Slides
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February 3, 2026 Investor Day 1
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For investor audiences only This presentation 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 2024 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2024, 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 presentation 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 presentation and are based on information available to Pharming as of the date of this presentation. 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. Forward-looking statements 2
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For investor audiences only Disclaimer This presentation has been prepared solely for informational purposes for the investor community. It is not intended to promote any product, provide medical or scientific advice, or influence prescribing, purchasing, or treatment decisions. Certain information in this presentation relates to research and development programs and investigational compounds that have not been approved by the U.S. Food and Drug Administration (FDA) or any other regulatory authority. The safety and efficacy of such products have not been established, and there can be no assurance that any investigational product will successfully complete clinical development or receive regulatory approval for any indication. Nothing in this presentation is intended to constitute advertising, promotion, or solicitation for any pharmaceutical product or for any off-label use of any approved product. This presentation is not intended for healthcare professionals or patients. 3
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For investor audiences only Agenda 4 Welcome and introduction Fabrice Chouraqui, CEO Financial outlook 2026 Kenneth Lynard, CFO Q&A R&D overview: Pipeline and programs Anurag Relan, CMO Program 1: leniolisib for primary immunodeficiencies (PIDs) with immune dysregulation Jocelyn Farmer, MD, PhD. Lahey Hospital & Medical Center Rebecca Marsh, MD. Medical Director Q&A Program 2: napazimone (KL1333) for primary mitochondrial disease Amel Karaa, MD. Massachusetts General Hospital Magnus Hansson, MD, PhD. Executive Medical Director Q&A Closing remarks Fabrice Chouraqui, CEO
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Fabrice Chouraqui, CEO Company overview 5
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For investor audiences only Commercial Combination of commercial and pipeline assets poised to deliver strong value creation Pipeline* *These product candidates are under investigation, and their safety and efficacy have not been established. There is no guarantee that these products will receive health authority approval or become commercially available for the uses being investigated HAE: Hereditary Angioedema, PIDs: Primary Immunodeficiencies, PMD: Primary Mitochondrial Disease, CVID: Common Variable Immunodeficiency 1. Walsh et al., Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment, Cell (2025), https://doi.org/10.1016/j.cell.2025.05.037 6 leniolisib for PIDs / CVID Phase II trials Joenja® (leniolisib) for APDS Significant near-term catalysts Up to 100x current prevalence1 RUCONEST® (recombinant C1 esterase inhibitor) Differentiated value proposition Highly specific manufacturing process HAE PMD PIDs with immune dysregulation > $1B revenue potential > $1B revenue potential Napazimone (KL1333) for mtDNA mitochondrial disease Registrational Phase II trial Positive interim analysis
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For investor audiences only Vision for the future Develop a leading global rare disease company with a diverse portfolio and presence in large markets, leveraging proven and efficient clinical development, supply chain, and commercial infrastructure 7
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For investor audiences only 8 Strong commercial and financial momentum FY 2024 FY 2025* Amounts in US$ million Revenues Announced preliminary 2025 revenues* of $376M (+ 27%) – above latest guidance Results reflect continued growth of RUCONEST® and acceleration in Joenja® APDS uptake Significant operating profit $30M and operating cash flow $44M in 9M 2025 Reiterated $304-308M operating expense guidance for 2025 – committed to cost discipline and deploying capital to high growth initiatives 297.2 376.0 * 2025 revenues are preliminary and unaudited. Final results may differ and will be reported in the financial results for the fourth quarter and full year 2025, to be published in March 2026. 8
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Kenneth Lynard, CFO Financial outlook 2026 9
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For investor audiences only 18 101 160 192 212 199 206 227 253 318 18 45 58 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Total revenues in $* millions Revenues (US$ million) RUCONEST® Joenja® Total 10 245 297 376* (Re-acquisition from Valeant) (Dec. 2016) Growth acceleration across the commercial portfolio 27% YoY , 22% CAGR (2022-25) From FY 2016 – FY 2020 Pharming Group reported earnings in EUR. Revenues during this time frame have been converted to USD. In 2021, Pharming Group began reporting earnings in USD. 4Q 2020 and 1Q 2021 quarterly fluctuations and volatility from COVID-19. * 2025 revenues are preliminary and unaudited. Final results may differ and will be reported in the financial results for the fourth quarter and full year 2025, to be published in March 2026. 10
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For investor audiences only 2026 financial guidance and long-term capital outlook Revenue and operating expenses (in constant currency): Continued RUCONEST® growth, and significant and accelerating Joenja® growth Strong financial discipline, and prioritized investments to drive value creation Available cash and future cash flows expected to cover current pipeline and pre-launch costs FY 2026 Guidance Notes Total Revenues US$405 - 425 million • 8 - 13% growth Operating Expenses US$330 - 335 million • US$60 million incremental R&D investments to advance pipeline • US$9 million structural G&A cost reductions (as announced in October 2025) 11
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Questions and Conversations Thank You 12
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Anurag Relan, CMO R&D overview: pipeline and programs 13
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For investor audiences only Diverse rare disease portfolio and pipeline RUCONEST® Napazimone KL1333 Preclinical Phase I Phase II Phase III / registrational study Regulatory submission Approval and commercialization Primary immunodeficiencies (PIDs) with immune dysregulation Primary mitochondrial disease Hereditary angioedema (HAE) JOENJA® : (Marketed in the U.S., U.K. - England & Wales) (Approved in Australia and Israel) activated phosphoinositide 3-kinase delta syndrome (APDS) acute HAE JOENJA® PIDs with immune dysregulation linked to PI3Kẟ signaling (genetically defined) JOENJA® CVID with immune dysregulation mtDNA mitochondrial disease JOENJA® APDS(Geographic expansion) JOENJA® APDS(Pediatric) 14
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For investor audiences only Napazimone (KL1333) pivotal trial Over 20 sites actively recruiting – site footprint expanding during 1H 2026 on track for late 2027 read-out Leniolisib sNDA for 4-11 yo APDS patients – requesting Type A meeting Responded to CHMP (EMA) outstanding questions – potential 1H 2026 approval Japan and other regulatory reviews on track for 2026 approvals Genetic PID and CVID phase II POC trials on track for 2H 2026 read-outs Executing on high value rare disease pipeline 15 APDS PIDs with immune dysregulation PMD 15
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For investor audiences onlyFor investor audiences only Agenda: leniolisib for PIDs with immune dysregulation PIDs with immune dysregulation have a considerable unmet need with large treatable population Leniolisib targets PI3Kδ and can modulate underlying immune dysregulation in PIDs Two multinational phase II clinical studies underway - top line data expected 2H26 PI3Kδ is a master regulator of the immune system 16
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For investor audiences only The combined targeted population of the 2 phase II studies plus APDS is ~44/million APDS is a PI3Kẟ driven monogenic disease within the IUIS CVID classification acting as proof of concept for CVID with Immune Dysregulation All PIDs PIDs with immune dysregulation CVID with infectious complications only CVID with immune dysregulation Genetic PIDs with immune dysregulation APDS IUIS: International Union of Immunological Societies 17Diagram for illustrative purposes and not to scale
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For investor audiences onlyFor investor audiences only Agenda: Napazimone (KL1333) Primary mitochondrial diseases – rare disorders with significant unmet medical need Napazimone (KL13330 positioned to become first standard of care in mitochondrial DNA (mtDNA) disease Pivotal study ongoing with positive interim analysis confirming FDA-agreed primary endpoints 18 Significant value creation potential for Pharming and patients
