUCONEST®, new patient enrollments, and the total number of patients, which together resulted in over 6% unit sales growth vs. 2023. We achieved over 100 new patient enrollments in the fourth quarter and total enrollments in 2024 were up 24% vs. 2023. We also increased the RUCONEST® physician prescriber base by 11% during the year, in many cases adding previously unknown HAE prescribers. Joenja® (leniolisib) marketed in the U.S. - the first and only approved disease modifying treatment for APDS Joenja® revenues increased to US$13.1 million in the fourth quarter of 2024, a 66% increase compared to the fourth quarter of 2023. This increase was mostly driven by higher volume from the increase in patients on paid therapy in the U.S. compared to the fourth quarter of 2023, and a significant increase in revenues from EU and Rest of World which are from product provided on a named patient basis. Revenue for 2024, the first full year of sales following launch in April 2023, was US$45.0 million, compared to US$18.2 million in 2023. The U.S. market contributed 90% of 2024 revenues, while the EU and Rest of World contributed 10%. As of December 31, 2024, we had 96 patients on paid therapy in the U.S. and an additional five patients enrolled and pending authorization, representing an increase of active patients during the fourth quarter and continued progress enrolling and transitioning eligible patients to paid therapy. APDS patient finding As of December 31, 2024, Pharming had identified over 880 diagnosed APDS patients in global markets, including over 240 patients in the U.S. Of the identified patients in the U.S., over 150 patients are 12 years of age or older and eligible for treatment with Joenja®. Pharming continues to advance several initiatives to diagnose additional APDS patients, including a sponsored genetic testing program in the U.S. and Canada, partnerships with several genetic testing companies who undertake their own testing efforts, and family testing programs. APDS patient finding - VUS resolution Pharming is aware of approximately 1,200 patients in the U.S. with a Variant of Uncertain Significance, or VUS, in the PIK3CD or PIK3R1 genes and is supporting validation studies with various laboratories to confirm which of these variants are pathogenic for APDS. Patients with disease-associated variants would receive a molecular diagnosis of APDS and, therefore, potentially be eligible for Joenja® treatment. Based on data from Pharming’s navigateAPDS sponsored genetic testing program, PIK3CD and PIK3R1 VUSs are found at four times the frequency of those mutations currently classified as pathogenic / likely pathogenic for APDS. Furthermore, a completed literature review and pilot study resulted in 20% of VUS patients being reclassified to APDS, suggesting that there could be a significant increase in the number of APDS patients in the US once those patients with a VUS are reclassified. As previously communicated, Pharming is supporting independent research to evaluate large numbers of VUSs without the need for additional patient testing. VUS resolution via high throughput screening methods is an established approach that is accepted as strong functional evidence for variant classification by various expert organizations including the American College of Medical Genetics (ACMG) and ClinGen (a National Institutes of Health-funded resource). One in vitro high throughput screening study was completed in the fourth quarter of 2024, identifying many novel variants leading to PI3Kδ hyperactivity. Pharming is now supporting clinical genetics laboratories across the US to be able to use their independent variant interpretation to reclassify variants and thus issue amended genetic testing reports for any variants these laboratories deem to be disease-causing. We anticipate that these endeavors will lead to the identification of new patients with APDS. Joenja® (leniolisib) developmentLeniolisib for APDS During 2024, we received regulatory approvals for leniolisib for patients 12 years of age or older in the U.K. and Israel, and advanced additional regulatory filings, to bring leniolisib to APDS patients outside of the U.S. We also made strong progress in our clinical trials to support APDS marketing approval for leniolisib in Japan and pediatric label expansion. In total, there are currently 188 patients in a leniolisib Expanded Access Program (compassionate use), an ongoing clinical study, or a named patient program. Pediatric clinical development On December 11, 2024, we announced positive top line results for the multinational Phase III clinical trial for children 4 to 11 years of age, which has been evaluating leniolisib tablets in 21 children with APDS. The data are consistent with the improvements seen in the previously reported randomized controlled trial in adolescent and adult APDS patients. Global regulatory filings are planned to begin with a U.S. submission in the second half of 2025. Japan clinical trial We completed an interim analysis, after 12-weeks of