Joenja (leniolisib) / Novartis, Pharming Group - LARVOL DELTA

ALPS, CVID, and LGL: When Autoimmune Cytopenias Are a Marker of Underlying Immune Disease (ASH 2024) - "Koneti Rao will discuss diagnosis and management of ALPS-FAS (Autoimmune Lymphoproliferative Syndrome due to FAS variants) and APDS (Activated PI3Kinase Delta Syndrome due to PIK3CD and PIK3R1 genetic variants) including recently licensed targeted treatment for the latter using a PI3Kinsae inhibitor, leniolisib...Treatment of the hematologic complications may require frequent and episodic use of corticosteroids, and/or rituximab; splenectomy is discouraged...Immunosuppressive agents (cyclophosphamide, methotrexate and cyclosporine) constitute the foundation of first line therapy. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting and hypomethylating agents, opening novel approaches in an otherwise incurable disease."

IO biomarker • Anemia • Endocrine Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Inflammatory Arthritis • Leukemia • Lymphoma • Neutropenia • Oncology • Primary Immunodeficiency • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Vasculitis • CCL2 • CCL22 • CTLA4 • IKZF1 • KMT2D • NFKB2 • PIK3CD • PIK3R1 • STAT1 • STAT3 • TET2 • TNFAIP3

APDS Treatment in Germany: Decision Criteria, Costs, and Contribution of Leniolisib to Outcomes (ISPOR-EU 2025) - "Decision criteria of German physicians for treating APDS are well in line with other therapeutic areas, with efficacy considered to be the most relevant issue. Based on data on leniolisib available today, mortality and several patient-relevant morbidity endpoints are expected to improve in future clinical practice in Germany. Leniolisib may also significantly modify the course of disease in APDS patients."

Bone Marrow Transplantation • Bronchiectasis • Hematological Malignancies • Infectious Disease • Lymphoma • Pulmonary Disease • Respiratory Diseases

Characterization of Activated Phosphoinositide 3-Kinase Delta Syndrome in the APDS-CHOIR Clinical Outcomes Registry (ACAAI 2025) - "Leniolisib was prescribed to 4 (13%) individuals during the baseline period, with 8 (26%) on leniolisib at 12-months; no discontinuations have been observed...Continued monitoring of APDS treatment outcomes through this registry can help support informed clinical decision-making. Data"

Clinical • Clinical data • Bone Marrow Transplantation • Genetic Disorders • Infectious Disease • PIK3CD • PIK3R1

Infliximab for Refractory Enteropathy in Activated PI3K Delta Syndrome (ACAAI 2025) - "In this case, infliximab was an effective treatment for APDS-associated colitis with IBD-like features. Importantly, controlling gastrointestinal inflammation may also improve the bioavailability of oral agents like leniolisib, enhancing therapeutic efficacy in APDS."

Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Musculoskeletal Pain • Respiratory Diseases • PIK3CD • PIK3R1

More Than Meets The Ig: Unveiling APDS2 In A Child With Hypogammaglobulinemia (ACAAI 2025) - "His course was further complicated by HSV lesions around the nares, prompting treatment with IV acyclovir...He was initially started on sirolimus, and although his IgG levels remained at the low end of normal despite appropriate IgRT dosing, this improved following initiation of leniolisib after FDA approval. Discussion This case underscores the value of genetic evaluation even in patients with presumed primary antibody deficiency, particularly when clinical findings evolve or suggest combined immunodeficiency. Identifying APDS2 has direct implications for care, including targeted therapies such as PI3Kδ inhibitors (leniolisib) and hematopoietic stem cell transplantation in select cases."

Clinical • Bone Marrow Transplantation • CNS Disorders • Epilepsy • Human Papillomavirus Infection • Immunology • Infectious Disease • Inflammation • Pneumonia • Primary Immunodeficiency • Respiratory Diseases • PIK3CD • PIK3R1

Impact of Leniolisib on Healthcare Utilization in Patients With Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) (ACAAI 2025) - "Infection-related visits PPY also showed a statistically significant 29% decrease, from mean (SD) 5.08 (6.76) pre-index to 3.72 (4.69) post-index (RR, 0.71; 95% CI, 0.55-0.91; P =0.008). Conclusion Significant reductions observed in OP/ED and infection-related visits following initiation of leniolisib suggest that treatment with leniolisib may reduce HCRU in patients with APDS."

Clinical • HEOR • Immunology • Infectious Disease • Primary Immunodeficiency

Real-World Adherence and Persistence With Leniolisib in Patients With Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) (ACAAI 2025) - "Counseling (n=15) improved adherence; mean (SD) PDC before and after counseling was 0.75 (0.17) and 0.87 (0.12), respectively. Conclusion Real-world adherence and persistence reflect strong patient engagement and suggest a perceived benefit that supports sustained use of leniolisib over time."

