Activated PI3K-delta Syndrome

Proof of concept clinical trial will evaluate leniolisib in PIDs with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes PIDs to include ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency, with prevalence approximately five times that of APDS Clinical trial being conducted at the National Institutes of Health (NIH) October 10, 2024: Pharming Group N.V. (“Pharming” or “the Company”) (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces the start of a Phase II, proof of concept, clinical trial evaluating leniolisib in primary immunodeficiencies (PIDs) with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes. The clinical trial is open for enrollment and will include PID patients with ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency, among others. These PID patients exhibit altered PI3Kẟ signaling in lymphocytes and likewise display similar clinical phenotypes to activated phosphoinositide 3-kinase delta syndrome (APDS) patients. Epidemiology suggests a prevalence of approximately seven 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 will be to assess safety and tolerability, pharmacokinetics, pharmacodynamics, and explore clinical efficacy of leniolisib in the targeted PID population. The trial has been designed to inform a subsequent Phase III program. The Phase II clinical trial is being conducted at the National Institute of Allergy and Infectious Diseases (NIAID) – part of the National Institutes of Health (NIH) – with lead investigator Gulbu Uzel, M.D., Senior Research Physician, and co-investigator V. Koneti Rao, M.D., FRCPA, Senior Research Physician, Primary Immune Deficiency Clinic (ALPS Clinic). Anurag Relan, MD, MPH, Chief Medical Officer of Pharming, commented: “The initiation of this study is an important milestone for Pharming as it represents the second primary immunodeficiency (PID) clinical program for leniolisib. Based on our experience in APDS, and the significant role of PI3Kd in regulating lymphocytes, leniolisib has the potential to address the underlying immune dysregulation and deficiency in a number of rare PID disorders with significant unmet medical needs, including ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN deficiency. We are excited to be leading this important scientific effort and to sharing the results of the study with the medical community.” The first patient is expected to be enrolled in the study in the coming weeks. This is the first clinical trial initiated by Pharming to study leniolisib in PIDs with immune dysregulation beyond APDS. The unique genetic drivers in ALPS-FAS, CTLA4 haploinsufficiency, NFKB1 haploinsufficiency and PTEN patients lead to enhanced PI3Kd signaling and clinical phenotypes of immune dysregulation shared with APDS. Specifically, PTEN patients with immunodeficiency are frequently described as ‘APDS-like’1, patients with ALPS-FAS display predominantly lymphoproliferative clinical manifestations with frequent cytopenic episodes2, and CTLA4 haploinsufficiency3 as well as NFKB1 haploinsufficiency4 patients demonstrate lymphoproliferative, cytopenic, and/or organ-specific autoimmune/inflammatory complications of immune dysregulation. Leniolisib is marketed in the U.S. and approved in several other countries, for the treatment of APDS in adult and pediatric patients 12 years of age and older. Leniolisib is an oral small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor approved in the U.S. and several other countries 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. 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.5,6 Leniolisib is currently under regulatory review in the European Economic Area, Canada and Australia for APDS, 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 and in a Phase II clinical trial in primary immunodeficiencies (PIDs) with immune dysregulation linked to altered PI3Kẟ signaling in lymphocytes. 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. 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. References Tsujita Y, et al. J Allergy Clin Immunol 2016;138:1672-80. Bride K & Teachey D. F1000Res. 2017;6:1928. Kuehn HS, et al. Science 2014;345:1623-27. Lorenzini T, et al. J Allergy Clin Immunol 2020;146:901-11. 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.

The Medicines and Healthcare products Regulatory Agency (MHRA) has approved Pharming Group’s Joenja (leniolisib) to treat patients with the rare immune disease activated phosphoinositide 3-kinase delta syndrome (APDS). Joenja is now the first drug to be approved in the UK for APDS and has been indicated for use in adults and adolescents aged 12 years and older who weigh at least 45kg. Approximately 30 to 40 people in the UK are affected by APDS, an inherited disorder where patients are unable to fight infections because their immune systems do not work properly. The main symptoms usually occur in the first two years of life and include repeated lung infections, as well as a failure to grow and develop normally. Patients are also more prone to develop blood cell cancers, such as lymphoma. Taken orally twice daily, Joenja is a small molecule phosphoinositide 3-kinase delta inhibitor that was approved for the same patient population in the US last year. The drug’s latest approval occurred through the International Recognition Procedure (IRP), a fast-track approval process that takes into account prior authorisations from other regulatory partners. The MHRA’s decision was supported by results from a 12‑week placebo-controlled study of 31 APDS patients. By day 85 of the trial, patients randomised to receive Joenja saw a reduction in lymph node size and a 37% improvement in naïve B cells counts compared to placebo. Julian Beach, interim executive director of healthcare quality and access, MHRA, said: “Approval of [Joenja] through the IRP means we have facilitated access for people suffering from this serious disease to an effective medicine to fight infections and reduce symptoms of the disease… As with all medicines, we will keep its safety under close review.” Also commenting on the authorisation, Pharming’s chief executive officer, Sijmen de Vries, said: “The MHRA approval of Joenja, the first treatment option specifically indicated for APDS, is an important milestone for people in the UK living with this debilitating disease.” Joenja is now being evaluated by the National Institute for Health and Care Excellence regarding reimbursement on the NHS, and applications are currently under review with other regulatory authorities globally.

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