The PI3Kδ inhibitor, leniolisib, improved markers of immune dysfunction among patients with an inborn error of immunity caused by activated PI3Kδ syndrome (APDS), according to the results of a phase 3 trial published in Blood.

APDS can cause profound morbidity and early mortality. Current treatment is empirical, with no agent targeted to the aberrant PI3Kδ signaling that causes the disease.

This triple-blind, phase 3 trial randomly assigned 31 patients aged 12 or older with APDS 2:1 to receive leniolisib or placebo for 12 weeks. The coprimary endpoints were the difference in lymph node size from baseline and percentage of naïve B-cells.

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At baseline, the median age was 20.0 (range, 12-54), 51.6% of patients were female, and the median weight was 67.1 kg. Lymphoproliferation was present among 71% of patients, chronic infections among 80.6%, pulmonary disease in 71.0%, bronchiectasis in 51.6%, asthma in 35.5%, cytopenia in 58.1%, and gastrointestinal disease in 54.8%. There were 58.1% of patients using baseline glucocorticoids and 41.9% using antibiotic prophylaxis.

Leniolisib resulted a significant reduction in index lymph node size, with a difference of -0.25 compared with placebo (P =.0006). Complete absence of index lymphadenopathy was achieved by 26% and partial response by 74% of patients in the leniolisib group. In the placebo group, 45% of patients achieved partial response and 44% had stable disease.

Spleen volume was reduced by a mean of -186 cm3 compared with placebo (P =.0020).  Among patients with baseline splenomegaly, 38% and 54% achieved complete or partial response with leniolisib at 12 weeks. In the placebo group, 20% of patients achieved complete response and 80% developed worsening disease.

The percentage of circulating naïve B cells was significantly higher in the leniolisib group compared with the placebo group, with a difference of 37.30% (P =.0002). Other lymphocyte subsets also improved with leniolisib, including transitional B cells, CD38-positive plasmablasts, nonswitched memory B-cells, serum IgM, CD8-positive senescent CD57-positive T-cells, and PD-1 T-cells.

Treatment-related adverse events (TRAEs) occurred more frequently in the placebo group, affecting 30.0% of patients compared with 23.8% in the leniolisib group. The majority of TRAEs were grade 1-2, with the most common in the leniolisib group including alopecia, taste disorder, vomiting, and weight increase.

The authors concluded that “treatment with leniolisib demonstrated targeted therapy of a rare but biologically relevant immune dysregulation and immune deficiency with a significant benefit over placebo.”

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.


Rao VK, Webster S, Sediva A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141:971-983. doi: 10.1182/blood.2022018546