PIK3R1

For media and investors only Indicated for adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) Leiden, the Netherlands, September 26, 2024: Pharming Group N.V. (“Pharming” or “the Company”) (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces that the United Kingdom (U.K.) Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorization for Joenja® (leniolisib) for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Leniolisib, an oral, selective PI3Kδ inhibitor, is the first treatment approved in the U.K. specifically for APDS, a rare and progressive primary immunodeficiency. 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.Sijmen de Vries, Chief Executive Officer of Pharming, commented:“The MHRA approval of Joenja®, the first treatment option specifically indicated for APDS, is an important milestone for people in the U.K. living with this debilitating disease. To date, management of APDS has relied on the treatment of the diverse symptoms associated with APDS or for some patients, the need to undergo hematopoietic stem cell transplantation. We are therefore delighted that this product is now approved in the U.K. Today also marks Pharming’s third country approval for APDS, bringing us closer to our goal of becoming a leading global rare disease company dedicated to patient communities with unmet medical needs.”The MHRA evaluated the Marketing Authorisation Application (MAA) for leniolisib through the International Recognition Procedure (IRP) pathway on the basis of the U.S. Food and Drug Administration (FDA) approval received in March 2023.Important Safety Information The full Summary of Product Characteristics (SPC/SmPC) for Joenja® (leniolisib) will be available on the MHRA website at https://products.mhra.gov.uk/. About Activated Phosphoinositide 3-Kinase δ Syndrome (APDS) 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. About leniolisibLeniolisib is an oral small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor approved in the U.S., the U.K. and Israel as the first and only targeted treatment indicated for activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Leniolisib 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 Australia, with plans to pursue further regulatory approvals in Japan and South Korea. Leniolisib is also being evaluated in two Phase III clinical trials in children with APDS. 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.   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. 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.   For further public information, contact:Pharming Group, Leiden, The NetherlandsMichael Levitan, VP Investor Relations & Corporate CommunicationsT: +1 (908) 705 1696E: investor@pharming.com FTI Consulting, London, UKVictoria Foster Mitchell/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 US PRChristina RenfroeE: Christina.Renfroe@precisionaq.com T: +1 (636) 352-7883 Attachment Pharming Group announces marketing authorization UK_EN_26SEP24

