Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib

Area of Science:

• Immunology
• Pharmacology
• Genetics

Background:

• Gain-of-function variants in PI3Kδ cause activated PI3Kδ syndrome (APDS), leading to immune deficiency and lymphoproliferation.
• Understanding the genetic basis of APDS enables precision medicine strategies like PI3Kδ inhibition.

Purpose of the Study:

• To evaluate the in vitro and in vivo efficacy of leniolisib, a selective PI3Kδ inhibitor, for treating APDS.
• To assess the safety, pharmacokinetics, and immunological effects of oral leniolisib in APDS patients.

Main Methods:

• Conducted in vitro studies using cell lines and patient-derived T-cell blasts to assess PI3Kδ pathway inhibition.
• Performed a 12-week, open-label, dose-escalation clinical trial with 6 APDS patients.
• Monitored PI3K/AKT pathway activity, immune cell populations, serum inflammatory markers, and lymphoproliferation.

Main Results:

• Leniolisib demonstrated dose-dependent suppression of PI3Kδ pathway hyperactivation.
• Observed normalization of transitional and naive B cells, and reduction of senescent T cells.
• Showed significant reduction in lymph node and spleen volumes, alongside decreased inflammatory markers.

Conclusions:

• Leniolisib is well-tolerated and effectively improves laboratory and clinical parameters in APDS patients.
• Targeted PI3Kδ inhibition represents a promising therapeutic strategy for APDS and related disorders.
• This study supports leniolisib as a targeted therapy for diseases driven by PI3Kδ pathway overactivation.