Primary and Safety Outcomes of a Phase 3 Open-Label, Single-Arm, 12-Week Study of Treatment with PI3Kδ Inhibitor Leniolisib in Pediatric Patients Aged 4–11 Years with Activated PI3Kδ Syndrome (APDS)

Leniolisib is an FDA-approved PI3Kδ inhibitor used to treat activated phosphoinositide 3-kinase delta syndrome (APDS) in patients aged ≥12 years who weigh ≥45 kg. Pediatric patients aged 4 to 11 years with APDS were enrolled in a two-part, prospective, open-label, single-arm, international study to evaluate the safety and efficacy of leniolisib (NCT05438407). Here we report safety and efficacy outcomes following the completion of 12 weeks of leniolisib treatment (part 1). Twenty-six patients were screened; 21 patients enrolled across the United States, France, and Japan (Table 1). Leniolisib was administered orally twice daily (BID) as tablets in 10- and 30-mg strengths, with doses ranging from 20 to 70 mg BID based on weight. Co-primary outcomes were change from baseline (CFB) at 12 weeks in log10-transformed sum of product of diameters (SPD) of index lymph nodes and normalization of naïve B cells. Additional outcomes included changes in spleen volume and quantitative immunoglobulin (Ig) levels, including IgM. Table 1.Patient demographics and baseline characteristics.Patient Characteristic (N=21)ValueAge at time of study, median (range), y7.0 (4-11)Sex, male to female, n13:8Self-identified race, n (%)White9 (42.9)Asian4 (19.0)Other1 (4.8)Not reported/unknown/missing7 (33.3)Self-identified ethnicity, n (%)Hispanic3 (14.3)Non-Hispanic12 (57.1)Not reported6 (28.6)Weight at baseline, median (range), kg23.9 (15.4-44.5)Time since APDS diagnosis, median (range), mo32.9 (2.2-142.2)APDS variant distribution, n (%)PIK3CD17 (81.0)PIK3R14 (19.0)APDS, activated phosphoinositide 3-kinase delta syndrome; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1. Both primary end points improved from baseline after 12 weeks of treatment with leniolisib across all dose levels. Mean CFB of log10-transformed SPD reduced by -0.1956 (n = 19). Mean CFB of naïve B cells (CD19+CD27-CD10-) from total B cells was 33.3% (SD, 13.1; n = 11). Mean CFB of spleen log10 volume reduced was -0.1222 (n = 21). Mean Ig levels (n = 14) changed from baseline after 12 weeks of leniolisib treatment: IgM, 2.7 g/L to 1.6 g/L; IgG, 10.1 g/L to 11.1 g/L; and IgA, 0.88 g/L to 0.83 g/L. Leniolisib was well tolerated (Table 2). Twenty patients had treatment-emergent adverse events (AEs). All were grades 1 or 2; none were serious. Five patients had treatment-related AEs, including headache, palpitations, abdominal pain, diarrhea, nausea, pruritus, fatigue, decreased neutrophil count, and increased aspartate aminotransferase. No AEs led to discontinuation of study drug treatment. Table 2.Summary of Treatment-Emergent Adverse Events.Adverse Events CategoryTotal No. of Patients, n (%)Any TEAE20 (95.2)Grade 120 (95.2)Grade 28 (38.1)Grade 30Grade 40Grade 50Any study treatment-related TEAE5 (23.8)Leading to discontinuation of study treatment0Leading to death0Any serious TEAE0TEAE, treatment-emergent adverse event. Overall, leniolisib was well tolerated, reduced lymphoproliferation, and improved normalization of naïve B cells, meeting the co-primary end points. All 21 patients completed part 1, and 20 transitioned to the 1-year treatment extension (one patient discontinued due to social reasons).