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For investor audiences only Disclaimer The information and views presented by Dr. Jocelyn Farmer during this session are solely her own, derived from her clinical expertise and professional judgment. They do not necessarily represent or reflect the positions, perspectives, or official guidance of Pharming Group N.V. or any of its affiliates. This presentation is provided for educational purposes only and should not be interpreted as company-endorsed direction or policy. 19
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Leniolisib: Transforming Treatment of Immune Dysregulation in Primary Immunodeficiencies Jocelyn Farmer, MD/PhD Associate Professor of Medicine, UMass Chan Medical School Director, Clinical Immunodeficiency Program, Beth Israel Lahey Health 20
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Disclosures • Consulting: Pharming • Investigator-initiated research grants: • Pharming • Bristol Myers Squibb • Pfizer 21
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Why am I speaking to you today? 22
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About Me (Dr. Jocelyn Farmer): - MD/PhD in microbiology & immunology (University of Michigan) - Board-Certified Allergist/Immunologist (A/I Fellowship at Mass General) - Post-Doc at Ragon Institute in PI3K signaling impacting B cell biology (MIT, Harvard, Mass General) - Hired on at Beth Israel Lahey Health in 2023 as Director, Clinical Immunodeficiency Program - Founded the New England Immune Deficiency Consortia in 2023 - Invited member of national and international guideline committees that define immunodeficiency (CVID) patient diagnosis & care - I approached Pharming in 2022 with a potential new clinical application for their drug – leniolisib – based on my research. 23
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What is PID? Why should you care about PID? Primary Immunodeficiency (PID) 24
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Primary Immunodeficiency = Unbalanced Immunity Figure prompted by Farmer, JR; generated by ChatGPT 5.2, January 18, 2026, OpenAI, https://chat.openai.com
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Kindle G, Alligon M, Albert MH, Buckland M, Edgar JD, Gathmann B, Ghosh S, Gkantaras A, Nieters A, Pignata C, Robinson P, Rusch S, Schuetz C, Sharapova S, Shillitoe B, Candotti F, Cant AJ, Casanova JL, Etzioni A, Fischer A, Meyts I, Notarangelo LD, Pergent M, Smith CIE; ESID Registry Working Party; Hammarström L, Grimbacher B, Seppänen M, Mahlaoui N, Ehl S, Seidel MG. Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients. medRxiv [Preprint]. 2025 Apr 16:2025.02.20.25322586. doi: 10.1101/2025.02.20.25322586. Update in: J Hum Immun. 2025 Sep;1(3):e20250007. doi: 10.70962/jhi.20250007. PMID: 40568655; PMCID: PMC12191083. Which PID patients do we see in the clinic? Most common PID = predominantly antibody deficiency (PAD) CVID (common) APDS (rare) 26 - APDS (activated PI3K-delta syndrome) rare PAD has FDA therapy (leniolisib) - CVID (common variable immunodeficiency) common PAD NO FDA therapy for immune dysregulation disease control
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What is PID? Why should you care about PID? Primary Immunodeficiency (PID) 27
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• No regulatory agency approved treatments • Adequate control not achieved with standard-of-care Immune Dysregulation Due to Immune Cell Auto-Reactivity Adequate control of infectious complications achieved through • Immunoglubulin replacement therapy (IRT) • Antibiotics Diagram Adapted from Baumann et. Al. Front. Immunol. August 2018 Blood (2012) 119 (7): 1650–1657. 3 Orphanet J Rare Dis 13, 201 (2018). https://doi.org/10.1186/s13023- 018-0941-0 Infections Due to Antibody Deficiency No FDA-approved therapies to treat immune dysregulation in CVID 28 (No products currently in development except for leniolisib)
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Patients with CVID are dying from immune dysregulation (11-fold higher risk of death with noninfectious complications) Bez P, Smits B, Geier C, Hirsch A, Caballero de Oyteza A, Proietti M, Grimbacher B, Wolkewitz M, Goldacker S, Warnatz K. Uncovering Risk Factors of Premature Mortality in Common Variable Immunodeficiency. J Allergy Clin Immunol Pract. 2025 Mar 14:S2213-2198(25)00256-9. doi: 10.1016/j.jaip.2025.03.009. Epub ahead of print. PMID: 40090481. Elmoursi A, Zhou B, Ong MS, Hong JS, Pak A, Tandon M, Sutherland N, DiGiacomo DV, Farmer JR, Barmettler S. A Cross- Sectional Study of Health-Related Quality of Life in Patients with Predominantly Antibody Deficiency. J Clin Immunol. 2024 Aug 7;44(8):173. doi: 10.1007/s10875-024-01781-y. PMID: 39110257; PMCID: PMC11658799. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Blood. 2012 Feb 16;119(7):1650-7. New York’s CVID cohort Germany’s CVID cohort Boston’s PAD cohort 29
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What do Patients with CVID Say? “For decades I faced the systemic complexities of CVID without the benefit of any approved therapeutic treatment. It was a lonely and depressing predicament, knowing that my organs would never last long enough for me to see my sons grow up, and perhaps make me a grandmother.” Direct quote from patient diagnosed with CVID and being managed by Dr. Farmer, provided 01-18-2026 30
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Can we apply clinical lessons from APDS (rare) to help the most patients with CVID (common)? 31
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APDS (PIK3CD,PIK3R1) gene unknown The clinical spectrum of CVID & APDS commonly overlap Figure prompted by Farmer, JR; generated by ChatGPT 5.2, January 18, 2026, OpenAI, https://chat.openai.com PI3Kδ-linked disorder (NFKB, CTLA4, PTEN) Genetic Diagnosis Diagnostic Testing
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CVID = many underlying single genetic conditions Within genotyped CVID cohorts we find…. - APDS = rare in CVID - PI3Kδ-linked disorders = less rare in CVID (e.g., NFKB, CTLA4) - unknown gene = most patients with CVID 33Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, Cunningham-Rundles C. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016 Jun 13;7:220. doi: 10.3389/fimmu.2016.00220. PMID: 27379089; PMCID: PMC4903998. J Hum Immun. 2025;2(1). doi:10.70962/jhi.20250157
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The Clinical Presentations are Similar CVID APDS Diagram Adapted from Baumann et. Al. Front. Immunol. August 2018 2 Blood (2012) 119 (7): 1650–1657. Diagram Adapted from APDS Symptoms | All about APDS 34
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OR (95% CI) p-value Hypogammaglobulinemia 0.90 (0.59 – 1.34) 0.5754 SAD 0.60 (0.30 – 1.15) 0.1227 IgGSD 0.63 (0.31 – 1.29) 0.2060 CVID 5.53 (4.09 – 7.49) <0.0001 Hyper IgM 0.00 (0.00 – Inf) 0.9755 Association between APDS-cluster and clinical diagnoses among patients with PAD APDS (n=46) PAD total (n=983) CVID subset (382) The Clinical Presentations Cluster APDS disease spectrum overlaps significantly with CVID disease spectrum We have defined clinical complications within CVID that are APDS-like, setting up for appropriate clinical trial endpoints in CVID: splenomegaly, lymphadenopathy cytopenias inflammatory lung disease inflammatory liver disease 75% of CVID Patients with Immune Dysregulation Exhibit an ‘APDS-like’ Endotype Unbiased Network Clustering of Noninfectious Disease Complications 35
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Can we apply biology learned from APDS (rare) to help the most patients with CVID (common)? 36
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l eniolisib Phase II (8201) l eniolisib Phase II (7201) l eniolisib a pproved Figure prompted by Farmer, JR; generated by ChatGPT 5.2, January 18, 2026, OpenAI, https://chat.openai.com CTLA4 NFKB1 ? PTEN ? ? PI3K PI3K PI3K APDS PI3Kδ-linked CVID 37
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Shared in APDS, PI3Kδ-linked, and CVID disease: Expansion of pathologic B cells (CD21(lo), PI3K/mTOR(hi)) Allard-Chamard H, Hillier K, Ramseier ML, Bertocchi A, Kaneko N, Premo K, Yuen G, Karpel M, Mahajan VS, Tsekeri C, Hong JS, Vencic J, Crotty R, Sharda AV, Barmettler S, Westermann-Clark E, Walter JE, Ghebremichael M, Shalek AK, Farmer JR, Pillai S. Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans. Blood Adv. 2025 Feb 11;9(3):520-532. doi: 10.1182/bloodadvances.2024013267. PMID: 39626280; PMCID: PMC11814514. Adapted from: Loss of B cell tolerance at the T2/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency Kirsty Hillier, Grace Yuen, Anson Hui, Suparna Kumar, Priyamvada Guha Roy, Joseph T. McColgan, Kimberly Zaldana, Hugues Allard- Chamard, Katie Premo, Naoki Kaneko, Nicole Ingram, Sara Barmettler, Musie Ghebremichael, Jolan E. Walter, Cory A. Perugino, Jishnu Das, Jocelyn R. Farmer, Shiv Pillai bioRxiv 2025.06.07.658167; doi: https://doi.org/10.1101/2025.06.07.658167 Healthy Control CVIDu APDS PI3Kδ- linked CVIDc
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Shared in APDS, PI3Kδ-linked, and CVID disease: Convergent break in B cell tolerance causing end-organ disease Loss of B cell tolerance at the T2/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency Kirsty Hillier, Grace Yuen, Anson Hui, Suparna Kumar, Priyamvada Guha Roy, Joseph T. McColgan, Kimberly Zaldana, Hugues Allard- Chamard, Katie Premo, Naoki Kaneko, Nicole Ingram, Sara Barmettler, Musie Ghebremichael, Jolan E. Walter, Cory A. Perugino, Jishnu Das, Jocelyn R. Farmer, Shiv Pillai bioRxiv 2025.06.07.658167; doi: https://doi.org/10.1101/2025.06.07.658167 Healthy APDS 39
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Can we apply treatment from APDS (rare) to help the most patients with CVID (common)? 40
