Rare Hematology News
Activated PI3K delta syndrome (APDS)
A rare, genetic, primary immunodeficiency disease characterized by recurrent bacterial and viral infections, lymphoproliferation, and/or autoimmune disease
Age of Onset
Activated PI3K delta syndrome, known as APDS (previously known as PASLI* Disease) is a rare primary immunodeficiency, first discovered in 2013. APDS is caused by genetic variants in either one of two genes known as PIK3CD or PIK3R1, which encode proteins that are vital to the normal development and function of immune cells. Signs and symptoms of APDS start in childhood, and patients are vulnerable to repeat infections and immune dysregulation such as lymphadenopathy, splenomegaly, autoimmune cytopenias, and even lymphoma.†
5 Facts you should know
APDS, a primary immunodeficiency, was only characterized in 2013; however, it shares many features of other immune disorders, which means APDS patients may have been previously misdiagnosed with other conditions.
Signs and symptoms of APDS start in childhood, and patients are vulnerable to repeat infections and immune dysregulation such as lymphadenopathy, splenomegaly, autoimmune cytopenias, and even lymphoma.
Initially, patients with APDS may seek care from hematologists because of swollen lymph nodes or low numbers of blood cells.
Overproduction of B and T cells has been shown to appear as swollen tonsils, lymphadenopathy, or a swollen spleen.
Genetic testing is the only way to definitively diagnose APDS and other primary immunodeficiencies that could lead to potentially fatal disorders like lymphoma.
Interest Over Time
Common signs & symptoms
Permanent enlargement of the airways of the lungs
Decreased circulating IgG2 level
Decreased proportion of class-switched memory B cells
Decreased specific pneumococcal antibody level
Increased circulating IgM level
Increased proportion of transitional B cells
Recurrent ear infections
Top Clinical Studies
|Extension to the Study of Efficacy of CDZ173 in Patients With APDS/PASLI||This study is designed to provide long-term CDZ173 treatment, a selective PI3Kδ inhibitor, to the patients with genetically activated PI3Kδ, i.e., patients with APDS/PASLI who participated in the CCDZ173X2201 study or who were treated previously with PI3Kδ inhibitors other than CDZ173. The study is open-label designed to establish the long-term safety, tolerability, efficay and pharmacokinetics of CDZ173 in the target population.||Phase 2|Phase 3||Recruiting||Drug: CDZ173||Novartis Investigative Site, Bethesda, Maryland, United States|Novartis Investigative Site, Minsk, Belarus|Novartis Investigative Site, Prague 5, CZE, Czechia|Novartis Investigative Site, Dublin, Ireland|Novartis Investigative Site, Palermo, PA, Italy|Novartis Investigative Site, Brescia, Italy|Novartis Investigative Site, Rotterdam, Netherlands||More Info|
|Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled Nemiralisib in Patients With APDS/PASLI||This is an open-label study conducted to investigate safety, pharmacokinetics and pharmacodynamics of repeat doses of inhaled nemiralisib (NEMI) in participants with activated phosphoinositide 3-kinase (PI3K) delta syndrome /p110 delta-activating mutation causing senescent T Cells, lymphadenopathy and immunodeficiency (APDS/PASLI)||Phase 2||Completed||Drug: Nemiralisib||GSK Investigational Site, Cambridge, United Kingdom||More Info|
|Study of Efficacy of CDZ173 in Patients With APDS/PASLI||This study is designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with APDS/PASLI. The study consists of two parts. Part I is the open label part designed to establish the safety and pharmacokinetics of CDZ173 in the target population, as well as to select the optimal dose to be tested in part II. Part II is designed to assess efficacy and safety of CDZ173 in this population.||Phase 2|Phase 3||Recruiting||Drug: CDZ173||National Institute of Health NIH, Bethesda, Maryland, United States|Novartis Investigative Site, Minsk, Belarus|Novartis Investigative Site, Prague 5, Czechia|Novartis Investigative Site, Paris cedex 15, France|Novartis Investigative Site, Dresden, Germany|Novartis Investigative Site, Dublin, Ireland|Novartis Investigative Site, Palermo, PA, Italy|Novartis Investigative Site, Brescia, Italy|Novartis Investigative Site, Rotterdam, Netherlands|Novartis Investigative Site, Moscow, Russian Federation|Novartis Investigative Site, Belfast, United Kingdom|Novartis Investigative Site, London, United Kingdom||More Info|
Top Treatments in Development
|Agent||Class/Mechanism of Action||Development Status||Company||Company Contact||Clinical Studies||More Information|
|leniolisib||Leniolisib is a small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA|
PI3K with immunomodulating and potentially anti-neoplastic activities. Leniolisib inhibits the
production of phosphatidylinositol-3-4-5-trisphosphate (PIP3). PIP3 serves as an important cellular
messenger specifically 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 (neutrophil, mast cells, and macrophages) strongly indicates that PI3Kẟ is a valid and potentially effective therapeutic target for several immune diseases. To date, leniolisib has proven to be safe and well tolerated in healthy subjects as well as the APDS patients during the Phase 1 first-in-human trial and an ongoing open label extension trial.
|Phase 3||Pharming Group N.V.||Anurag Relan, MD|
Chief Medical Officer
|More Info||More Information|
|Sirolimus (Rapamycin)||The mTOR inhibitor, Sirolimus (Rapamycin) has been found to decrease in non-neoplastic lymphoproliferation. mTOR (mammalian target of rapamycin) is activated downstream of PI3K and has a prominent role in T cell metabolism and the regulation of immune responses. Previously Sirolimus therapy had been reported in a case of APDS to reduce hepatosplenomegaly and lymphadenopathy, increase naïve T cell frequencies, and restore T cell proliferation and IL-2 secretion. Recently Maccari et al. published the initial findings of the ESID APDS registry.||Phase 1/2||This agent is being studied by Children's Hospital of Fudan University||n/a||More Info||More Information|
|Nemiralisib||The inhaled PI3Kδ inhibitor, GSK2269557 or Nemiralisib, is also currently being studied in APDS sponsored by GlaxoSmithKline (NCT02593539). Though an oral inhibitor maybe more effective for lymphoproliferation; it is proposed an inhaled inhibitor could benefit patients primarily affected by airway infection and bronchiectasis. The GSK2269557 clinical trial has not as yet reported results, but is described as a “multi-center, non-randomized, open-label, uncontrolled, single group study to investigate the safety and pharmacokinetics during 84 days repeat dosing treatment with 1,000 micrograms of inhaled in addition to standard of care, in subjects with APDS.” GSK2269557 is also currently being investigated as an anti-inflammatory treatment in Chronic Obstructive Pulmonary Disease (COPD).||Phase 2||GSK||n/a||More Info||More Information|
† All About APDS https://allaboutapds.com