treatment, for the Phase III clinical trial in Japan evaluating leniolisib for the treatment of APDS in adult and pediatric patients 12 years of age and older. The study’s safety and efficacy findings were in line with data from the randomized controlled trial used to support approvals in adolescent and adult APDS patients in the U.S. and other countries, and support a regulatory filing with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) which is planned for mid-2025. An approval decision would be expected in nine months based on priority review of the application due to orphan drug designation (ODD) by the Ministry of Health, Labour and Welfare of Japan (MHLW) for the treatment of APDS. European Economic Area (EEA) We are on track to complete the manufacturing activities requested by the European Medicines Agency’s (EMA) Committee for Human Medicinal Products (CHMP) in regard to the ongoing review of the Marketing Authorisation Application (MAA) for leniolisib for the treatment of adult and pediatric patients 12 years of age and older and submit a response prior to the January 2026 deadline. United Kingdom On September 25, 2024, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorization for Joenja® (leniolisib) for the treatment of APDS in adult and pediatric patients 12 years of age and older. Leniolisib is currently under evaluation by the National Institute for Health and Care Excellence (NICE) regarding reimbursement within the National Health Service (NHS) in England and Wales. Additional markets In Australia, we filed a regulatory submission for patients 12 years of age and older in the third quarter of 2023 and, after positive feedback from the Australian Advisory Committee on Medicines, expect a final decision by mid-March 2025. We filed a regulatory submission in Canada for APDS patients 12 years of age and older in the third quarter of 2023. We have had ongoing interactions with Health Canada that recently granted an extension to February 2026 to respond to a request for additional CMC data, in line with the EMA extension. We plan to respond in early 2026 and expect a regulatory decision in 2026. Leniolisib for additional primary immunodeficiencies (PIDs) We made strong progress during 2024 on our leniolisib indication expansion efforts. We are developing leniolisib for additional primary immunodeficiencies, or PIDs, which affect significantly more patients than APDS. These include (i) genetically identifiable PIDs with immune dysregulation linked to altered PI3Kδ signaling and (ii) common variable immunodeficiency, or CVID, with immune dysregulation identified independently of genetics. We started the Phase II clinical trial evaluating leniolisib for PIDs with immune dysregulation linked to altered PI3Kẟ signaling in October 2024, and started a Phase II clinical trial for CVID with immune dysregulation in February 2025. Primary immunodeficiencies (PIDs) with immune dysregulation linked to altered PI3Kδ signaling On October 10, 2024, Pharming announced the start of a Phase II, proof of concept, clinical trial evaluating leniolisib in PIDs with immune dysregulation linked to PI3Kẟ signaling in lymphocytes, with similar clinical phenotypes and unmet medical needs to APDS. The first patient was dosed in the study on October 29, 2024 and enrollment is progressing. The clinical trial includes PID patients with ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency, among others. Epidemiology suggests a prevalence of approximately seven and a half patients per million in this targeted PID population, compared to one to two patients per million for APDS. The Phase II clinical trial is a single arm, open-label, dose range-finding study to be conducted in approximately 12 patients. The objectives for the trial are to assess safety and tolerability, pharmacokinetics, pharmacodynamics, and explore clinical efficacy of leniolisib in the targeted PID population. In February 2025, the FDA granted Fast Track designation for leniolisib for the treatment of PIDs linked to PI3Kẟ signaling. Fast Track is an FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Common variable immunodeficiency (CVID) with immune dysregulation CVID with immune dysregulation represents a much larger group of PID patients, which may be identified independently of genetics, and with a targeted population prevalence of approximately 39 patients per million. The majority of CVID patients with immune dysregulation exhibit a spectrum of noninfectious autoimmune and end-organ lympho-infiltrative disease manifestations with similarities to APDS. We engaged with the FDA and EMA on the CVID indication, and received positive feedback regarding the large unmet medical need and the rationale for evaluating leniolisib in CVID patients with immune dysregulation. We have initiated a Phase II study for leniolisib in CVID patients with immune dysregulation, with the first patient expected to be dosed in late March 2025. Acquisition of Abliva AB In December 2024, we announced the proposed