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Demographics: 64-year-old female Immune Diagnosis: CVID (with unknown genetic cause) Life-threatening co-morbidities from CVID: chronic infections (sinus, lungs, skin), nodular regenerative hyperplasia (NRH) of liver, granulomatous and interstitial (GLILD) disease of lung, neutropenia, splenomegaly, lymphocytopenia, small fiber polyneuropathy, mastocytosis (in current remission) Prior therapies without adequate auto-inflammatory disease control: - high dose IVIG (partial response only) - rituximab (serum sickness on dose 2) - anakinra (partial response only) - tofacitinib (non-responder) - avapritinab (responder but concern for progression to immune suppression with COVID persistence) Alternatives for immune modulation not aligned with goals of care at this time: b cell depletion (serum sickness with rituximab); limited data that B cell targeting in isolation ameliorates NRH; cellcept (too risky with CD4+ T cell count ~ 200 cells/uL); abatacept (limited data that ameliorates NRH); sirolimus (not preferred in the setting of ongoing neutropenia) Single Patient IND Experience in CVID 41IND, Investigational New Drug
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Healthy control Patient APDS Single Patient IND Experience in CVID PI3K-mTOR signaling by (p)S6 level flow cytometry of stimulated B cells 42IND, Investigational New Drug
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Reduction in pathologic CD21(lo) B cells on leniolisib therapy over one year. 43 Single Patient IND Experience in CVID IND, Investigational New Drug
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Restoration of antibody-making switched memory (sm) B cells on leniolisib therapy over one year. 44 Single Patient IND Experience in CVID IND, Investigational New Drug
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“Leniolisib has given me hope that my immunological deficits can be stabilized and ultimately repaired. Dr. Farmer and her zealousness to obtain compassionate release of leniolisib has renewed my hope for the future and my longevity. Dreams can come true.” Direct quote from patient diagnosed with CVID and being managed by Dr. Farmer, provided 01-18-2026 45 Single Patient IND Experience in CVID: Patient Perspective IND, Investigational New Drug
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Unlocking the potential of leniolisib to transform care for immune dysregulation in PIDs Rebecca Marsh, MD Medical Director 46 Acting With Urgency
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For investor audiences only Disclaimer Leniolisib is being investigated for a new indication that has not been approved by the FDA or any other regulatory authorities. The safety, efficacy, and appropriate use of leniolisib have not been established for this indication. There is no guarantee that this product will successfully complete clinical development or receive regulatory approval for any new indication. 47
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For investor audiences only Our mission is to transform the care of additional PID patients with immune dysregulation This mission is well-founded, supported by: • Clear and significant patient need • Strong scientific rationale • Clinical experience from HCP- requested single patient IND treatment (N=6, 5 CVID)* *Abstract submitted for potential presentation at the 2026 annual meeting of the Clinical Immunology Society. 48
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For investor audiences only Pharming has developed clinical trials targeting PID disorders with immune dysregulation under the influence of PI3K Genetic PIDs Linked to PI3K Signaling APDS (PIK3CD, PIK3R1) CVID With Immune Dysregulation 1 2 3 49
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For investor audiences only PI3Kẟ is a master regulator of the immune system and imbalance contributes to immune dysregulation Lymphoproliferation GI Disease Autoimmunity Pulmonary Disease Cell proliferation p110δ p85ɑ AKT/PKB FOXO mTOR PI3Kδ Cell Differentiation Cell trafficking Apoptosis inhibition/survival Cell Growth APDS Genetic PIDs linked to PI3Kẟ CVID with immune dysregulation Immune dysregulation pathology Shared pathology under the influence of PI3K 50 PI3Kẟ is a master regulator of the immune system and influences
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For investor audiences only APDS exemplifies a PID characterized by immune dysregulation and serves as a proof-of-concept model for understanding related disorders being studied by Pharming Pharming successfully completed a phase III study in APDS which led to the approval of leniolisib in APDS patients 12 years of age and older PI3Kẟ is a master regulator of the immune system and influences Cell proliferation p110δ p85ɑ AKT/PKB FOXO mTOR PI3Kδ Cell Differentiation Cell trafficking Apoptosis inhibition/survival Cell Growth Genetic PIDs Linked to PI3K Signaling APDS (PIK3CD, PIK3R1) CVID With Immune Dysregulation 51
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For investor audiences only p85ɑ Leniolisib is a first-in-class medicine in APDS and acts by modulating PI3Kẟ and consequently immune dysregulation Change from baseline in index nodes* 21 x 16 mm Prior to Treatment Log10-transformed SPD of index lesions Joenja (n=18) Placebo (n=8) Baseline mean (SD) 3.03 (0.42) 3.05 (0.39) Change from baseline, LS mean (SE) -0.27 (0.04) -0.02 (0.05) Difference vs placebo (95% CI) -0.25 (-0.38, -0.12) Joenja Placebo n=18 n=8 p=0.0006 -46% -5% *Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood 2023; 141 (9): 971–983. PI3Kẟ is a master regulator of the immune system and influences Cell proliferation p110δ p85ɑ AKT/PKB FOXO mTOR PI3Kδ Cell Differentiation Cell trafficking Apoptosis inhibition/survival Cell Growth Pivotal study leading to multiple regulatory approvals showed leniolisib has a significant impact on lymphadenopathy* After 12 Weeks 12 x 9 mm leniolisib Percentage CFB at D85 in SPD of Index Lymph Node Lesions 52
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For investor audiences only We believe leniolisib may be a transformative medicine in additional PIDs with immune dysregulation under the influence of PI3Kẟ Lymphoproliferation GI Disease Autoimmunity Pulmonary Disease PI3Kẟ is a master regulator of the immune system and influences Cell proliferation p110δ p85ɑ AKT/PKB FOXO mTOR PI3Kδ Cell Differentiation Cell trafficking Apoptosis inhibition/survival Cell Growth APDS Genetic PIDs linked to PI3Kẟ CVID with immune dysregulation Immune dysregulation pathology Shared pathology under the influence of PI3K 53
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For investor audiences only Our phase II trials are designed to evaluate safety, optimal dosing, and the impact of leniolisib on common/serious clinical manifestations Average annual prevalence rate per 100,000 over the period 2004 –2014. Odnoletkova I, Kindle G, Quinti I, et al . The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis. 2018 Nov 12;13(1):201. Ducasa M, Marsh RA, Mojebi A, et al. A systematic literature review of CVID reveals pervasive detrimental noninfectious manifestations. J Hum Immun 5 January 2026; 2 (1): e20250157. Rates of Complications Impact of Complications on Mortality 54
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For investor audiences only Phase II proof of concept trial in ‘genetic PIDs linked to PI3K signaling’ Developed in collaboration with Dr. Gulbu Uzel, National Institutes of Health PTEN deficiency reduces PIP3 degradation, mimicking APDS-like PI3K activation (Tsujita et al., 2016). ALPS-FAS involves impaired apoptosis and enhanced PI3K signaling (Völkl 2016; Bride & Teachey 2017; Fajqenbaum 2019). NRAS/KRAS mutations directly increase PI3K activity (Castellano et al., 2011). SOCS1 and CTLA-4 haploinsufficiency amplify PI3K signaling through altered receptor interactions (Reif 2003; Xia 2004; Körholz 2021; Verma 2017; Rowshanravan 2018). NFKB1 variants promote PI3K-linked inflammatory signaling (unpublished data). Of note: additional disorders alter signaling (PRKCD, LRBA, DEF6, CARD11 GOF...) 55 Tsujita Y, Mitsui-Sekinaka K, Imai K, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016 Dec;138(6):1672-1680.e10. Völkl S, Rensing-Ehl A, Allgäuer A, et al. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation inautoimmune lymphoproliferative syndrome. Blood. 2016 Jul 14;128(2):227-38. Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017 Nov 1;6:1928. Fajgenbaum DC, Langan RA, Japp AS, et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease. J Clin Invest. 2019 Aug 13;129(10):4451-4463. Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another Effector Pathway. Genes Cancer. 2011 Mar;2(3):261-74. Reif S, Lang A, Lindquist JN. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression. J Biol Chem. 2003 Mar 7;278(10):8083-90. . GOF, gain of function; RALD, RAS-associated autoimmune leukoproliferative disorder; SOCS1, suppressor of Cytokine Signaling 1. Xia H, Nho RS, Kahm J, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004 Jul 30;279(31):33024-34. Körholz J, Gabrielyan A, Sowerby JM, et al. One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency. Front Immunol. 2021 Aug 5;12:680334. Verma N, Burns SO, Walker LSK, Sansom DM. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol. 2017 Oct;190(1):1-7. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018 Jan 4;131(1):58-67.
