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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

ageofonset-infancy.svg

ICD-10

D81.82

Inheritance

Autosomal dominant

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10 Warning Signs of APDS

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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.

*PASLI, p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.

RV APDS 1@2 https://raremedicalnews.com/wp-content/uploads/2021/10/smiling-girl-with-blonde-hair-wearing-black-crew-neck-shirt-stockpack-pexels-scaled.jpg

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.

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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Patients with APDS (activated PI3K delta syndrome) are often misdiagnosed with…?

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

Current treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

Antibiotic prophylaxis

Use of antimicrobial prophylaxis is reported in 61-79% of patients, with antibiotics being the most common treatments.

Hematopoietic stem cell transplant (HSCT)

Hematopoietic stem cell transplant (HSCT) has been used to treat a small proportion (9-17%) of patients with APDS1; while HSCT has the potential to resolve the clinical symptoms of APDS, it is associated with a relatively high risk of post-transplant morbidity and mortality.

Immunoglobulin replacement (IRT)

IRT can be used to address sinopulmonary infections or autoimmune cytopenias and its use has been reported in 63-89% of patients with APDS, starting at a reported median age of 5 years of age, with nearly half of patients receiving treatment by age 10 years.

Joenja (leniolisib)

Leniolisib is the first approved treatment specifically for activated phosphoinositide 3-kinase delta syndrome in adult and pediatric patients 12 years of age and older. 

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, NetherlandsMore Info
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 KingdomMore Info
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 KingdomMore Info

Top Treatments in Development

AgentClass/Mechanism of ActionDevelopment StatusCompanyCompany ContactClinical StudiesMore 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/aMore InfoMore 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/aMore InfoMore Information

† All About APDS https://allaboutapds.com