acquisition of Abliva AB, via a public cash offer to the shareholders to acquire all issued and outstanding shares of Abliva, for approximately US$66.1 million. Abliva’s lead product KL1333 is currently in a pivotal clinical trial in mitochondrial DNA-driven primary mitochondrial diseases and has the potential to significantly enhance our future growth trajectory. We announced that we did not require external funding to fund the acquisition and development costs for KL1333. KL1333 for mitochondrial DNA-driven primary mitochondrial diseases KL1333 is in a pivotal clinical study (FALCON) in adult patients with genetically confirmed primary mitochondrial disease (PMD) with mitochondrial DNA (mtDNA) mutations who experience consistent, debilitating fatigue and muscle weakness (myopathy), and reduced life expectancy. Over 30,000 patients diagnosed with mtDNA mitochondrial disease would be potentially addressable by KL1333 in the U.S., EU4 (France, Germany, Italy, Spain) and the UK, offering blockbuster potential for this product in the U.S. alone. KL1333 has shown positive clinical effects in a proof-of-concept Phase 1b study, and a pre-planned interim analysis of the ongoing pivotal FALCON trial demonstrated promising differences over placebo in both alternate primary efficacy endpoints passing futility. KL1333 has received Fast Track designation in the U.S. and Orphan Drug Designation for the treatment of PMD in the U.S. and EU. We are now moving to start the second wave of patient recruitment for the pivotal FALCON clinical trial as soon as possible. We anticipate the trial to read-out in 2027 with potential FDA approval by end of 2028. Organizational updates Ms. Inés Bernal was appointed Chief People Officer, or CPO, as of December 1, 2024, to lead the development, execution and monitoring of Pharming's people and culture strategy.On October 24, 2024, we announced that Mr. Sijmen de Vries, Executive Director and Chief Executive Officer, had informed the Board of Directors that he would not be available for reappointment at our next AGM. Subsequent events On January 21, 2025, we announced that the Board of Directors had nominated biopharmaceutical leader Mr. Fabrice Chouraqui as Pharming’s new Chief Executive Officer and Executive Director, succeeding Mr. Sijmen de Vries. Mr. Chouraqui was appointed for a term of four years at the Extraordinary General Meeting of Shareholders (EGM) that took place on March 4, 2025. Upon the appointment of Mr. Chouraqui, Mr. Sijmen de Vries resigned from the Board of Directors. To ensure a smooth hand-over of tasks and responsibilities, Mr. de Vries will remain a strategic advisor to the new CEO until December 31, 2025. On February 20, 2025, we announced ownership of shares and voting rights in Abliva AB exceeding 90% and thereby initiated the necessary activities to delist the Company from the Nasdaq Stockholm exchange. Following delisting, we expect to be able to start the second wave of patient recruitment for the ongoing pivotal FALCON clinical trial for KL1333 for the treatment of mtDNA-driven primary mitochondrial diseases. Pharming has initiated a compulsory acquisition procedure in respect of the remaining shares in Abliva under the Swedish Companies Act. On March 3, 2025, Nasdaq Stockholm approved Abliva’s application for delisting and the last day of trading will be March 17, 2025. With these events, the acquisition of Abliva is now completed. The acquisition of Abliva will be accounted for as a business combination. Substantially all of the value of the acquisition is concentrated in a single asset, KL1333. Following delisting as expected in March 2025, the acquisition would be reflected in our financial statements beginning with the first quarter 2025. At this point we expect the US$66.1 million acquisition price to be allocated to the fair value of the acquired identifiable assets and liabilities, with any excess to be recorded as goodwill. We do not expect any P&L impact at the acquisition date, besides recognition of acquisition costs incurred in 2025.Financial Summary Consolidated Statement of Income4Q 20244Q 202320242023Amounts in US$m except per share data Total Revenues92.781.2297.2245.3Cost of sales(12.2)(7.1)(35.4)(25.2)Gross profit80.574.1261.8220.1Other income0.10.62.223.3Research and development(22.3)(11.6)(83.2)(68.9)General and administrative(24.6)(24.1)(70.6)(55.9)Marketing and sales(27.0)(37.9)(118.8)(124.0)Other Operating Costs(73.9)(73.6)(272.6)(248.8)Operating profit (loss)6.71.1(8.6)(5.4)Fair value gain (loss) on revaluation(0.2)(0.9)5.0(0.9)Other finance income3.11.66.83.7Other finance expenses(2.5)(4.5)(9.9)(9.1)Share of net profits in associates using the equity method(0.5)0.7(1.8)(0.3)Profit (loss) before tax6.6(2.0)(8.5)(12.0)Income tax credit (expense)(2.9)(1.1)(2.5)1.5Profit (loss) for the period3.7(3.1)(11.0)(10.5)Share Information Basic earnings per share (US$)0.005(0.004)(0.016)(0.016)Diluted earnings per share (US$)0.005(0.004)(0.016)(0.016)Segment information - Revenues4Q 20244Q 