A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Abstract

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70-mg leniolisib or placebo twice daily for 12 weeks. Co-primary outcomes were differences from baseline in index lymph node size and in percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% CI) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P=0.0006; N=26) and for percentage of naïve B cells was 37.30 (24.06, 50.54; P=0.0002; N=13). Leniolisib reduced spleen volume compared to placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P=0.0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (mostly grades 1-2) compared to those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the co-primary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. (Funded by DIR/NIAID, Novartis, and Pharming Group, NV; ClinicalTrials.gov identifier: NCT02435173.)

Common variable immunodeficiency, cross currents, and prevailing winds

“…More recently, JAK inhibitors have returned equilibrium to an ever‐enlarging list of STAT and JAK gain‐of‐function mutations 109–111 . For hyperproliferative defects, sirolimus has become a therapeutic mainstay joined in 2023 by leniolisib, a PIK3CD inhibitor, approved by the US Food and Drug Administration under orphan drug and rare pediatric disease designations 112 . Although each therapy listed above has a different mechanism of action, each success follows the same winning blueprint: (1) understand human diseases by studying human patients, (2) identify disease mechanisms that harm patients, (3) target harmful pathways, preferably through repurposed therapies, and (4) repeat.…”

Clinical updates in inborn errors of immunity: a focus on the noninfectious clinical manifestations

“…Elevated immunoglobulin M (IgM) levels have also been frequently seen in APDS patients [26–29]. Hematopoietic stem cell transplantation can be curative for APDS, however there is also a targeted PI3K inhibitor, leniolisib, that is now FDA approved for the treatment of APDS [26,30 ▪ ,31,32 ▪ ].…”

Model‐Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen

“…Peter N. Morcos 1, * , † , Jonathan Moss 2, † , Josh Veasy 2 , Florian Hiemeyer 3 , Barrett H. Childs 1 and Dirk Garmann 3 Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefitrisk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies.…”

“…with an intermittent dosing schedule while most other approved or investigational PI3K inhibitors are dosed orally using a continuous dosing schedule. [2][3][4][5] The intermittent ; We investigated exposure-efficacy relationships from 2-year follow-up of CHRONOS-3 and pooled exposure-safety relationships from CHRONOS-1 and CHRONOS-3. A clinical utility index function was constructed to consider tradeoffs of the characterized ER relationships in a model-based benefit/ risk framework.…”

“…Uniquely, copanlisib is administered intravenously (i.v.) with an intermittent dosing schedule while most other approved or investigational PI3K inhibitors are dosed orally using a continuous dosing schedule 2–5 . The intermittent dosing schedule was guided by preclinical investigations which suggested that robust antitumor activity can be achieved from transient PI3K inhibition, whereas treatment‐free intervals enabled tissue recovery; thereby maximizing efficacy with acceptable tolerability 6–8 …”