Interim analysis: Open-label extension study of leniolisib for patients with APDS

Abstract

Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation.

Objective: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study.

Methods: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation.

Results: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets.

Conclusions: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS.

Clinicaltrials: gov identifier: NCT02859727.

Keywords: APDS; B cells; PI3Kδ inhibitor; PIK3CD; PIK3R1; T cells; clinical trial; long-term safety; lymphoproliferation; primary immunodeficiency.

Figure 1.. Adverse events (AE) and AE grades.

(A) Total percentage of patients with all reported AEs, treatment-related AEs (TRAE) and serious AEs (SAE). (B) Percentage of patients stratified by grades of AEs.

Figure 2.. Lymphoproliferation outcomes.

(A) Representative radiographic renderings of lymph node diameters from patients at screen (Scr), end of the dose-finding or RCT trial (12 weeks), and readout at either extension day (ED) 168 or 252 of the OLE (OLE). (B) Individual values of untransformed SPD of index lymph nodes for scr (n=24; n=8), 12 weeks (n=24; n=7) and OLE (n=19; n=7) (prior leniolisib; no prior leniolisib). (C) Representative radiographic renderings of spleen volumes from patients at Scr, 12 weeks, and OLE. (D) Individual spleen volumes for Scr (n=25; n=8), 12 weeks (n=25; n=8) and OLE (n=20; n=6) (prior leniolisib; no prior leniolisib) gray shaded box indicates normal range.

Figure 3.. Changes in B-cell and immune parameters.

(A) Mean naïve B-cell percentages over time. N values for ED 1, ED 84, ED 168, and ED 252 are as follows: 34, 34, 28, 24. (B) Mean transitional B-cell percentages over time. n values for ED 1, ED 84, ED 168, ED 252 are as follows: 34, 34, 28, 24. (C) Mean mature B-cell percentages over time. n values for ED 1, ED 84, ED 168, and ED 252 are as follows: 34, 34, 28, 24. (D) Mean plasmablast (CD19⁺CD27⁺CD38⁺⁺) percentages overtime. n values for ED 1, ED 84, ED 168, and ED 252 are as follows: 34, 34, 28, 23. (E) Mean switched (CD19⁺CD27⁺IgD⁻) and nonswitched (CD19⁺CD27⁺IgD⁺) memory B-cell percentages overtime. n values for ED 1, ED 84, ED 168, and ED 252 for each group are as follows: switched memory B cells, 34, 34, 28, 24; non-switched memory B cells, 34, 34, 28, 24. (F) Mean values of circulating CXCL13 in pg/mL for ED 1 (n=31), 84 (n=29), 168 (n=26) and 252 (n=26). (G) Individual IgM values over time. n values for ED 1, ED 84, ED 168, and ED 252 are as follows: 10, 9, 7, 7. In A-D and F-G gray shaded boxes indicate normal range values for respective measurements. In E gray shaded box indicates normal range for switched memory B cells, and dashed lines indicate normal range for non-switched memory B cells.

Figure 4.. T-cell parameters.

(A) Mean senescent T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: CD4⁺, 31, 32, 28, 24; CD8⁺, 30, 32, 28, 21. (B) Mean CD4⁺ and CD8⁺ PD-1⁺ T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: CD4⁺, 32, 33, 28, 24; CD8⁺, 32, 32, 28, 20. (C) Mean CD4⁺ and CD8⁺ T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: CD4⁺, 32, 33, 28, 24; CD8⁺, 32, 33, 28, 24. (D) Mean naïve (CD45RA⁺ CD62L⁺) CD4⁺ and CD8⁺ naïve T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: CD4⁺, 31, 33, 28, 24; CD8⁺, 32, 32, 28, 21. (E) Mean central memory (CD45RO⁺ CD62L⁺) CD4⁺ and CD8⁺ naïve T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: CD4⁺, 32, 33, 28, 24; CD8⁺, 32, 32, 28, 21. (F-G) Mean effector memory and effector memory cells reexpressing CD45RA (CD45RA⁺ CD62L⁺) CD4⁺ and CD8⁺ T-cell percentages over time. n values for ED1, ED84, ED168, and ED252 for each group are as follows: effector memory, CD4⁺, 32, 33, 28, 24; CD8⁺, 32, 32, 28, 21; effector memory RA, CD4⁺, 31, 32, 28, 27; CD8⁺, 32, 32, 28, 21 Gray shaded boxes indicate normal ranges for CD4⁺ cells, and dashed lines indicate normal range for CD8⁺ cells.

Figure 5.. Changes in baseline cytopenias.

(A) Individual female patients’ hemoglobin levels over time (n=5). (B) Individual male patients’ hemoglobin levels over time (n=4). (C) Platelet levels overtime for individual patients that started with low levels at screen time (n=6). (D) Lymphocyte values over time for individual patients (n=5). (E) Neutrophil levels over time for individual patients (n=3). Gray shaded boxes indicate normal range values for respective measurements.