202320242023Amounts in US$m Revenue - RUCONEST® (US)78.271.9246.6221.2Revenue - RUCONEST® (EU and RoW)1.41.45.65.9Total Revenues - RUCONEST®79.673.3252.2227.1Revenue - Joenja® (US)11.87.640.517.9Revenue - Joenja® (EU and RoW)1.30.34.50.3Total Revenues - Joenja®13.17.945.018.2 Total Revenues - US90.079.5287.1239.1Total Revenues - EU and RoW2.71.710.16.2 Total Revenues92.781.2297.2245.3Consolidated Balance SheetDecember 31, 2024December 31, 2023Amounts in US$m Cash and cash equivalents, restricted cash and marketable securities169.4215.0Current assets278.7316.3Total assets400.8462.9Current liabilities73.878.0Equity221.9218.8 Financial highlights Fourth quarter 2024 Revenues in the fourth quarter of 2024 increased by 14% to US$92.7 million from US$81.2 million in the fourth quarter of 2023 (US$74.8 million in the third quarter of 2024). RUCONEST® revenues amounted to US$79.6 million, a 9% increase compared to the fourth quarter of 2023. A volume increase in the U.S., and a U.S. price increase in line with CPI, were the primary factors behind this increase in RUCONEST® revenues. Joenja® revenues amounted to US$13.1 million in the fourth quarter of 2024, a 66% increase compared to the fourth quarter of 2023. This increase was primarily driven by an increase in volume. Gross profit increased by US$6.4 million or 9% to US$80.5 million (4Q 2023: US$74.1 million), mainly due to the increase in revenues. This was partially offset by increased cost of sales, in part due to a one-off inventory impairment due to a power outage during the production process (US$ 1.1 million). The operating profit amounted to US$6.7 million compared to an operating profit of US$1.1 million in the fourth quarter of 2023. This increase was primarily due to the increase in gross profit mentioned above, offset by the increase in operating expenses from US$73.6 million in the fourth quarter of 2023 to US$73.9 million. Fourth quarter 2024 operating expenses increased by US$9.2 million from US$64.7 million in the third quarter of 2024. Part of this 2024 increase was caused by one-off expenses, totaling US$6.2 million, including the full impairment of US$5.1 million (4Q 2023: US$4.7 million) on the leased DSP facility at Pivot Park in Oss, the Netherlands. Also contributing to the fourth-quarter increase were legal and advisory fees associated with the acquisition of Abliva AB, totaling US$1.1 million for the fourth quarter of 2024. The net finance result amounted to a gain of US$0.4 million compared to a loss of US$3.8 million in the fourth quarter of 2023. This was primarily driven by favorable EUR/USD exchange rate developments, resulting in a foreign currency gain of US$2.6 million compared to a loss of US$2.9 million in the fourth quarter of 2023. Interest expense increased by US$1.5 million in the fourth quarter of 2024 compared to the previous year, following the convertible bond issuance in the second quarter of 2024. In the fourth quarter of 2024, a net profit of US$3.7 million was realized, in contrast to a net loss of US$3.1 million in the fourth quarter of 2023. This improvement was primarily driven by the rise in gross profit supported by favorable EUR/USD exchange rate developments, partially offset by the increase in operating expenses. Cash and cash equivalents, including restricted cash and marketable securities, decreased from US$173.3 million at the end of third quarter of 2024 to US$169.4 million at the end of the fourth quarter of 2024. This decrease was primarily driven by EUR/USD exchange rate developments (vast majority of cash and marketable securities position is EUR denominated), offset by positive cash flows from operations of US$9.3 million (4Q 2023: US$11.6 million), which includes a deduction of US$1.7 million in paid taxes (4Q 2023: US$0.7 million). Full year 2024 In 2024, Pharming revenues increased by 21% to US$297.2 million. However, the operating loss declined to a loss of US$8.6 million, compared to a loss of US$5.4 million in 2023. Similarly, the net loss declined to US$11.0 million, compared to a net loss of US$10.5 million in 2023. This section will further elaborate on Pharming's financial performance in 2024. Revenues and Gross Profit Total revenues for 2024 grew by 21%, reaching US$297.2 million, compared to US$245.3 million in 2023. Total RUCONEST® revenues were 11% higher at US$252.2 million, compared to revenues of US$227.1 million for 2023. Joenja® revenues amounted to US$45.0 million in 2024, a 147% increase compared to 2023 (first sales commenced at the start of the second quarter of 2023). This increase was primarily driven by an increase in volume. Cost of sales increased by 40% from US$25.2 million in 2023 to US$35.4 million in 2024. Cost of inventories recognized as expenses in 2024 amounted to US$25.6 million compared to US$21.4 million in 2023. In addition to the higher unit sales volume, the rise was primarily attributed to rising production costs for RUCONEST®. The remainder of the increase in cost of sales in 2024 mainly stem from one-off impairment