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For investor audiences only Phase II proof of concept trial in ‘genetic PIDs linked to PI3K signaling’ Developed in collaboration with Dr. Gulbu Uzel, National Institutes of Health PTEN deficiency reduces PIP3 degradation, mimicking APDS-like PI3K activation (Tsujita et al., 2016). ALPS-FAS involves impaired apoptosis and enhanced PI3K signaling (Völkl 2016; Bride & Teachey 2017; Fajqenbaum 2019). NRAS/KRAS mutations directly increase PI3K activity (Castellano et al., 2011). SOCS1 and CTLA-4 haploinsufficiency amplify PI3K signaling through altered receptor interactions (Reif 2003; Xia 2004; Körholz 2021; Verma 2017; Rowshanravan 2018). NFKB1 variants promote PI3K-linked inflammatory signaling (unpublished data). Of note: additional disorders alter signaling (PRKCD, LRBA, DEF6, CARD11 GOF...) 56 Tsujita Y, Mitsui-Sekinaka K, Imai K, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016 Dec;138(6):1672-1680.e10. Völkl S, Rensing-Ehl A, Allgäuer A, et al. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation inautoimmune lymphoproliferative syndrome. Blood. 2016 Jul 14;128(2):227-38. Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017 Nov 1;6:1928. Fajgenbaum DC, Langan RA, Japp AS, et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease. J Clin Invest. 2019 Aug 13;129(10):4451-4463. Castellano E, Downward J. RAS Interaction with PI3K: More Than Just Another Effector Pathway. Genes Cancer. 2011 Mar;2(3):261-74. Reif S, Lang A, Lindquist JN. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression. J Biol Chem. 2003 Mar 7;278(10):8083-90. . GOF, gain of function; RALD, RAS-associated autoimmune leukoproliferative disorder; SOCS1, suppressor of Cytokine Signaling 1. Xia H, Nho RS, Kahm J, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004 Jul 30;279(31):33024-34. Körholz J, Gabrielyan A, Sowerby JM, et al. One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency. Front Immunol. 2021 Aug 5;12:680334. Verma N, Burns SO, Walker LSK, Sansom DM. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol. 2017 Oct;190(1):1-7. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018 Jan 4;131(1):58-67.
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For investor audiences only Phase II proof of concept trial in ‘genetic PIDs linked to PI3K signaling’ Developed in collaboration with Dr. Gulbu Uzel 30mg 70mg10mg BID, twice daily; GLILD, granulomatous-lymphocytic interstitial lung disease; mTOR, mammalian target of rapamycin; OLE, open-label extension. RALD, RAS-Associated Autoimmune Leukoproliferative Disorder. • Single arm, open-label, dose range-finding single center study at NIH (N=12) • Dosing: 10/30/70 mg BID: 4/4/12 weeks treatment, respectively Key inclusions: • 12 to 75 years of age • Pathogenic/likely pathogenic variant: CTLA4, NFKB1, SOCS1, PTEN, FAS (germline or somatic) or somatic RALD-associated variants in NRAS or KRAS • Cytopenia, splenomegaly, lymphadenopathy or GLILD Key exclusions: • Hematopoietic stem cell transplant • Immunosuppressive medications: mTOR inhibitor, rituximab, steroids >25 mg/day prednisone equiv., others All patients with option to continue to separate 3 yr leniolisib open label extension 57
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For investor audiences only Phase II proof of concept trial in ‘CVID with Immune Dysregulation’ • Single arm, open-label, dose confirmation multi-center study (N=20) • Dosing: 10/30/70 mg BID: 4/4/16 weeks treatment, respectively Key inclusions: • 12 to 75 years of age • Clinical CVID diagnosis (genetic diagnosis not required) • Splenomegaly or lymphadenopathy PLUS ONE OF: symptoms of splenomegaly or lymphadenopathy, cytopenias, interstitial lung disease, autoimmune enteropathy Key exclusions: • Hematopoietic stem cell transplant • Immunosuppressive medications: mTOR inhibitor, rituximab, steroids >25 mg/day prednisone equiv., others • Significant T cell deficiency including CD4+ T cells <200/μL • Significant NK cell deficiency including NK cells <1% or <50/μL • Clinical history of opportunistic infections 30mg 70mg10mg All patients have option to continue to 3 yr leniolisib open label extension (OLE) study Developed in collaboration with Dr. Jocelyn Farmer 58
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For investor audiences only Shared phase II objectives and endpoints support pivotal trial design Objective: To assess safety and tolerability of leniolisib; confirm dosing strategy Endpoints: AEs; PK/PD Objective: To estimate the clinical efficacy ofleniolisib for immune dysregulation Endpoints: Changes in imaging, laboratory, and functional measurements including: • Lymph node and spleen size • Blood cell counts • CT-scored lung disease, pulmonary function tests • Others Objective: To evaluate the mechanistic impact of leniolisib Endpoints: Phenotypic readouts of B cell maturation and other subset changes Objective: To pilot correlative biomarker assessments Endpoints: CXCL13, IFN, soluble IL-2R, others Objective: To pilot a modified scoring system used in PIDs Endpoints: mIDDA scoring Objective: To pilot standard and custom* PRO tools Endpoints: PRO scores *Custom PROs developed through structured discussions with clinical experts (n=4) and formal interview studies with CVID patients (n=20) 59
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For investor audiences only Epidemiology of genetic PIDs linked to PI3K signaling* Genetic PID type Prevalence references Current/future9 prevalence estimate (per million) % Targeted for leniolisib treatment Diagnosed targeted population (per million) ALPS-FAS ESID registry (236 patients): 6 /mill.1 PID KOLs – 4 /mill2 5/10 30%3 3 CTLA4 ESID registry (38 patients): 1 /mill.4 USIDNET registry (28 patients): 2 /mill.5 Pharming lit review: 1.5/mill.13 PID KOLs – 10 /mill.2 2/4 50%6 2 NFKB1 ESID registry (25 patients): 0.75 /mill.10 USIDNET registry (6 patients): 0.4 /mill. 11 Pharming lit review: 2/mill.12 PID KOLs – 10 /mill.2 2/4 50%14 2 PTEN All PTEN patients NORD: 5/ mill.7 PID KOLs – 4 /mill.2 5/10 5%8 0.5 TOTAL Population (includes future patient diagnosis) 7.5** *some of these genetic disorders are classified by IUIS as CVID ** SOCS1 and NRAS/KRAS patient pools also included in the phase 2 study provide some additional, however limited, contributions to the estimated prevalence References on file at Pharming Group Included in CVID Programme Epidemiology 60
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For investor audiences only Epidemiology of CVID with immune dysregulation: CVID patients numbering ~39/million may be APDS-like Prevalence references Total CVID (p/mill; median) CVID with immune dysregulation (p/mill) Targeted APDS-like endotype population (p/mill) ESID registry (4228 patients): 100 p/mill.1 USIDNET registry (1823 patients): 125 p/mill.2 PID KOL views – 40 p/mill.3 Immunodeficiency Foundation - 40 p/mill. 4 PID US Health Survey – 290 p/mill. 5 CVID global review of registries & literature – 34 p/mill.6 US Symphony Claims Data – 113 p/mill.7 US PharMetrics Claims Data – 185 p/mill.8 1069 5311,12,13 3910 Note: overall prevalence includes patients with both unknown & known genetic drivers (including CTLA4, NFKB1, PTEN) 61 References on file at Pharming Group Assumptions: • ~50% of CVID patients present with immune dysregulation (53 patients/million); the other 50% with infectious phenotype only are well- treated with Ig therapy & anti-microbials 11,12,13 • 74% of CVID with immune dysregulation patients present with an ‘APDS-like’ endotype10 • Market research and KOL discussions indicate 50-60%14,15 of diagnosed targeted patients may be treated with leniolisib
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For investor audiences only Leniolisib: we have the potential to transform care for ~44/million PID patients with immune dysregulation 62 All PIDs PIDs with immune dysregulation CVID with infectious complications only CVID with immune dysregulation Genetic PIDs with immune dysregulation APDS 3/m 4.5/m 1.5/m 34.5/m Diagram for illustrative purposes and not to scale
