PIK3R3

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

New MTX-531 Research in Nature Cancer Highlights Promising Dual Inhibitor Strategy for Overcoming Cancer Resistance MINNEAPOLIS, July 11, 2024 /PRNewswire/ -- MEKanistic Therapeutics Inc., a biotechnology company pioneering the development of next-generation kinase inhibitors for cancer treatment, today announced the peer-reviewed publication of new preclinical research on its lead candidate, MTX-531, an investigational dual-targeting therapy, in Nature Cancer. MTX-531 is a potential first-in-class therapy uniquely designed to inhibit both EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase), two critical proteins involved in cancer cell survival and proliferation. "We are excited to share the positive MTX-531 preclinical research published in Nature Cancer, which we believe show promising signals toward a novel solution to addressing the root cause of resistance to current cancer treatments," said Danny Cunagin, chief executive officer, MEKanistic Therapeutics. "By targeting critical adaptive resistance mechanisms with a dual inhibition strategy, we aim to significantly halt cancer progression compared to single-target treatments, and look forward to advancing this innovative therapy to patients in clinical trials." Key Findings of MTX-531 Study High Potency, Selectivity Leading to First of Its Kind Tolerability Preclinical studies demonstrated that MTX-531 exhibits nanomolar potency against both EGFR and PI3K (14.7 nM for EGFR, 6.44 nM for PI3K), with a high degree of selectivity as determined by broad kinome testing. In addition, MTX-531 did not cause hyperglycemia in mice at therapeutic doses, unlike other known pan-PI3K inhibitors, which have been reported to significantly increase blood glucose and insulin levels both in preclinical and clinical settings. Judith Sebolt-Leopold, PhD, chief scientific officer, MEKanistic Therapeutics, commented, "MTX-531 is the first PI3K inhibitor capable of selectively co-targeting EGFR and the first known pan-PI3K inhibitor that does not induce hyperglycemia, a known challenge with PI3K inhibitors that often leads to treatment discontinuation. This unique feature, achieved through precise targeting enabled by MTX-531's computational design, confers a favorable therapeutic index and resilience to adaptive resistance mechanisms not observed in prior PI3K inhibitor clinical programs." Robust Tumor Suppression as Monotherapy and in Combination Therapy MTX-531 monotherapy led to significant tumor regression in preclinical models of head and neck squamous cell carcinoma (HNSCC). Oral therapy effectively inhibited PI3K and EGFR signaling in a balanced fashion, achieving objective responses in every HNSCC model evaluated. Complete tumor regressions were observed across a broad dose range, with survival improvement ranging from 62% to >500% across models. In addition, when combined with a MEK inhibitor (trametinib) or a KRAS inhibitor (sotorasib), treatment with MTX-531 more than doubled the incidence of tumor regressions achieving a 100% objective response rate in multiple KRAS mutant colorectal (CRC) and pancreatic tumor models. Dr. Sebolt-Leopold added, "Our collective preclinical data show that MTX-531 effectively inhibits tumor growth in cancers with PIK3CA and KRAS mutations, which often lead to aggressive behavior and resistance to standard therapies. MTX-531 was well tolerated and outperformed the combination of drugs that individually target EGFR and PI3K. These findings highlight the versatility and broader potential of MTX-531 in treating hard-to-treat cancers." The scientific paper can be accessed at the following link: About MTX-531 Development Investigational new drug-enabling toxicology studies sponsored by the National Cancer Institute's Experimental Therapeutics (NExT) Program are currently underway. The NExT Program aims to advance clinical practice by supporting promising new drug discovery and development projects. Through this program, MEKanistic Therapeutics collaborates with NCI staff and contractors on a milestone-driven project team to conduct these studies and assess MTX-531's safety and efficacy in patients with cancer. "Our partnership with the NCI is a testament to the promising potential of MTX-531," said Christopher Whitehead, PhD, co-founder and chief operating officer, MEKanistic Therapeutics. "With their support and our focused efforts on GMP manufacturing and drug product development, we are poised to make significant strides in bringing this innovative therapy closer to clinical trials and ultimately to patients in need." About MEKanistic Therapeutics, Inc. MEKanistic Therapeutics Inc. is a privately held, Minneapolis, MN based biotechnology company focused on developing innovative kinase inhibitors for the treatment of cancer. The company studies the landscape of signal transduction pathways to create more effective cancer treatments. By targeting compensatory signaling in response to pathway intervention, MEKanistic designs drugs that prevent tumors from developing resistance to targeted therapies. The company's lead candidate is MTX-531, a single molecule that was rationally designed to selectively block two key pathways (EGFR and PI3K) that promote tumor progression. For more information, visit mekanistic.com and engage with MEKanistic on LinkedIn. Media Contact: Priyanka Shah [email protected] Forward-Looking Statements This press release may contain "forward-looking statements" within the meaning of the federal securities laws, which involve risks and uncertainties including statements regarding the potential benefits, safety, and efficacy of MTX-531, and which can be identified by the use of forward-looking terminology such as "may," "will," "expect," "plan," "anticipate," "believe," "estimate," or "continue" or the negative thereof or other variations thereon or comparable terminology. MEKanistic Therapeutics Inc. has based these forward-looking statements on its current expectations and forecasts about future events. Actual results could differ materially from those projected in such forward-looking statements due to a number of factors. SOURCE MEKanistic Therapeutics, Inc.

