Abstract

PI3Kδ Activation Syndrome (APDS) is a rare congenital immunodeficiency caused by mutations that result in hyperactivation of the PI3Kδ signaling pathway. The persistent activation of the AKT/mTOR signaling pathway leads to impaired survival, proliferation and activation of both B and T lymphocytes. There are two genetic forms of APDS, associated with autosomal dominant transmission. APDS patients face recurrent bacterial and viral infections, frequent respiratory symptoms due to infections or bronchospasm, and persistent benign lymphoproliferations (lymphadenopathies and hepatosplenomegaly) with a high risk of develop lymphomas and/or autoimmune diseases (e.g. cytopenia). APDS treatments are similar to those implemented in management of immunodeficiencies, such as immune prophylaxis and antimicrobial therapies, administration of replacement immunoglobulins and various anti-inflammatory and immunosuppressive drugs. Several PI3Kδ inhibitors have been evaluated in clinical trials for the treatment of APDS, but only leniolisib has been approved by the FDA (March 2023) as an orphan drug for APDS due to its good efficacy, safety and tolerability profile. Leniolisib has the high potential to be disease modifying drug for the treatment of APDS patients, also considering its pharmacodynamic properties (selectivity for the δ isoform of PI3K). Further studies and clinical trials have been performed and are ongoing to confirm the long-term effect and safety profile of the drug. Preliminary results show positive data in terms of efficacy, safety and long-term tolerability.

INTRODUCTION

Inborn Errors of Immunity (IEI), or Primary Immunodeficiencies (PID), are a heterogeneous group of diseases caused by mutations in genes encoding proteins with essential functions in the immune system (IS). Although these diseases are rare, the disease’s consequences and clinical management is associated to high direct and indirect costs, representing a problem for the sustainability of the healthcare system 1,2. PIDs are a group of immune system inherited/congenital diseases, now defined as congenital errors of immunity (IEI), which are characterized by a broad spectrum of clinical manifestations that include, infections susceptibility, and manifestations of immune dysregulation, such as allergy, autoimmunity, autoinflammation, and lymphoproliferation. Approximately, 485 genetic defects associated with IEI are currently known 3,4. IEIs are generally diagnosed in childhood, and these diseases are rare (approximate prevalence of 1:10,000), with the exception of immunoglobulin A deficiency (Selective IgA Deficiency, SIgAD), which is found in approximately of every 500 individuals 5 . However, the discovery of new immunodeficiencies and better clinical evaluation of patients has allowed to re-evaluate the frequency of these pathologies, currently considered around 1:1000-1:5000 6. In severe and combined forms, early diagnosis is crucial for the efficacy of treatment, before the onset of complications or organ damage which characterize disease progression. A delay in diagnosis, and thus delayed correct treatment and prophylaxis, can lead to the development of complications (such as bronchiectasis or chronic otitis/sinusitis), persistent autoimmune manifestations and uncontrolled progression of the lymphoproliferative disease.

Phospholipase 3-kinases delta (PI3Kδ) is composed of a catalytic unit p110δ expressed mainly in lymphocytes, and a ubiquitous p85α regulatory subunit. APDS (activated PI3Kδ syndrome) is a rare disorder due generally to autosomal dominant mutations in one of the two genes encoding for the two subunits. However, autosomal recessive cases have been described, in a total of three relatives 7.

PI3Kδ proteins are crucial for the activation of the PI3K-Akt-mTOR signaling pathway, which is involved in several cellular processes such as metabolism, proliferation, cell survival, differentiation 8,9. PI3Ks are heterodimeric proteins consisting of two subunits, a regulatory p85α and a catalytic p110. The latter has four isoforms (α, β, γ, δ): α and β isoforms are expressed in most cells in the body, while γ and δ isoforms mainly in cells of the immune system. In particular, δ is expressed in B and T lymphocytes, natural killer (NK) cells and monocytes. The most frequent mutations responsible for APDS are localized in the PIK3CD gene, which encodes for the p110δ catalytic subunit, and those in the PIK3R1 gene, which encodes for the p85α regulatory subunit. These two mutations characterize respectively: APDS1 (75% of cases) with a kinase hyperactivation, gain of function (GOF) mutation in the PIK3CD gene, and APDS2 (25% of cases) characterized by a loss of function (LOF) of the p85α subunit, resulting in PI3Kδ hyperactivity 10,11. There is another germline mutation that induces a syndrome defined as APDS-like, i.e. a LOF related to the activity of phosphatase PTEN (phosphatase and tensin homolog), a phosphatase that does not hydrolyze PIP3 leading to the activation of AKT 12,13. In March 2023, the Food and Drug Administration (FDA) approved leniolisib as an orphan drug for APDS, which inhibits PI3Kδ 14.

The most frequent infections in APDS patients include bacterial infections by Streptococcus pneumoniae and Haemophilus influenzae 15,16. In addition to respiratory infections, patients can be exposed to infections of other organs or systems (eyes, skin, lymph nodes (lymph node abscesses), digestive system (gastroenteritis)), up to severe systemic infections. In addition, viral infections with Cytomegalovirus (CMV) and Epstein Barr (EBV) can have chronic course in APDS individuals. The chronic replication of EBV in B lymphocytes may favor the development of lymphomas in the long term 13,17. In particular, 13% of patients with APDS are prone to develop forms of lymphomas 15,16,18. Autoimmune manifestations are also frequent in APDS, such as autoimmune hemolytic anemia or plateletopenia.

