WMMH schreef op 5 februari 2023 09:01:
Activated Phosphoinositide 3-kinase Delta Syndrome
Leniolisib (Pharming Group), a selective phosphoinositide 3-kinase delta (PI3Kd) inhibitor, to treat the rare primary immunodeficiency activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and adolescents 12 years of age and older, is looking to March 29 for the FDA to take action.
APDS is a rare primary immunodeficiency that occurs in one in 1 million people. It is caused by variants in either of two genes, PIK3CD or PIK3R1, which regulate maturation of white blood cells. Variants of these genes lead to hyperactivity of the PI3Kd pathway. Balanced signaling in the pathway is essential for physiologic immune function. When this pathway is hyperactive, immune cells fail to mature and function properly, leading to immunodeficiency and dysregulation. APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity and enteropathy. Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, people with APDS are frequently misdiagnosed and suffer a median seven-year diagnostic delay. As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.
A phase 2/3 study of leniolisib met its co-primary end points of reduction in index lymph node size and correction of immunodeficiency in the target population. Leniolisib produced a significant reduction from the baseline size of participants’ index lymphadenopathy lesions (P=0.006) and normalization of their immune function, as shown by an increased proportion of naive B cells from baseline (P=0.002). These findings indicate a reduction in disease markers associated with APDS, whose clinical hallmarks include significant lymphoproliferation and immune dysfunction, as well as increased risk for lymphoma.
Leniolisib is a small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K with immunomodulating and potentially antineoplastic activities. Leniolisib inhibits the production of phosphatidylinositol-3-4-5-trisphosphate (PIP3). PIP3 serves as an important cellular messenger activating AKT (via PDK1), and regulates many 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 of hematopoietic origin. The central role of PI3K delta in regulating numerous cellular functions of the adaptive immune system (B-cells and, to a lesser extent, T cells), as well as the innate immune system (neutrophils, mast cells and macrophages), strongly indicates that PI3K delta is a valid and potentially effective therapeutic target for several immune diseases.