Activated Phosphoinositide 3-kinase Delta Syndrome (“APDS”)

APDS is a primary immunodeficiency (PID) where white blood cells in the immune system don’t work correctly, particularly ones that are called B cells and T cells. Normally, these cells recognize and attack viruses and bacteria to prevent infection. In APDS, the white blood cells are abnormal so these patients often have frequent infections, particularly in the airways and lungs, which in time can lead to a condition called bronchiectasis. This long-term condition damages the passages leading from the windpipe to the lungs (bronchi) and can cause significant breathing problems. Furthermore, individuals can be at greater risk of developing conditions linked with the over production of white blood cells (such as swollen lymph nodes and lymphoma). APDS affects approximately 1-2 per million globally and there is currently no specific pharmacologic treatment available, instead treatment options are limited to symptom reduction.

APDS is a disorder that impairs the immune system. Individuals with the condition often have low levels of white blood cells, which normally recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. Beginning in childhood, people with APDS develop recurrent infections, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory tract infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. APDS affects approximately 1-2 per million globally and there is currently no approved treatment available.

We, in partnership with our collaborator Novartis, are currently studying leniolisib to assess the efficacy and safety of leniolisib in patients with APDS. The study, a phase 2/3 potentially registration enabling study is composed of 2 sequential parts, the first part including 6 patients was an open-label dose escalation study that was designed to assess the safety, tolerability, pharmakodynamics and pharmacokinetics of leniolisib, a dose-finding study that has since completed. The second part is a randomized, blinded, placebo-controlled study that that includes 30 additional patients and is designed to assess the efficacy of leniolisib in APDS patients. (NCT: NCT02435173) The co-primary endpoints of the second part of the study are (i) change in the size of lesions from baseline and (ii) change in baseline in percentage of naive B cells out of total B cells.

Leniolisib is a small molecule inhibitor of the delta isoform of the 110 kilodalton, or kDa, catalytic subunit of class IA PI3K with immunomodulating and potentially antineoplastic activities. Leniolisib inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, or PIP3. PIP3 serves as an important cellular messenger specifically activating the protein-serine/threonine kinase AKT (via PDK1) and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Unlike PI3K alpha and PI3K beta which are ubiquitously expressed, PI3K delta and PI3K gamma are expressed primarily in cells that are hematopoietic in origin. The central role of PI3K delta in regulating numerous functions of cells of the adaptive immune system (B cells and T cells) as well as the innate immune system (neutrophil, mast cells, and macrophages) strongly indicates the PI3K delta is a valid and potentially effective therapeutic target for several immune diseases.

This study was temporarily halted due to COVID-19 but has since resumed. Subject to COVID-19-related delays, data is expected in the first half of 2022, followed by review by regulatory authorities in the second half of 2022. If approved, the drug is planned to launch late 2022.