Pharming announces publication of data from Phase 3 Study of leniolisib in patients with APDS in ASH's Blood
Leniolisib was well tolerated and significant improvement over placebo was notable in the co-primary endpoints, reflecting a favorable impact on patients' immune dysregulation and deficiency
The peer-reviewed publication heightens international understanding of APDS, a rare and recently characterized immunodeficiency
The paper, entitled 'Randomized, Placebo-Controlled, Phase 3 Trial of PI3Kδ Inhibitor Leniolisib for Activated PI3Kδ Syndrome', outlined results from the multinational, triple-blind, placebo-controlled, randomized clinical trial, which enrolled 31 patients with APDS aged 12 years or older. Patients were randomly assigned in a 2:1 ratio to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Improvement over placebo was significant in the co-primary endpoints which evaluated reduction in lymph node size and increase in naïve B cells, reflecting the impact on immune dysregulation and correction of immunodeficiency in these patients, respectively. 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 was well tolerated, and fewer patients receiving leniolisib reported study treatment-related adverse events (mostly grades 1-2) compared to those receiving placebo (23.8% vs 30.0%).
"As we continue to seek a better understanding of APDS as a recently characterized rare disease, we remain committed to sharing our findings with researchers and doctors around the world. With this commitment in mind, we are pleased the results of this Phase III clinical trial in leniolisib have been published in the flagship journal of the
The APDS patient population, and their families, have lived with unmet needs and without targeted therapies, and the publishing of this study is an integral step in improving the patient journey for this community. We are proud to share these results which demonstrated leniolisib to be a well-tolerated, targeted therapy for APDS. We thank all of our study participants and investigators for their efforts and the essential role they played in the development of leniolisib."
About Activated Phosphoinositide 3-Kinase δ Syndrome (APDS)
APDS is a rare primary immunodeficiency that affects approximately 1 to 2 people per million. APDS is caused by variants in either of two genes, PIK3CD or PIK3R1, that regulate maturation of white blood cells. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway.2,3 Balanced signaling in the PI3Kδ pathway is essential for physiological immune function. When this pathway is hyperactive, immune cells fail to mature and function properly, leading to immunodeficiency and dysregulation.2,4 APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.5,6 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 7-year diagnostic delay.7 As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.5-8 The only way to definitively diagnose this condition is through genetic testing.
Leniolisib is a small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K. PI3Kδ is expressed predominately in hematopoietic cells and is essential to normal immune system function through conversion of phosphatidylinositol-4-5-trisphosphate (PIP2) to phosphatidylinositol-3-4-5-trisphosphate (PIP3). Leniolisib inhibits the production of PIP3 and PIP3 serves as an important cellular messenger activating AKT (via PDK1) and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Unlike PI3Kα and PI3Kβ, which are ubiquitously expressed, PI3Kẟ and PI3Kγ are expressed primarily in cells of hematopoietic origin. The central role of PI3Kẟ 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 PI3Kẟ is a valid and potentially effective therapeutic target for immune diseases such as APDS. To date, leniolisib has been well tolerated during both the Phase 1 first-in-human trial in healthy subjects and the Phase II/III registration-enabling study in patients with APDS.
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