charges on inventory of US$4.8 million (2023: US$1.7 million) and royalty payments to Novartis on Joenja® sales of US$4.9 million (2023: US$2.1 million). Gross profit increased by US$41.7 million, or 19%, to US$261.8 million for the year 2024. The primary driver for this increase was higher sales volumes of RUCONEST® and Joenja®. Other income Other income decreased to US$2.2 million compared to US$23.3 million in 2023. Other income in 2023 was supported by the sale of the Rare Pediatric Disease Priority Review Voucher (PRV) to Novartis for a pre-agreed, one-time payment of US$21.3 million. Operating Profit (loss) and Other Operating Costs For 2024, the operating loss increased to a loss of US$8.6 million compared to a loss of US$5.4 million for the prior year. This change was mainly due to the decrease in other income and the expected increase in operating expenses from US$248.8 million in 2023 to US$272.6 million, offset by the above mentioned increase in gross profit in 2024. The increase in operating expenses in 2024 was primarily related to a combination of continuing investments in Joenja® in the U.S., launch preparation for leniolisib outside of the U.S., increasing R&D investments to expand the addressable patient population for leniolisib, and increased payroll expenses due to business growth. Operating expenses in 2024 include one-off expenses, totaling US$6.2 million, including expenses related to the full impairment of the DSP facility at Pivot Park in Oss, the Netherlands, amounting to US$5.1 million (2023: US$4.7 million). Also contributing to the increase were legal and advisory fees associated with the acquisition of Abliva AB, totaling US$1.1 million in the fourth quarter of 2024. Operating Profit (loss) excluding one-time events The 2023 operating expenses included milestone payments for Joenja® of US$10.5 million in the second quarter and other income included one-time proceeds from the PRV sale of US$21.3 million. When compared on a like-for-like basis, excluding these one-time events in 2023, the operating loss decreased from US$16.2 million in 2023 to US$8.6 million in the current year. Finance income and expenses The net finance result amounted to a gain of US$1.9 million compared to a loss of US$6.3 million in 2023. This was primarily driven by a fair value gain of US$7.0 million upon the reclassification of the convertible bond-related derivative to equity. This fair value gain was a result of the decrease in value of the option component classified as a derivative from issuance until the physical settlement date of the newly issued convertible bond. Further positive results stem from favorable EUR/USD exchange rate developments, which led to a foreign currency gain of US$2.0 million compared to a loss of US$3.0 million in 2023. In addition, interest income from investments in marketable securities, which commenced in the second quarter of 2023, increased by US$1.2 million. These positive results were partially offset by the negative fair value adjustments in the BioConnection preference share of US$2.1 million (2023: US$0.9 million negative), US$2.8 million higher interest expenses and fees of US$1.2 million related to the 2024 issued convertible bond. Income tax credit (expense)Income tax credit (expense) shifted from a US$1.5 million credit for the year ending December 31, 2023, to a US$2.5 million expense for the year ending December 31, 2024. This tax expense mainly results from the profits of Pharming in the US being taxed against a US Federal and State combined tax rate of 27.96%, while the losses in the Netherlands only partly result in an offsetting tax credit, as the share-based compensation expenses and losses in associates are generally non-deductible based on Dutch tax law.Net loss for the year The Company had a net loss of US$11.0 million in 2024, compared to a net loss of US$10.5 million in 2023. In addition to the support in other income from the PRV and the milestone payments for Joenja® in 2023, the change was mainly due to an increase in gross profit, favorable EUR/USD exchange rate developments and the fair value gain upon the reclassification of the convertible bond-related derivative to equity, offset by an increase in operating expenses, higher tax expenses and higher interest expenses and fees on the 2024 issued convertible bonds. Intangible assets In 2024, intangible assets decreased by US$10.2 million, from US$71.3 million in 2023 to US$61.0 million in 2024. This decrease primarily resulted from regular amortization (amounting to US$6.3 million) and negative foreign currency effects (equivalent to US$4.0 million). The amortization relates to regular amortization of software, the RUCONEST® licenses (US and EU) and the Joenja® license. The RUCONEST® license has a remaining amortization period of 13 years for the US and 7 years for the EU. The Joenja® license has a remaining amortization period of 12 years. Property, plant and equipment The value of property, plant and equipment decreased from US$9.7 million