Rare Hematology News

Spotlight On

Activated PI3K delta syndrome (APDS)

A rare, genetic, primary immunodeficiency disease characterized by recurrent bacterial and viral infections, lymphoproliferation, and/or autoimmune disease

Prevalence

<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of Onset

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ICD-10

D81.8

Inheritance

Autosomal dominant

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Autosomal recessive

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Mitochondrial/Multigenic

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X-linked dominant

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X-linked recessive

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5 Facts you should know

FACT

1

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.

FACT

2

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.

FACT

3

Initially, patients with APDS may seek care from hematologists because of swollen lymph nodes or low numbers of blood cells.

FACT

4

Overproduction of B and T cells has been shown to appear as swollen tonsils, lymphadenopathy, or a swollen spleen.

FACT

5

Genetic testing is the only way to definitively diagnose APDS and other primary immunodeficiencies that could lead to potentially fatal disorders like lymphoma.

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Interest Over Time

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Activated PI3K delta syndrome is also known as...

Activated PI3K delta syndrome is also known as

PASLI disease, p110 delta-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency

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Common signs & symptoms

Bronchiectasis

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

Lymphadenopathy

Swollen lymph nodes

Recurrent ear infections

Frequent ear infections

Top Clinical Studies

TitleDescriptionPhasesStatusInterventionsLocationsMore Information
Extension to the Study of Efficacy of CDZ173 in Patients With APDS/PASLIThis 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 3RecruitingDrug: CDZ173Novartis 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, Netherlandshttps://ClinicalTrials.gov/show/NCT02859727
Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled Nemiralisib in Patients With APDS/PASLIThis 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 2CompletedDrug: NemiralisibGSK Investigational Site, Cambridge, United Kingdomhttps://ClinicalTrials.gov/show/NCT02593539
Study of Efficacy of CDZ173 in Patients With APDS/PASLIThis 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 3RecruitingDrug: CDZ173National 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 Kingdomhttps://ClinicalTrials.gov/show/NCT02435173

Top Treatments in Development

AgentClass/Mechanism of ActionDevelopment StatusCompanyCompany ContactClinical StudiesMore Information
leniolisibLeniolisib 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 3Pharming Group N.V.Anurag Relan, MD
Chief Medical Officer		https://clinicaltrials.gov/ct2/results?cond=&term=leniolisib&cntry=&state=&city=&dist=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 1/2This agent is being studied by Children's Hospital of Fudan Universityn/ahttps://clinicaltrials.gov/ct2/results?cond=APDS&term=rapamycin&cntry=&state=&city=&dist=More Information
NemiralisibThe 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 2GSKn/ahttps://clinicaltrials.gov/ct2/show/NCT02593539More Information