SAN FRANCISCO--( BUSINESS WIRE )-- BIOMAKERS , a Precision Medicine & Biotech Company that supports data-driven Drug Development globally, and TOPAZIUM , an AI-driven healthtech company specializing in drug discovery and human wellbeing, have announced the results of their innovative collaborative project. This partnership showcases the power of AI systems in leveraging real-world DNA sequencing data to identify novel targets aimed at improving the efficacy of immunotherapy for non-small cell lung cancer (NSCLC) treatment. The findings were presented at the prestigious 2024 American Society of Clinical Oncology (ASCO) meeting in Chicago. The study used Whole Exome Sequencing (WES) data from biopsies of squamous and adenocarcinoma NSCLC processed through BIOMAKERS ' advanced DNA sequencing platforms. The data was then analyzed using GFPrint™, a proprietary algorithm developed by TOPAZIUM , that generates virtual representations of tumor exomes in a latent space defined by the genetic features of the samples. “The advent of drugs targeting the PD-1/PD-L1 axis has revolutionized NSCLC treatment. Although promising, individual responses to these therapies can vary, and we believe this ongoing project will help to better understand mechanisms involved in PD1/PD-L1 expression, optimize treatment protocols, and identify which patients are most likely to benefit from these therapies. In this study, DNA sequencing and GFPrint™ were employed to identify mutations in genes linked to PD-L1 expression in NSCLC adenocarcinoma tumor samples,” said Dr. Rubén Salanova, Chief Medical Officer & Co-Founder of BIOMAKERS . “Using this strategy, we have identified a subpopulation of adenocarcinoma patients with increased PD-L1 expression levels, enriched in non-silent mutations of 10 genes of interest, mostly included in the HIF-1α signaling pathway. Notably, 6 of these mutated genes (PIK3R1, HK1, NOS2, NRAS, BRAF, ITGA1) were uniquely found in adenocarcinomas” said Juan Manuel Domínguez, Head of Preclinical & Biostatistics at TOPAZIUM . “All these newly identified genes deserve further studies to validate them as potential targets for pharmacological intervention concomitant with PD-1/PD-L1 blockade, and as potential biomarkers for patient selection to improve the efficiency of immunotherapy in NSCLC treatment,” added Andrea Mendoza, Head of R&D at BIOMAKERS . For more details, the abstract can be accessed at: https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e13600 For more information about GFPrint™, visit: https://www.biorxiv.org/content/10.1101/2024.03.08.584090v4 About BIOMAKERS: BIOMAKERS is an Oncology Precision Medicine Company with a Comprehensive Genomic Platform and reach throughout LATAM, delivering care-changing solutions. In addition to its strong focus on physician support and patient care, their Life Science division partners with biopharma companies to advance R&D programs by providing support for Drug Discovery and Drug Development. This innovative work is enabled by direct partnerships with renowned Health Institutions across 17 different countries. contacto@biomakers.net About TOPAZIUM: TOPAZIUM is committed to supporting medical research with artificial intelligence (AI) through state-of-the-art analytical tools. They have developed a comprehensive AI engine that utilizes multiple medical data types to assist in identifying new disease patterns and the most promising therapeutic approaches, striving to achieve one of the most challenging global goals: health for all. info@topazium.com