in 2023 to US$7.8 million in 2024. This decline was primarily driven by regular depreciation (US$2.3 million) and negative foreign currency effects (US$0.5 million), partially offset by capital expenditures (US$0.8 million). Right-of-use assets The right-of-use assets decreased from US$23.8 million in 2023 to US$16.1 million in 2024. This decline was primarily driven by regular depreciation (amounting to US$3.9 million), negative foreign currency effects (equivalent to US$0.9 million) and the full impairment of the DSP facility at Pivot Park in Oss, the Netherlands (totaling US$5.1 million). The decrease in the right-to-use assets is partially offset by additions of cars (US$2.4 million) and building remeasurements (US$0.3 million). The 2024 building remeasurements were related to adjustments in the existing right-of-use assets to account for inflation-related higher lease payments. Investments Investments decreased by US$6.2 million to US$4.2 million as of December 31, 2024. This decline was primarily driven by the disposal of the equity investment in Orchard of US$2.1 million (following take-over), Pharming’s share in the net loss of BioConnection of US$1.1 million and US$0.6 million impairment to equity value (accounted for using the equity method) and a fair value decrease of US$2.1 million in the preference share in BioConnection, carried at fair value through the statement of profit and loss (FVTPL). Inventories Inventories decreased from US$56.8 million as of December 31, 2023 to US$55.7 million as of December 31, 2024. Cash and cash equivalents and marketable securities Cash and cash equivalents alone decreased by US$6.8 million to US$54.9 million as of December 31, 2024. The cash and cash equivalents position is managed in combination with the marketable securities position. The combined total of cash and cash equivalents, together with restricted cash and marketable securities decreased from US$215.0 million at year-end 2023 to US$169.4 million at year-end 2024. This decrease was primarily driven by paid taxes of US$15.6 million and the repurchase of the outstanding convertible bonds amounting to US$134.9 million, offset by net proceeds of US$104.5 million for newly issued convertible bonds. Following negative operating cash flow in the first half of 2024, the third and fourth quarter operating cash flows were positive, also when adjusted for share based compensation. Shareholders’ equity Shareholders’ equity increased by US$1.6 million from US$218.8 million for the year ended December 31, 2023 to US$220.4 million for the year ended December 31, 2024. This increase was primarily driven by transactions recognized directly in equity relating to share based compensation and exercised options (totaling US$13.9 million) and the recognition of the value conversion rights of US$12.2 million related to the issued convertible bond in 2024. These increases were offset by the net loss of US$12.5 million and the other comprehensive loss of US$11.9 million. The other comprehensive loss was primarily driven by currency translation differences. Convertible bond The convertible bond position has decreased by US$56.0 million to US$82.4 million at year-end 2024, moving from US$138.4 million as of December 31, 2023. This decrease was mainly driven by the repurchase of the outstanding convertible bonds amounting to US$134.9 million, offset by the initial recognition of the newly issued convertible bonds for US$81.8 million. The difference between the initial recognition of the newly issued convertible bonds and the respective net proceeds of US$104.5 million relates to the initial value of the conversion option component. Following a fair value gain of US$7.0 million until the physical settlement date, the value of the conversion option component was reclassified to equity. Subsequently, the value of this equity component is not remeasured and amounts to US$12.2 million, net of income tax effects, at December 31, 2024. Lease liabilities Lease liabilities decreased by US$3.2 million, moving from US$33.1 million as of December 31, 2023 to US$29.9 million as of December 31, 2024. This decrease was primarily driven by monthly or quarterly lease payments of US$5.1 million and for the most part offset by new leases (amounting to US$2.4 million). Outlook/Summary For 2025, the Company anticipates: Total revenues between US$315 million and US$335 million (6% to 13% growth), with quarterly fluctuations expected.Total operating expenses not to exceed the prior year pre-Abliva impact, and a preliminary estimate of US$30 million in Abliva-related operating expenses, including research and development and non-recurring transaction and integration expenses.Significant progress finding additional APDS patients in the U.S., supported by VUS validation efforts and subsequently converting patients to paid Joenja® (leniolisib) therapy.Increasing ex-U.S. revenues for leniolisib - driven by funded access programs and commercial availability in the U.K.Progress towards additional regulatory