Adherence • Clinical • HEOR • Real-world • Real-world evidence • Immunology • Primary Immunodeficiency

Symptoms/Quality of Life in Pediatric Patients With Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Receiving Leniolisib (ACAAI 2025) - P3 | "Conclusion This study is the first to assess both symptoms and HRQoL in pediatric patients receiving leniolisib. Caregiver- and clinician-reported outcomes showed consistently reduced symptoms and improved HRQoL by week 12, reinforcing the clinical benefit of leniolisib."

Clinical • HEOR • Pediatrics • Rare Diseases

Effectiveness of Leniolisib in Reducing Infections Among Patients With Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) (ACAAI 2025) - "Conclusion Treatment with leniolisib consistently demonstrated significant reductions in infection rates, regardless of patients' infection history. These results align with the significant reduction in annualized infection rates observed in an open-label extension study of leniolisib in patients with APDS."

Clinical • Immunology • Infectious Disease • Primary Immunodeficiency

Adult/Pediatric Perspectives and Experiences With Activated Phosphoinositide-3-Kinase Delta Syndrome (APDS) and Leniolisib: APPEAL Survey (ACAAI 2025) - "At 12M, leniolisib satisfaction was 100% with no reported dissatisfaction; 75.0% reported that positive aspects somewhat or greatly outweighed negative aspects. Conclusion Real-world experience suggests improvement in APDS symptoms, HRQoL, and satisfaction with leniolisib."

Clinical • Pediatrics

From Infiltrates to Obstruction: A Case of Rapidly Progressive Colorectal Lymphoma in Activated PI3K Delta Syndrome (ACG 2025) - "We present a case of a patient with APDS who developed a rapidly progressive large bowel obstruction due to non-Hodgkin lymphomaCase Description/ 25-year-old male with APDS (on Leniolisib), eosinophilic esophagitis, and chronic colitis, presented to the emergency department (ED) with nausea, vomiting, and small-volume bloody bowel movements...Given prior symptom improvement on prednisone and mesalamine, another course was initiated at outpatient follow up...The risk of colonic lymphoma and IBD in APDS remains unclear but the PI3K-AKT-PTEN pathway is implicated in both. This case highlights the importance of early oncology evaluation and flow cytometry in patients with APDS and atypical lymphoid proliferation, with consideration of surgical or chemotherapeutic intervention to address this aggressive disease course."

Clinical • Colorectal Cancer • Eosinophilic Esophagitis • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Inflammatory Bowel Disease • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Primary Immunodeficiency • Solid Tumor • PIK3CD • PIK3R1

Humanistic Burden of Sjögren's Disease: A Systematic Review of Treatment Efficacy on Health-Related Quality-of-Life (ACR Convergence 2025) - "In randomized controlled trials (RCTs) involving rituximab, leniolisib, and abatacept, no significant differences in ESSPRI scores were found between treatment and placebo groups, indicating similar levels of symptom burden reduction (Table 2). In contrast, iguratimod and dazodalibep demonstrated significant improvements in overall ESSPRI scores compared to placebo in small or local trials. An RCT of tocilizumab failed to show significant improvements in anxiety or depression outcomes compared to the control group (Table 3)... Both systemic treatments and non-pharmacological interventions have generally shown limited efficacy in reducing the HRQoL burden in SjD. Although some treatments have demonstrated potential, these findings are primarily derived from clinical studies with small sample sizes and require validation. There remains a significant unmet need for therapies that can effectively alleviate the quality-of-life burden in patients with SjD."

Clinical • HEOR • Review • CNS Disorders • Depression • Fatigue • Hematological Malignancies • Immunology • Lymphoma • Mood Disorders • Psychiatry • Sjogren's Syndrome • Xerostomia

Pediatric Patients Aged 4 to 11 Years With APDS (clinicaltrials.gov) - P3 | N=15 | Active, not recruiting | Sponsor: Pharming Technologies B.V. | Trial primary completion date: Jul 2025 ➔ Oct 2025

Trial primary completion date • Pediatrics

Pediatric Patients Aged 1 to 6 Years With APDS (clinicaltrials.gov) - P3 | N=16 | Active, not recruiting | Sponsor: Pharming Technologies B.V. | Trial completion date: Feb 2026 ➔ Oct 2026 | Trial primary completion date: Apr 2025 ➔ Jul 2026

Trial completion date • Trial primary completion date • Pediatrics • PIK3CD • PIK3R1

Key outcomes in treatment of activated phosphoinositide 3-kinase delta syndrome: An e-Delphi panel study and responder threshold application. (PubMed, PLoS One) - P2/3 | "This study provides expert consensus on outcomes important in assessing APDS treatment effectiveness and improvement thresholds in 6 treatment outcomes indicative of a clinically meaningful benefit. These outcomes may help optimize APDS treatment in the clinic."