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读：超过一半的肝细胞癌（HCC）患者因化疗耐药而严重影响了化疗效果。然而，化疗诱导耐药基因上调的机制尚未完全阐明。 7月31日，北京大学杜晓娟研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“Chemotherapy-induced acetylation of ACLY by NAT10 promotes its nuclear accumulation and acetyl-CoA production to drive chemoresistance in hepatocellular carcinoma”，在这项研究中，研究人员揭示了一种新的机制，控制核酸乙酰辅酶A的产生，激活耐药基因在HCC中的转录。在HCC组织中，NAT10的表达上调，其上调与HCC患者的不良预后相关。NAT10也在耐药的HCC细胞中上调。靶向NAT10可增加HCC细胞和小鼠异种移植物对化疗的毒性。在化疗期间，NAT10从核仁转移到细胞核中，激活CYP2C9和PIK3R1的转录。此外，NAT10还特异性上调核酸乙酰辅酶A的表达。机制上，NAT10在细胞核中与ACLY结合，在K468位点乙酰化ACLY，以对抗SQSTM1-介导的降解。ACLY K468-Ac特异性地在细胞核中积累，通过增强H3K27ac来增加核酸乙酰辅酶A的产生，从而激活CYP2C9和PIK3R1的转录。值得注意的是，K468是ACLY在细胞核中定位所必需的。重要的是，HCC组织中ACLY K468-Ac的表达上调，敲除ACLY K468-Ac可增强HCC细胞和小鼠异种移植物对化疗的敏感性。 这些研究结果共同表明，NAT10是一种新型的耐药驱动因子。阻断NAT10介导的ACLY K468-Ac具有缓解HCC耐药性的潜力。 https://www.nature.com/articles/s41419-024-06951-9#Sec12 背景知识 01 肝细胞癌（HCC）是全球第三大癌症死亡原因，每年约有60万人因此死亡。大多数HCC患者在晚期被诊断出来，失去了进行手术切除的机会。化疗和酪氨酸激酶抑制剂（TKIs）已成为晚期HCC患者的主要治疗手段。最近有报道称，基于化疗的肝动脉灌注（HAIC）可以避免经动脉化疗栓塞术（TACE）引起的缺氧，使HCC患者的总生存期延长5.1个月，比索拉非尼为基础的TKIs治疗效果更好，成为治疗晚期HCC患者的一种有前景的治疗手段。然而，约54%的HCC患者对化疗为基础的HAIC没有反应，因为存在化疗耐药性。因此，更好地了解化疗耐药的机制将为改善HCC的治疗效果提供新的策略。 化疗耐药是由药物转运、药物代谢、细胞存活信号通路和DNA损伤修复相关基因的转录上调引起的。在这些通路中，细胞色素P450 (P450)酶的表达和活性的增加通过促进药物在HCC中的代谢来降低全身药物水平。更重要的是，AKT信号通路的过度激活通过抑制凋亡和促进细胞存活来促进肝癌的化疗耐药。因此，这些基因的转录上调在化疗耐药中起着驱动作用。 基因转录通过组蛋白乙酰化激活，乙酰化中和组蛋白正电荷，从而放松组蛋白和DNA之间的相互作用，从而促进转录因子与启动子的结合。乙酰辅酶A (acetyl- coa)是蛋白质乙酰化的必需乙酰供体，而乙酰辅酶A对组蛋白乙酰化高度敏感。鉴于乙酰辅酶A是一种高能量且不稳定的分子，乙酰辅酶A在细胞核内的快速生成可能确保其在DNA损伤的化疗中用于组蛋白乙酰化。此外，乙酰辅酶A在不同的亚细胞区室中的丰度受到生理条件或应激的精确控制。因此，探索乙酰辅酶A核内产生的机制将有助于更好地理解在化疗耐药中基因转录的上调。 靶向NAT10可使肝癌细胞和小鼠异种移植瘤对化疗敏感 02 研究人员分析了人类蛋白质图谱(HPA)数据库中的免疫组化数据，评估了NAT10在人肝癌组织中的表达水平。与非肿瘤肝组织相比，NAT10在HCC肿瘤组织中表达上调。此外，NAT10高表达与较短的生存期相关，提示靶向NAT10可能改善HCC患者的预后。为了探索NAT10在肝癌化疗耐药中的作用，研究人员建立了Huh7- oxa -r细胞，发现NAT10在Huh7- oxa -r细胞中的表达较亲本细胞上调。研究人员以Huh7-NAT10 shRNA-1、Huh7-NAT10 shRNA-2和Huh7-control shRNA细胞为研究对象，检测了各组细胞对阿霉素和奥沙利铂的IC50。敲低NAT10降低了这些化疗药物的IC50。此外，敲低NAT10在OXA和多柔比星(DOX)处理下抑制肝癌细胞生长并诱导凋亡。这些结果表明靶向NAT10可使肝癌细胞对化疗增敏。另外，异位表达Flag-NAT10增强了肝癌细胞的化疗耐药性，而乙酰转移酶死亡突变体Flag-NAT10 G641E则无法做到这一点。 这些结果表明，NAT10通过其乙酰转移酶活性促进HCC化疗耐药。 靶向NAT10使肝癌细胞和小鼠异种移植物对化疗增敏 为了进一步证实NAT10在体内化疗耐药中的作用，研究人员将Huh7-NAT10 shRNA-1、Huh7-NAT10 shRNA-2和huh7 -对照shRNA细胞皮下植入BALB/c裸鼠。当肿瘤体积达到50-100 mm3时，每周腹腔注射奥沙利铂2次，当肿瘤最大直径达到1.5 cm时结束实验。在小鼠异种移植瘤模型中，敲低NAT10可显著降低肿瘤体积和重量。 因此，研究人员证明NAT10促进HCC细胞和体内的化疗耐药。 ACLY K468-Ac赋予HCC细胞和小鼠异种移植物化疗耐药性 03 为了确定ACLY K468-Ac是否控制HCC细胞的化疗耐药，研究人员测定了奥沙利铂和阿霉素在Huh7-GFP、Huh7-GFP-ACLY和Huh7-GFP-ACLY K468R细胞中的IC50值。奥沙利铂和阿霉素的IC50值在GFP-ACLY细胞中升高，而在GFP-ACLY K468R细胞中升高，表明ACLY K468-Ac驱动HCC的化疗耐药。为了进一步证实ACLY K468-Ac在体内化疗耐药中的作用，研究人员将Huh7-GFP、Huh7-GFP-ACLY和Huh7-GFP-ACLY K468R细胞皮下植入BALB/c裸鼠，并用奥沙利铂治疗小鼠。来自Huh7-GFP-ACLY的异种移植物肿瘤体积和重量显著增加，而来自Huh7-GFP-ACLY K468R的异种移植物肿瘤体积和重量显著增加，表明ACLY K468-Ac赋予HCC细胞和小鼠异种移植物化疗耐药性。PIK3R1和CYP2C9在小鼠异种移植物中的表达也通过ACLY K468-Ac上调。此外，与非肿瘤组织相比，HCC肿瘤组织中ACLY K468-Ac水平上调。 这些结果表明ACLY K468-Ac驱动HCC的化疗耐药。 研究小结 04 总之，本研究揭示了化疗诱导的ACLY K468被NAT10乙酰化驱动HCC化疗耐药。抑制NAT10-ACLY K468-Ac轴为加强晚期HCC患者化疗疗效提供了一种有希望的策略。 参考资料： https://www.nature.com/articles/s41419-024-06951-9#Sec12 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情