approvals for leniolisib for APDS patients 12 years of age or older, and submitting regulatory filings in Japan and for pediatric label expansion in key global markets.Advancing the two ongoing Phase II clinical trials in PIDs with immune dysregulation to significantly expand the long-term commercial potential of leniolisib.Advancing the ongoing pivotal FALCON clinical study for KL1333 in mitochondrial DNA-driven primary mitochondrial diseases.Continued focus on potential acquisitions and in-licensing of clinical stage opportunities in rare diseases. Financing, if required, would come via a combination of our strong balance sheet and access to capital markets. No further specific financial guidance for 2025 is provided. Additional informationPresentation The conference call presentation is available on the Pharming.com website from 07:30 CET today. Conference Call The conference call will begin at 13:30 CET/08:30 am EDT on Thursday, March 13. A transcript will be made available on the Pharming.com website in the days following the call. Please note, the Company will only take questions from dial-in attendees. Webcast Link: https://edge.media-server.com/mmc/p/7qvoovac Conference call dial-in details: https://register.vevent.com/register/BI7d716758d12d4ad588b70fdbca665b6a Additional information on how to register for the conference call/webcast can be found on thePharming.com website. Financial Calendar 2025 Annual Report and 20-F 2024 April 31Q 2025 financial results May 8Annual General Meeting of Shareholders June 112Q/1H 2025 financial results July 313Q 2025 financial results November 6 For further public information, contact: Pharming Group N.V., Leiden, the NetherlandsMichael Levitan, VP Investor Relations & Corporate Communications T: +1 (908) 705 1696E: investor@pharming.com FTI Consulting, London, UKSimon Conway/Alex Shaw/Amy ByrneT: +44 203 727 1000 LifeSpring Life Sciences Communication, Amsterdam, the NetherlandsLeon MelensT: +31 6 53 81 64 27E: pharming@lifespring.nl About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules and biologics. Pharming is headquartered in Leiden, the Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. For more information, visit www.pharming.com and find us on LinkedIn. Risk profile We continue to closely monitor and manage the key risks and opportunities, and will respond appropriately to any emerging risk. We will issue a full overview of our risk profile in our Annual report 2024 to be published on April 3, 2025. Related party transactions There are no material changes in the nature, scope, and (relative) scale in this reporting period compared to last year. Auditor’s involvement The Condensed Consolidated Interim Financial Statements have not been audited by the Company’s statutory auditor. Forward-looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management’s current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as “aim”, “ambition”, ‘‘anticipate’’, ‘‘believe’’, ‘‘could’’, ‘‘estimate’’, ‘‘expect’’, ‘‘goals’’, ‘‘intend’’, ‘‘may’’, “milestones”, ‘‘objectives’’, ‘‘outlook’’, ‘‘plan’’, ‘‘probably’’, ‘‘project’’, ‘‘risks’’, “schedule”, ‘‘seek’’, ‘‘should’’, ‘‘target’’, ‘‘will’’ and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory, commercial, competitive and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2023 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any forward-looking statement as a result of new information, future events or other information. Inside Information This press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation. Pharming Group N.V. Condensed Consolidated Financial Statements in U.S. Dollars (unaudited) For the period ended December 31, 2024 Condensed consolidated statement of incomeCondensed consolidated statement of comprehensive incomeCondensed consolidated balance sheetCondensed consolidated statement of changes in equityCondensed consolidated statement of cash flow CONDENSED CONSOLIDATED INTERIM STATEMENT OF INCOMEFor the period ended December 31 Amounts in US$ ‘00020242023Revenues297,200245,316Costs of sales(35,399)(25,212)Gross profit261,801220,104Other income2,17723,349Research and development(83,161)(68,914)General and administrative(70,619)(55,877)Marketing and sales(118,819)(124,049)Other Operating Costs(272,599)(248,840)Operating profit (loss)(8,621)(5,387)Fair value gain (loss) on revaluation4,990(930)Other finance income6,8203,663Other finance expenses(9,944)(9,069)Finance result, net1,866(6,336)Share of net profits (loss) in associates using the equity method(1,758)(289)Profit (loss) before tax(8,513)(12,012)Income tax credit (expense)(2,514)1,464Profit (loss) for the period(11,027)(10,548)Basic earnings per share (US$)(0.016)(0.016)Diluted earnings per share (US$)(0.016)(0.016)CONDENSED CONSOLIDATED INTERIM STATEMENT OF COMPREHENSIVE INCOMEFor the period ended December 31 Amounts in US$ ‘00020242023Profit (loss) for the period(11,027)(10,548)Currency translation differences(11,992)5,936Items that may be subsequently reclassified to profit or