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For investor audiences onlyFor investor audiences only Summary: leniolisib for PIDs with immune dysregulation High mortality, no approved treatments or other products in development Combined target population ~44/million, significantly broader than APDS prevalence of 1.5/million PIDs with immune dysregulation have a considerable unmet need with large treatable population APDS clinical trials and real-world experience HCP-requested individual IND case experience in CVID Leniolisib targets PI3Kδ and can modulate underlying immune dysregulation in PIDs Two multinational phase II clinical studies underway - top line data expected 2H26 PI3Kδ pathway imbalances contribute to immune dysregulation Dysregulation contributes to lymphoproliferation, autoimmunity, GI disease and pulmonary disease Genetic PIDS with immune dysregulation linked to PI3K CVID with immune dysregulation 63For investor audiences only PI3Kδ is a master regulator of the immune system
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Questions and Conversations Thank You 64
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For investor audiences onlyFor investor audiences only Agenda: Napazimone (KL1333) Primary mitochondrial diseases – rare disorders with significant unmet medical need Napazimone (KL1333) positioned to become first standard of care in mitochondrial DNA (mtDNA) disease Pivotal study ongoing with positive interim analysis confirming FDA-agreed primary endpoints 65 Significant value creation potential for Pharming and patients For investor investor audiences only
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For investor audiences only Disclaimer The information and views presented by Dr. Amel Karaa during this session are solely her own, derived from her clinical expertise and professional judgment. They do not necessarily represent or reflect the positions, perspectives, or official guidance of Pharming Group N.V. or any of its affiliates. This presentation is provided for educational purposes only and should not be interpreted as company-endorsed direction or policy. 66
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67 Amel Karaa, MD Director of the Mito Clinic Massachusetts General Hospital Harvard Medical School Primary Mitochondrial Diseases
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For investor audiences only 68 Disclaimer: The information presented are my own professional insights & considerations and not those of my employer, organization, committee or other group or individual I work with.
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For investor audiences only 69 Mitochondrial disease is a distinct set of genetic metabolic disorders International classification of inherited metabolic disorders http://www.icimd.org/
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For investor audiences only 70 Mitochondrial disease is a distinct set of genetic metabolic disorders International classification of inherited metabolic disorders http://www.icimd.org/
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For investor audiences only 71 Mitochondrial disease is caused by mutations in either mitochondrial or nuclear DNA mtDNA disorders: Typically adult onset (~50–70% mtDNA) Recessive nuclear DNA disorders Typically pediatric onset (~75–90% nDNA) www.newcastle-mitochondria.com How is mitochondrial DNA different to nuclear DNA? The mitochondrial genome is a circular DNA molecule that contains approximately 16500 bases and has 37 genes. There are many copies of mitochondrial genomes within each mitochondria. Mitochondrial DNA forms a circular DNA molecule Chromosome A chromosome is a single piece of coiled DNA. Humans have 23 pairs of chromosomes located in the nucleus. Nuclear DNA contains approximately 3 billion bases and has in excess of 20,000 genes. A single strand of nuclear DNA contains many genes and nucleotide sequences The mitochondrial genome
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For investor audiences only 72 Regina’s story Diagnosis: mitochondrial DNA myopathy (m.8344A>G) Family history: Brother and son with a very similar presentation. Daughter with a milder phenotype Symptoms: SNHL (using hearing aids), myoclonus, ataxia, dysarthria, ptosis, proximal myopathy, lipomatosis Treatments: exercise, dietary supplements Impacts on daily life: decreased mobility, inability to work, inability to do house chores, inability to socialize
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For investor audiences only 73 Path to mitochondrial disease diagnosis (video 1) The videos featured can be viewed in the recording of the live event, which can be accessed here: https://www.pharming.com/pharming-investor-day-2026
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For investor audiences only 74 Impact of mitochondrial disease (video 2) The videos featured can be viewed in the recording of the live event, which can be accessed here: https://www.pharming.com/pharming-investor-day-2026
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For investor audiences only 75 Multifactorial diagnostic evaluation centered around genetic testing Genetic Testing mtDNA sequencing Nuclear panels WES WGS Davis et al. Neurology. 2022 Aug 16;99(7) Biochemistry Lactate, pyruvate CPK, aldolase GDF-15/FGF-21 Metabolic profiling Tissue pathology RRF COX (-)/SDH (+) fibers CoQ10 levels End-Organ Assessments Heart Kidney Brain, eye…
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For investor audiences only 76 Ivaniuk et al. Neurology 2025 Feb 25;104(4):e209779 Commun Biol 6, 22 (2023) Mortality by decade Mitochondrial disease is progressive and impacts mortality over the course of life
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For investor audiences only 77 Li et al. Metabolites. 2021 Apr 10;11(4):233. PMID: 33920115 Mitochondrial disease impairs mitochondrial function Increased Mitochondrial ROS levels Defective Mitochondrial Biogenesis Altered Mitochondrial Dynamics Impaired Mitochondrial trafficking Dysfunctional OXPHOS Metabolism Defective Mitophagy Mito Dysfunction
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For investor audiences only 78 Vafai and Mootha, Nature 2012 Mitochondrial diseases have diverse clinical implications
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For investor audiences only 79 PLoS ONE 13(5): e0197513 Mitochondrial disease symptoms Muscle weakness and debilitating fatigue are among the most frequently reported mitochondrial disease symptoms in adults across studies • Two of the highest frequency symptoms in the North American Disease Consortium (NAMDC) registry* • Two most frequent and prioritized symptoms by patients for trial participation in the NIH Rare Disease Clinical Research Network (RDCRN) PMD cohort** *A. Karaa et al. / Molecular Genetics and Metabolism 119 (2016) 100–108 **Zolkipli-Cunningham et al. PLoS ONE 13(5): e0197513
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For investor audiences only 80 In the past 7 days… Never Rarely Some times Often Always How often did you experience extreme exhaustion? ☐ ☐ ☐ ☐ ☐ How often did you run out of energy? ☐ ☐ ☐ ☐ ☐ How often did you feel tired? ☐ ☐ ☐ ☐ ☐ How often were you too tired to enjoy life? ☐ ☐ ☐ ☐ ☐ How often did you have to push yourself to get things done because of your fatigue? ☐ ☐ ☐ ☐ ☐ How often were you too tired to do your household chores? ☐ ☐ ☐ ☐ ☐ How often were you too tired to take a bath or shower? ☐ ☐ ☐ ☐ ☐ How often were you too tired to leave the house? ☐ ☐ ☐ ☐ ☐ How often were you too tired to think clearly? ☐ ☐ ☐ ☐ ☐ PROMIS® Fatigue Mitochondrial Disease Short Form Validated scale to assess mitochondrial disease fatigue symptoms and impacts on daily life Fatigue in mitochondrial disease has a high impact on quality of life and functional abilities Fatigue characteristics Fatigue impacts S. Clifford… A. Karaa. Molecular Genetics and Metabolism, 145(4) 2025, 109153.