Journal • Hematological Disorders • Pediatrics • Thrombocytopenia

Pharming Group announces U.S. FDA acceptance and Priority Review of supplemental New Drug Application for leniolisib in children with APDS aged 4 to 11 years (GlobeNewswire) - "The application has been granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date of January 31, 2026. The sNDA submitted to the FDA is based on positive data from the multinational, single-arm Phase III study in children aged 4 to 11 years, which showed improvements over 12 weeks in two clinically relevant hallmarks of the condition, reduced lymphadenopathy and increased naïve B cells..."

PDUFA • Priority review • Primary Immunodeficiency

Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics. (PubMed, Cureus) - "Therapeutic advances, particularly the development of PI3Kδ inhibitors such as leniolisib and duvelisib, have significantly improved patient outcomes by targeting the underlying molecular defects. Despite these advances, challenges such as delayed diagnosis, treatment-related complications, and variability in clinical presentation persist. Continued research on targeted therapies, long-term outcomes, and gene-editing technologies is essential to optimize care and enhance the quality of life for individuals with APDS."

Journal • Review • Bone Marrow Transplantation • Hematological Disorders • Immunology • Infectious Disease • Primary Immunodeficiency • Transplantation • PIK3CD • PIK3R1

Activated phosphoinositide 3-kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment. (PubMed, Pediatr Discov) - "Targeted therapies, such as the mTOR inhibitor sirolimus and the elective Phosphoinositide 3-kinase delta inhibitor leniolisib, have emerged as promising options, demonstrating both safety and effectiveness. Continuous monitoring and further research are essential to optimize treatment strategies and understand the long-term implications of these interventions. This review aims to summarize the pathogenesis, clinical manifestations, and treatment of APDS."

Journal • Review • Bone Marrow Transplantation • CNS Disorders • Immunology • Infectious Disease • Oncology • Psychiatry • Respiratory Diseases • Transplantation • PIK3CD • PIK3R1

MANAGEMENT OF A COMPLEX CASE OF ACTIVATED PI3KΔ SYNDROME-1 (APDS-1) IMPROVED BY LENIOLISIB: A CASE REPORT (EHA 2025) - "At adulthood, his condition remained stable without severe infections, besides mild lymphoproliferation, lasting for over a decade.He was referred to our center in 2022 due to CMV infection, successfully treated initially with ganciclovir. In conclusion, Leniolisib appears to be an effective treatment of APDS even in patients with severe and life-threatening complications. Transitioning from Sirolimus seems feasible after a short wash out period and durable responses can be anticipated."

Case report • Clinical • IO biomarker • Anemia • Autoimmune Hemolytic Anemia • Cytomegalovirus Infection • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Lymphoma • Oncology • CD24 • CD38 • CD8 • IGH • NCAM1 • PIK3CD

Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment. (PubMed, Cell) - "Leniolisib, an FDA-approved PI3Kδ inhibitor, rescued aberrant signaling and dysfunction in GOF-harboring T cells and revealed partially drug-resistant PIK3R1 hotspots that responded to novel combination therapies of leniolisib with mTORC1/2 inhibition...Integrating our screens with population-level genomic studies revealed that APDS may be more prevalent than previously estimated. This work exemplifies a broadly applicable framework for removing ambiguity from sequencing in IEI."

Journal • PIK3CD • PIK3R1

Introducing Joenja: Clinical experience with the first and only licensed disease-specific therapy for APDS (EAACI 2025) - "Sponsored By Pharming."

Clinical • Immunology

Joenja efficacy and safety data (EAACI 2025) - "Sponsored By Pharming."

Clinical • Immunology

Primary and Safety Outcomes of a Phase 3, Open-Label, Single-Arm, 12-Week Study of Treatment with PI3Kδ Inhibitor Leniolisib in Paediatric Patients Aged 4–11 Years With Activated PI3Kδ Syndrome (APDS) (EAACI 2025) - P3 | "Conclusion Overall, leniolisib was generally well tolerated and met the co-primary endpoints, reducing lymphoproliferation and improving normalisation of naïve B cells. All 21 patients completed part 1 and 20 transitioned to the 1-year treatment extension (one patient discontinued due to social reasons)."

Clinical • Late-breaking abstract • P3 data • Immunology • CD27 • MME • PIK3CD

An Open-label, Single-arm Extension Study to Evaluate the Long-term Safety, Tolerability, and Efficacy of Leniolisib for Immune Dysregulation in Primary Immunodeficiency Disorders (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Pharming Technologies B.V.

New P2 trial • Immunology • Primary Immunodeficiency

Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood-Onset Lupus Nephritis Due to Activated PI3K-Delta Syndrome (APDS). (PubMed, Arthritis Rheumatol) - "This investigation advances rheumatology by demonstrating that APDS1-associated LN displays a specific tissue immune signature and responds to targeted inhibition of the causative molecular pathway. Our findings provide mechanistic insights into genetic drivers of autoimmunity and support pathway-specific therapeutic approaches for refractory autoimmune manifestations in primary immunodeficiencies."

Journal • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Pediatrics • Primary Immunodeficiency • Renal Disease • Rheumatology • CD8 • PIK3CD