loss(11,992)5,936Fair value remeasurement investments791,167Items that shall not be subsequently reclassified to profit or loss791,167Other comprehensive income (loss), net of tax(11,913)7,103Total comprehensive income (loss) for the period(22,940)(3,445)CONDENSED CONSOLIDATED INTERIM BALANCE SHEET Amounts in US$ ‘000December 31, 2024December 31, 2023Non-current assets Intangible assets61,03971,267Property, plant and equipment7,7529,689Right-of-use assets16,38223,777Long-term prepayments9092Deferred tax assets31,09029,761Investment accounted for using the equity method4662,285Investments in equity instruments designated as at FVTOCI—2,020Investment in debt instruments designated as at FVTPL3,7676,093Restricted cash1,5051,528Total non-current assets122,091146,512Current assets Inventories55,72456,760Trade and other receivables55,07946,158Marketable securities112,949151,683Cash and cash equivalents54,94461,741Total current assets278,696316,342Total assets400,787462,854Equity Share capital7,7697,669Share premium488,990478,431Other reserves(222)(2,057)Accumulated deficit(274,675)(265,262)Shareholders’ equity221,862218,781Non-current liabilities Convertible bonds78,154136,598Lease liabilities26,96829,507Total non-current liabilities105,122166,105Current liabilities Convertible bonds4,2451,824Trade and other payables66,61172,528Lease liabilities2,9473,616Total current liabilities73,80377,968Total equity and liabilities400,787462,854CONDENSED CONSOLIDATED INTERIM STATEMENT OF CHANGES IN EQUITYFor the period ended December 31Attributable to owners of the parent Amounts in US$ ‘000Share capitalShare premiumOther reservesAccumulated deficitTotal equityBalance at January 1, 20237,509462,297(8,737)(256,431)204,638Profit (loss) for the period———(10,548)(10,548)Reserves—————Other comprehensive income (loss) for the period——7,103—7,103Total comprehensive income (loss) for the period——7,103(10,548)(3,445)Other reserves——(423)423—Income tax benefit from excess tax deductions related to share-based payments———204204Share-based compensation———9,2519,251Options exercised / LTIP shares issued16016,134—(8,161)8,133Value of conversion rights of convertible bonds—————Total transactions with owners, recognized directly in equity16016,134(423)1,71717,588Balance at December 31, 20237,669478,431(2,057)(265,262)218,781 Balance at January 1, 20247,669478,431(2,057)(265,262)218,781Profit (loss) for the period———(11,027)(11,027)Reserves——1,555(1,555)—Other comprehensive income (loss) for the period——(11,913)—(11,913)Total comprehensive income (loss) for the period——(10,358)(12,582)(22,940)Other reserves——(31)31—Income tax benefit from excess tax deductions related to share-based payments———(66)(66)Share-based compensation———11,24811,248Options exercised / LTIP shares issued10010,559—(8,044)2,615Value of conversion rights of convertible bonds——12,224—12,224Total transactions with owners, recognized directly in equity10010,55912,1933,16926,021Balance at December 31, 20247,769488,990(222)(274,675)221,862CONDENSED CONSOLIDATED INTERIM STATEMENT OF CASH FLOWSFor the period ended December 31 Amounts in $’00020242023Profit (loss) before tax(8,513)(12,012)Adjustments to reconcile net profit (loss) to net cash used in operating activities: Depreciation, amortization, impairment of non-current assets16,07015,925Equity settled share based payments11,2489,251Fair value loss (gain) on revaluation(4,990)930Gain on disposal from PRV sale—(21,279)Disposal of leases22—Other finance income(6,820)(3,663)Other finance expenses9,8879,069Share of net profits in associates using the equity method1,758289Other—(1,079)Operating cash flows before changes in working capital18,662(2,569)Changes in working capital: Inventories(503)(14,434)Trade and other receivables(6,783)(18,539)Payables and other current liabilities(2,769)16,228Restricted cash(17)(216)Total changes in working capital(10,072)(16,961) Interest received5,2012,883Income taxes received (paid)(15,584)(655)Net cash flows generated from (used in) operating activities(1,793)(17,302) Capital expenditure for property, plant and equipment(790)(1,437)Proceeds on PRV sale—21,279Investment intangible assets(6)(27)Disposal of investment designated as at FVOCI2,098—Purchases of marketable securities(284,314)(382,014)Proceeds from sale of marketable securities314,630232,811Net cash flows generated from (used in) investing activities31,618(129,388) Payment of lease liabilities(4,008)(4,038)Interests on lease liabilities(1,141)(1,088)Net proceeds of issued convertible bonds104,539—Repurchase of convertible bonds(134,924)—Interests on convertible bonds(4,457)(4,046)Settlement of share based compensation awards5,5798,133Net cash flows generated from (used in) financing activities(34,412)(1,039) Increase (decrease) of cash(4,587)(147,729)Exchange rate effects(2,210)2,128Cash and cash equivalents at the beginning of the period61,741207,342 Total cash and cash equivalents at December 3154,94461,741 ---ENDS--- Attachment Pharming reports 4Q_FY 2024 financial results_EN_13MAR25