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For investor audiences only 81 Category Estimated Worldwide Count Pathogenic mtDNA variant carriers (genetic) ~32–40 million Clinically manifest mtDNA disease (all variants) ~0.8–1.6 million Clinically manifest m.3243A>G disease ~300,000–400,000 Clinically manifest single large-scale deletion disease ~100,000–150,000 Mitochondrial disease is a common uncommon disease Disease prevalence studies: 1. Mitochondrion, 2007; (7), Issue 3:230-233. 2. ANN NEUROL. 2015;77:753–759. 3. PLOS ONE. 2022; 17(4): e0265744. 4. Orphanet J Rare Dis. 2023; 18, 43. 5. J Epidemiol. 2023; 5;33(2):68-75. 6. BMJ Neurology Open. 2024;6:e000546. 7. Internal Medicine Journal. 2024; 54:388–397
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For investor audiences only 82 Limited treatment and management options Minimize energy losses Avoid stressors Adequate rest Optimize energy gains Restorative Sleep Nutrition Exercise
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For investor audiences only 83 Targets of Biogenesis NAD+/NADH ratio modulation KL1333 Resveretrol Nicotinic acid, Nicotinamide Nicotinamide riboside Acipimox Gene transcription Omaveloxolone REN001 ASP0367 Bezafibrates AICAR Antioxidants/RedOx Idebenone PTC743 (EPI734) Sonlicromanol OMT-28 Gene Therapy Lenti-TYMP AAV2/8-ETHE1 AAV2/8-MPV17 AAV2/9-NDUFS4 AAVPhP .B-Scl25a46 AAV9-ndufs3 rAAV2/2-ND4 scAAV2-P1ND4 AAV9-ZnF (m.5024C>T) AAV9-MITOTALEN (m.5024C>T) MitoArcus Membrane stabilizers Elamipretide Miscellaneous Dichloroacetate Sodium Phenylbutyrate CD34+ MNV-BLD Mitochondrial transplant Enzyme Bypass MT-1621 (dC+dT) Nitric Oxide modulators L-citrulline L-arginine IW-6463 Sildenafil Targets of Mitophagy API-009 Rapamycin A range of potential therapeutic approaches
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For investor audiences only 84 Two recent approvals in ultra rare subsets of mitochondrial disease
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For investor audiences only 85 Established US mitochondrial community Centers of excellence and expert networks in US Mitochondrial Care network Mitochondrial Medicine Society North American Mitochondrial Disease Consortium TREAT MITO US Patient Organizations Driving awareness, research, educations and support Patients, health care professionals and research audiences Annual disease conferences – Monthly education series Disease registries - Natural history studies Patient support programs Research funding Sponsored genetic testing programs
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86 Thank you
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Magnus Hansson, MD, PhD Executive Medical Director Napazimone (KL1333) for primary mitochondrial disease 87
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For investor audiences only Disclaimer Napazimone (KL1333) is investigational drug and has not been approved for use by any regulatory authority. Its safety and efficacy have not been established, and it is currently under clinical evaluation. There is no guarantee that this drug will receive regulatory approval or become commercially available. 88
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For investor audiences only Napazimone (KL1333) designed to target the underlying pathology in mtDNA mitochondrial disease NADH NAD+ OXPHOS mtDNA mutations Impaired OXPHOS Low NAD+/NADH ratio Decreased energy production and decreased mitochondrial biogenesis Debilitating symptoms such as fatigue and muscle weakness significantly impairing activities of daily living Napazimone (KL1333) is designed to target the underlying pathology by restoring NAD+/NADH ratio: Dysfunctional mitochondria 89
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For investor audiences only Napazimone (KL1333) is designed to restore NAD+/NADH ratio and energy production 90 In mitochondrial disease, pathogenic variants in mtDNA impact OXPHOS complex synthesis and function, leading to altered NAD+/NADH ratio and reduced energy production Normal cellular energy production is regulated by the balance of NAD+/NADH Napazimone (KL1333) is designed to restore energy production via facilitating the conversion of NADH to NAD+ and stimulating ATP synthesis through a redox cycling of the compound 1. Seo et al. 2018. KL1333, a Novel NAD+ Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts (https://www.frontiersin.org/articles/10.3389/fneur.2018.00552/)
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For investor audiences only In vitro, napazimone (KL1333) restores NAD+/NADH ratio and mitochondrial biogenesis in MELAS patient fibroblasts NAD+/NADH Mitochondrial mass ETC protein ETC activity Seo et al. 2018. KL1333, a Novel NAD+ Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts (https://www.frontiersin.org/articles/10.3389/fneur.2018.00552/) 91
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For investor audiences only Reduction of fatigue Changes from baseline to day 101 In a phase Ia/b study, napazimone (KL1333) demonstrated positive changes in outcome measures 1. Pizzamiglio C et al., Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease, Brain 2025;148(1):39-46 https://pmc.ncbi.nlm.nih.gov/articles/pmid/39657714/ Improvement Improvement in muscle function Changes from baseline to day 101 Biomarker changes Lactate: Pyruvate ratio1 Improvement 92
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For investor audiences only A PopPK model was developed from 3033 observations in 42 healthy participants and 6 patients with PMD in phase 1a/b study KL1333-2018-102 Napazimone (KL1333) effects on disease biomarkers demonstrate target engagement at anticipated exposure levels KL1333 Exposure and changes in lactate and lactate: pyruvate ratio had a clear exposure-response relationship Ching et al. PoP-PK and exposure response analysis, presented at Mitochondrial Disease Conference, Pisa, Italy Jan 23-25 2026 93
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For investor audiences only Napazimone (KL1333) MoA has the potential to address high unmet need of mtDNA mitochondrial disease 94 Unmet Need in mitochondrial disease (Scale 1-7) High Unmet Need No Unmet Need 1 7 6.4 65432 HCPs n=16 (US) “Most patients, unfortunately, don’t have a cure. They have a way of dealing with the issue but not necessarily reversing the problem. It affects patients both physically, but also cognitively and psychologically.” - Endocrinologist The videos featured can be viewed in the recording of the live event, which can be accessed here: https://www.pharming.com/pharming-investor-day-2026
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For investor audiences only 95 Napazimone (KL1333) pivotal study program targets a specific but common subset of adult Mitochondrial Disease which can be diagnosed with a genetic test International Classification of Inborn Metabolic Disorders (ICIMD) ICIMD category Category 6 – Mitochondrial DNA- related disorders • Impairs OXPHOS function mtDNA mutations causing multisystemic disease include • m.3243A>G • single large-scale mtDNA deletions, • m.8344A>G • similar pathogenic point mutations in mtDNA http://www.icimd.org/
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For investor audiences only Abstract presented at: mtDNA variants targeted in pivotal program cause the majority of adult disease mtDNA point mutation m.3243A>G disease (prevalence ~4 per 100,000) (34%) m.8344A >G (5%) mtDNA Single Large-scale Deletion disease (~1.5 per 100,000) (12%) Three pathogenic variants of mtDNA causes >50% of adult mitochondrial disease m.8344A>G is typically the cause of MERFF (Myoclonal Epilepsy with Ragged Red Fibers) Myopathy and fatigue are common m.3243A>G caused disease accounts for about 35% of all adult mitochondrial disease Most patients have mixed phenotypes, with myopathy and fatigue A small proportion of patients have stroke-like episodes (=MELAS syndrome) Mitochondrial diabetes and hearing loss are also common symptoms (=MIDD) The Single Large-Scale Deletion of mtDNA is the second most common genetic cause for adult disease Typically causes the CPEO-KSS spectrum of disease Myopathy and fatigue are common symptoms Mitochondrial Medicine – Therapeutic Development 21 -23 November 2022 Wellcome Genome Campus, UK and Virtual 1. MitoCohort registry study – Collaboration with Newcastle University. Over 500 adults with active entries over the past 3 years were analyzed 96