Researchers have analyzed how an antidiabetic treatment could help control the growth of tumors, potentially paving the way for the design of better cancer treatments. Flinders University researchers have analysed how an antidiabetic treatment could help control the growth of tumours, potentially paving the way for the design of better cancer treatments. The new study investigated what happens when metformin, a type 2 diabetes medication, is used to treat colorectal cancer cells, in the process demonstrating that it could be exploited to develop new cancer therapies. Previous epidemiology studies show that taking metformin helps protect diabetes patients from developing some forms of cancer including bowel, or colorectal, cancer. The Flinders' researchers sought to understand how taking metformin medication impacts cancer cells and how this could help with future cancer treatments. "Using the latest techniques, we analysed how metformin helps to stop colorectal cancer cells from growing and multiplying by controlling certain 'pathways' inside the cells that help to regulate growth and division," says lead author Dr Ayla Orang from Flinders University's College of Medicine and Public Health. "Importantly, our work has pinpointed that metformin uses small pieces of RNA (called microRNAs) to act as a 'circuit breaker' and turn off certain genes that are involved in cell growth and division, so it is possible that our findings could eventually be used to develop a new targeted cancer therapy. "In particular, we found that metformin increases the levels of certain microRNAs, like miR-2110 and miR-132-3p, which then target specific genes and slow down the growth and progression of tumours. "With this information we may be able to develop RNA-based therapies -- new treatments for cancer that target RNA molecules (like microRNAs)," she says. The research, Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study, used advanced techniques to study microRNAs, and the entire set of genes being expressed in the colon cancer cells, to help understand how metformin affects the cells. Metformin increased the levels of certain microRNAs (miR-2110 and miR-132-3p) that target a specific gene (PIK3R3). This process helps to slow down the growth of cancer cells and stop them from multiplying too quickly. Another gene (STMN1) was also targeted by different microRNAs, which led to slower cell growth and a delayed cell cycle. Senior authors of the study, Associate Professor Michael Michael and Professor Janni Petersen say the results are a step forward in our understanding of the way metformin disrupts cancer cell growth and how they could be used to fight cancer. "Our research provides new insights into the molecular mechanisms of how metformin works, and how we might be able to target genes responsible for turning normal cells cancerous," says Associate Professor Michael. "This is important because it shows the potential of metformin as a preventive agent for reducing the growth of cancer in the bowel, and the emergence of RNA therapeutics as a promising new avenue for exploring the clinical efficacy of these findings. "We need to further investigate the potential therapeutic benefits of targeting specific miRNAs or pathways using RNA-based therapies for the treatment of cancer. Having used metformin to unravel metabolism in cancer cells, the next stage of research is focusing on specific cell pathways, which should lead to animal studies and then human clinical trials."