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For investor audiences only Napazimone (KL1333) clinical trial design to enable first-in-class treatment Phase I a/b study1 Pivotal FALCON Trial - Efficacy & safety evaluation2 Open-label extension study 180 patients with mtDNA-caused PMD (60% KL1333, 40% placebo) 48 weeks 25-50 mg bid Two alternate primary efficacy end points • Change from baseline in PROMIS Fatigue (validated for PMD3) • 30 Second Sit-to-Stand test Interim analysis by IDMC • Positive outcome - both primary endpoints passed futility, acceptable safety and tolerability profile Randomized, blinded, placebo-controlled 8 patients with genetically confirmed PMD 10 days 50 mg qd Target engagement and notable improvements on exploratory Myopathy and Fatigue assessments Randomized, blinded, placebo- controlled patient cohort • Open to all patients completing FALCON pivotal study • Potential expansion following completed FALCON recruitment Initiating Q2 2026 25-50 mg bid Nonrandomized, open-label, long-term study Long-term safety, tolerability, and efficacy qd, once a day; bid, twice a day; PMD, primaphosphoinositide 3-kinase delta; SPD, sum of product diameters 1. Pizzamiglio C et al. Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease, Brain, 2025, 148(1):39-46. 2. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05650229 3. Clifford et al. Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form. Molecular Genetics and Metabolism, 2025, 145(4):109153. 97
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For investor audiences only Pivotal FALCON study design de-risks program Placebo Week 48 Week -8 to -12 Primary Efficacy Analysis MAIN STUDY (48 weeks) PARTICIPANTS: Adult Primary Mitochondrial Disease patients (mtDNA mutations*) with myopathy and fatigue DESIGN: Randomized, double-blind, parallel-group, placebo-controlled (40% placebo, 60% active) ALTERNATIVE PRIMARY ENDPOINTS: PROMIS® Fatigue Mitochondrial Disease Short Form, 30 Second Sit-to-Stand test Follow-up (5 weeks) Screening / Run-in Week 24 Interim Futility Analysis Napazimone (KL1333) Treatment (tablets twice daily) RANDOMIZATION SCREENING Week 53 Safety Follow-up STUDY END 1. Extended run-in period during patient screening to ensure symptom severity and stability 2. Evaluate the safety profile and the potential of both primary endpoints to be successful of after 24 weeks of dosing 3. Two alternative primary endpoints: Study is positive if either, or both, demonstrate benefit** *Including m.3243A>G associated spectrum disease, single large scale mtDNA deletion disorders, m.8344A>G and other multisystemic mitochondrial DNA-related disease. **Hochberg step-up procedure – statistical method for multiple hypotheses 98
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For investor audiences only Interim analysis results further de-risked pivotal study Positive outcome achieved, with both primary endpoints having passed futility Promising differences favoring the active arm vs. placebo for both primary efficacy endpoints; if trends continue consistently, we expect a successful result at the completion of this trial Data monitoring committee (DMC) recommended continuing with wave 2: • Safety and tolerability profile acceptable • No safety signals in labs, vital signs or ECGs • Adverse Event (AE) profile consistent with benign profile seen in phase 1 studies • No drug-related Serious Adverse Events (SAEs) to date • No changes to study design • 180 total patients confirmed in the study 99
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For investor audiences only No Serious Adverse Events (SAEs) Mild dose-dependent gastrointestinal (GI) AEs at high doses Healthy volunteers and patients – similar PK and safety profile No Serious Adverse Events; No safety signals Tolerability at higher doses limited by mild-moderate GI-related side effects – improved by dividing the dose Weak inhibitor of CYP1A2 Negligible effects on other CYP450 substrates No safety signals in labs, vital signs or ECGs No drug-related SAEs Adverse Event (AE) profile consistent with benign profile seen in phase 1 studies Napazimone (KL1333) has demonstrated a benign safety profile in phase 1 studies and FALCON wave 1 100 Phase 1 Single Ascending Dose study (101) Phase 1 a/b Multiple Ascending Dose study (102) Phase 1 Drug-Drug Interaction study (103) Pivotal FALCON study (104A) Wave 1 (w48)
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For investor audiences only Napazimone (KL1333) Boicedelpar Mavodelpar Sonlicromanol Elamipretide Astellas Reneo Khondrion Stealth Biotherapeutics Current status Pivotal Phase 2 FALCON study (NCT05650229) Program terminated at Phase 2 (NCT04641962) Program terminated at Phase III (NCT05267574) Phase IIb trial failed (NCT04165239) Phase III failed (NCT03323749) MOA NAD+/NADH modulator PPARδ agonist PPARα agonist Oxidative Stress modulator, Prostaglandin Synthase inhibitor Cardiolipin stabilizer Patient population 180 mtDNA disease patients with myopathy and debilitating fatigue Adults with nuclear DNA and mtDNA mutations with myopathy 200 adult mtDNA patients with myopathy 27 adults with m.3243A>G MELAS spectrum disease 218 adults with nuclear DNA and mtDNA mutations with myopathy End point(s) 30s Sit-to-Stand (PE) PROMIS Fatigue (PE) 6-minute walk test (PE) Neuro QoL, 5XSTS, MFIS (SE) 12-minute walk test (PE) FACIT Fatigue (SE) Cognitive function (PE) multiple SE 6 Minute Walk Test (MWT), fatigue score on mitochondrial myopathy symptom assessment Potential Reasons for failure N/A • MoA may not impact underlying disease • Mixed population of nuclear and mitochondrial DNA mutations • Safety concerns • MoA may not impact underlying disease • 12-minute walk test was not the right endpoint for patients who have mobility issues and fatigue • Primary endpoint strategy changed between several PoC trials • MoA is not fully clear • Mixed population of patients with both nuclear and mitochondrial DNA mutations Terminated Terminated Phase 3 study changed endpoint strategy (now similar to FALCON) Follow-up study with refined patient population – results not reported Incorporating lessons learned from previous programs Previous studies likely failed due to mechanism of action not targeting a critical underlying cause of disease, using a mixed patient population (e.g., mtDNA + nDNA) or using insensitive endpoints 101
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For investor audiences only Napazimone (KL1333) Target Product Profile based on FALCON study attractive to HCPs and patients • HCPs see mechanism as rational and likely to be efficacious because of the nicotinamide adenine dinucleotide’s role in the respiratory chain • Perceived as disease modifying as a “mitochondrial supplementation” to increase function of mitochondria • Efficacy data is promising for multiple reasons: • Fatigue and myopathy / muscle weakness are key symptoms for patients, so improvements in those metrics are critical to improve patient QOL and function • Lack of approved therapies increases enthusiasm for any option that will improve patient symptoms and / or reduce progression • Based on level of unmet need in indication, HCPs report willingness to prescribe with FDA approval, even with only one statistically significant primary endpoint I think it is a very promising mechanism of action; it deals with the pathophysiology of the disease. I am impressed with the route of administration. I would have expected infusion therapy, which could be a problem. - Metabolic Disorders Pediatrician “ “ N=10 Patients (US) MELAS- Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes Extremely willing Not at all willing 6.4 1 765432 HCPs n=16 • Efficacy data is promising for multiple reasons: • Fatigue and myopathy / muscle weakness are key symptoms for patients, and fatigue reduction is therefore viewed as a major benefit and quality of life improvement by N=7 patients • Improved daily functioning and physical activity is also cited by N=4 patients as a key factor driving the decision to speak to their HCP about KL1333 My initial impression of [KL1333] is that it would be amazing. Anything that helps with fatigue to get through the day to make it less overwhelming … the underlier is the constant fatigue. - MELAS Patient “ “ Extremely willing Not at all willing 6.5 1 765432 Patients n=10Willingness to speak to HCP about KL1333 Willingness to prescribe product X 102
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For investor audiences only Significant addressable patient population for napazimone (KL1333) 1 Gorman, G.S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015 May;77(5):753-9. 2 Gorman, G.S. et al. Mitochondrial Diseases. Nat. Rev. Vol 2, 1-22 (2016). *mtDNA mutations including m.8344A>G MELAS-MIDD, MERRF, KSS-CEPO, large scale mtDNA deletions >30,000 diagnosed mtDNA mitochondrial disease patients addressable in the US, EU4 and UK PMD Prevalence 1 per 4,3001 US 78,200; EU4 and UK 76,400 Diagnosed mtDNA 9.6 per 100,0002 US 32,300; EU4 and UK 31,600 FALCON Trial Inclusion Criteria* 51% US 16,500; EU4 and UK 16,100 103
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For investor audiences onlyFor investor audiences only Summary: Napazimone (KL1333) *in US, EU4 and UK Severe fatigue, myopathy (muscle weakness), and reduced life expectancy Poor quality of life (e.g., loss of job, social isolation, depression) Primary mitochondrial diseases – rare disorders with significant unmet medical need Novel mechanism of action addresses the underlying disorder >30,000 patients* Napazimone (KL1333) positioned to become first standard of care in mitochondrial DNA (mtDNA) disease Patient recruitment for second wave of pivotal FALCON clinical trial ongoing Read-out anticipated in 2027 with launch in early 2029 Pivotal study ongoing with positive interim analysis confirming FDA-agreed primary endpoints Builds on Pharming’s existing rare disease expertise and infrastructure Concentrated centers of excellence and strong advocacy groups Significant value creation potential for Pharming and patients 104
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Questions and Conversations Thank You
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For investor audiences only Building momentum across commercial, financial and pipeline 2025 revenue ~$376M: • High dbl-digit growth for RUCONEST® and Joenja® Significant operating profit and operating cash flow (9M 2025) 2026 revenue guidance: $405-425M: • Continued RUCONEST® growth, significant and accelerating Joenja® growth Strong growth momentum Sustained growth of commercial portfolio Significant Joenja® APDS growth catalysts: • Pediatric label, VUSs, targeted geo expansion, prevalence expansion Strategic growth priorities Joenja® (leniolisib) for PIDs/CVID with immune dysregulation • Phase II readouts (2026) High value pipeline Growth-oriented leadership team Proven commercial and development capabilities Scalable organization Building a leading rare disease company 106 Enhanced capital allocation driving growth Napazimone KL1333 for mtDNA mitochondrial disease • Pivotal study readout (2027)
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Questions and Conversations Thank You
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NASDAQ: PHAR | EURONEXT Amsterdam: PHARM www.pharming.com
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For investor audiences only Epidemiology of genetic PIDs linked to PI3K signaling References: 1. Based on 1.4% of PID patients reported as ALPS in the ESID registry & overall PID prevalence of 1/2500. 2. Median from survey of 7 PID KOL opinions. 3. Most ALPS-FAS patients are well treated, with 30% in need of better treatment (KOL opinions including Konneti Rao/David Teachey – leading global KOLs). 4. Based on 0.2% of PID patients reported as CTLA4 in the ESID registry & overall PID prevalence of 1/2500. 5. Based on 0.5% of PID patients reported as CTLA4 in the USIDnet registry (5489 patients usidnet.org) & overall PID prevalence of 1/2500. 6. 1/3 of CTLA4 patients are considered asymptomatic, others well treated (Hao & Cook. Front Immunol. 2022 12:806043). 7. Overall PTEN Hamartoma Tumor Syndrome prevalence (NORD). 8. Based on Pharming literature review, KOL feedback and PTEN Foundation registry review (>500 patients) identifying PTEN patients with an immune dysregulation phenotype. 9. 2x scaling for additional undiagnosed patients to be identified through future patient finding activities and VUS resolution. This is based on Pharming APDS experience. 10. Based on 0.15% of PID patients reported as NFKB1 in the ESID registry & overall prevalence of 1/2500. 11. Based on 0.11% of PID patients reported as NFKB1 in the USIDnet registry (5489 patients usidnet.org) & overall PID prevalence of 1/2500. 12. Pharming literature review (6 NFKB1 pubs): of all CVID patients with genetic drivers 6% were NFKB1; CVID prevalence ~100 /mill., 30% with genetic drivers (30 /mill.), 30*0.06 = 2/mill 13. Pharming literature review (7 CTLA4 pubs): of all CVID patients with genetic drivers 5% were CTLA4; CVID prevalence ~100 /mill., 30% with genetic drivers (30 /mill.), 30*0.05 = 1.5/mill 14. KOL opinions approx. half of NFKB1 patients need better therapy • Prevalence calculations for target PID subgroups is based on IUIS reported ‘all PID’ prevalence of 1/2500 (Tangye et al J Clin Immunol. 2020; 40(1): 24–64). • ESID registry publication includes total PID patients 16486 (Thalhammer et al Allergy Clin Immunol 2021;148:1332-41). 109
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For investor audiences only Epidemiology of CVID with immune dysregulation CVID patients numbering ~39/million may be APDS-like References: 1. Based on overall PID prevalence of 1/2500, with 26% of PID patients reported as CVID in the ESID registry 2. Based on overall PID prevalence of 1/2500 with 33% of PID patients reported as CVID in the USIDnet 5489 patient registry (usidnet.org) 3. Median from survey of 7 PID KOL opinions 4. Immunodeficiency Foundation - https://primaryimmune.org/ 5. PID US health survey – Boyle & Buckley 2007 J Clin Immunol 6. CVID global epi review article – Weifenback et al 2020 J Immunol Res 7. Pharming Symphony Claims Data CVID search 8. Jordan et al 2023 IPIC abstract 9. Median of sources on CVID prevalence 10. Defining an activated PI3K-delta syndrome-like endotype within broader common variable immunodeficiency. Daniel V. DiGiacomo, Sara Barmettler, Paul J. Maglione, Aditi Jogdand, Joseph S. Hong, Rebecca A. Marsh, Kevin S. Thorneloe, Karen Gilbert, Mei-Sing Ong*, Jocelyn R. Farmer*NEIDC CVID cohort (N=423): APDS-like endotype analysis of CVID with immune dysregulation cohort indicates 74% as APDS-like 11. Resnick ES, et al. Blood. 2012 119(7): 1650-1657. 12. Boileau J, et al. J Autoimmun. 2011 36(1): 25-32. 13. Ramirez NJ, et al. Curr Opin Immunol. 2021 72: 176-185. 14. Data on file KOL interviews (50%) #Based on: • current unmet medical need in APDS-like CVID with immune dysregulation population • anticipated benefit/risk profile of leniolisib • value delivered by currently utilized off label therapies 15. Data on file from Market research conducted by Trinity Life Sciences (60%) 110