The alteration of the PI3K signaling pathway affects the activation of several molecular targets, including AKT, mTOR, which regulate the differentiation and activity of B and T lymphocytes 19,20. Hyperactivation of PI3Kδ leads to a reduction in the number of näive T lymphocytes (both CD4+, Thelper and CD8+, Tcytotoxic) and increases the proportion of mature T lymphocytes. On the other hand, B lymphocytes remain immature, thus unable to produce immunoglobulins. For these reasons, the immune system in APDS patients is inefficient against infections, given the lack of antibodies (by mature memory B lymphocytes) against antigens, as in the case of autoimmune diseases 10,17,21. On the other hand, is possible to find high levels of IgM (produced by immature B lymphocytes) combined with low levels of IgG and IgA (hypogammaglobulinemia). Furthermore, PI3Kδ hyperactivation results in hyperproliferation of immature lymphocytes and consequently enlarged lymph nodes (lymphadenopathy) 15,22,23.

TREATMENTS FOR APDS

APDS treatment, as for many immunodeficiencies, includes immunosuppressive therapies in order to prevent and treat both bacterial or viral infections, due to the immune deficiency and autoimmune processes 24,25. Scientific research has shown that some molecules are effective in reducing the pathological aspects of APDS, as in the case of rapamycin, an mTOR inhibitor, which reduces lymphoproliferation, but which is less effective on other APDS clinical manifestations, such as cytopenias and inflammatory bowel disease 24. Moreover, its long-term use at immunosuppressive doses (higher than those used for lymphoproliferative diseases) has been associated with several adverse effects, such as insulin resistance; the target of rapamycin (mTOR) is also involved in the insulin and growth hormone signaling pathway 13,26. As mentioned above, the designation of leniolisib as an orphan drug by the FDA 27 has revolutionized the treatment of APDS, as this molecule can selectively modulate the hyperactivation of PI3Kδ in APDS1 and APDS2 (Fig. 1). Treatment with leniolisib is effective and well-tolerated on the clinical manifestations of the disease and some of its immunological markers 13,28-30.

Leniolisib pharmacodynamics and pharmacokinetics

Leniolisib reduces PI3Kδ activity by occupying the ATP-binding site on the catalytic site of the p110δ subunit 30. The binding affinity of leniolisib for the PI3Kδ isoform is higher than the affinity for the other isoforms: PI3Kα subunit (28-fold), β (43-fold) and γ (257-fold) 31. In vitro studies have shown that leniolisib significantly reduces AKT phosphorylation and thus its activation, inhibiting proliferation of B and T lymphocytes 28. By reducing PIP3 production and regulating the activation of the entire mTOR/AKT pathway, leniolisib is able to reduce the dysregulation of B- and T-cells induced by PI3Kδ hyperactivation. In this way, it has an effect on other cells of the innate immune system, such as neutrophils, monocytes, macrophages 32. The systemic drug concentration increases in a dose-dependent manner (AUC and Cmax); two daily doses (oral administration, 70 mg in adults) are administered every 12 hours, and steady-state (steady-state concentration, Css) is reached after approximately two/three days. Maximum drug concentration in the blood is reached one hour after administration (Tmax). Leniolisib binds 94.5% to plasma proteins and the apparent distribution volume is estimated to be 28.5 liters in APDS patients. Approximately 60% of the drug is metabolized by the liver; mainly by CYP3A4 (94.5%), CYP1A2 (0.7%) and CYP2D6 (0.7%). The half-life of leniolisib is approximately 7 hours 33. The selectivity profile of leniolisib towards the different PI3K isoform, which has been accounted to its chemical structure, different from other PI3Kδ inhibitors, which characterizes different interaction modes at the ATP pocket of PI3K 32,34-37.

Safety and tolerability of leniolisib

Adverse events associated with pan-PI3K inhibitors are neutropenia, hypertriglyceridemia, hyperglycemia, diarrhea/colitis, and liver problems 38,39 as well as cardiotoxicity 40,41. The most serious adverse events have been associated with inhibition of all four isoforms α, β, δ, γ or in the case of inhibitor therapy (Copanlisib, Idelalisib, Duvelisib, Umbralisib) with a reduced selectivity for the δ isoform 42,43. In contrast, leniolisib shows a good safety profile in APDS patients 42. Notably, the results of the clinical trials NCT02435173 and NCT02859727 show that leniolisib is well tolerated; no adverse events were observed, which are detected with other PI3K inhibitors used for treatment of blood cancers 28-30. The trial NCT02435173 included two different designs, referred to part I and part II. Part I included 6 APDS patients in a non-randomized, open-label, dose-finding trial (DFT) design 28. Part II had a randomized, controlled study design with a fixed dose of leniolisib (randomized, investigator and sponsor-blinded, placebo-controlled, 70 mg b.i.d.); 31 patients were recruited, including the 6 from part I 29. In part I of NCT02435173, no signs of toxicity or serious side effects were observed in the 6 patients recruited and treated with leniolisib (n = 6 patients with the GOF mutation, PIK3CD gene) 28. No side effects were observed on the 6 patients, who were subsequently included in part II of the same trial. Rao et al., 2023 29, reported the results of part II of the NCT02435173 trial, which included a 12-week treatment with 70 mg leniolisib (o.s., b.i.d.) in the experimental arm. In all, 31 patients with APDS were randomized into two arms: 21 patients treated with leniolisib and 10 patients in the placebo group. In part II of NCT02435173, minor adverse events were reported in 85% of APDS patients treated with leniolisib and in 90% of APDS patients in the placebo group. Drug-related adverse events were reported in 8 patients, with a lower incidence in the leniolisib group (23%) compared to the placebo group (30%). Five patients reported serious adverse events, but none of these were considered to be associated with leniolisib. Skin rash and neutropenia, two of the side effects observed during treatment with PI3K inhibitors used for hematological tumors (idelalisib 44, duvelisib 45), were recorded in a very low percentage of APDS patients treated with leniolisib and, if present, were mild and not severe. Grade 1 maculo-papular rash was recorded in one leniolisib-treated patient, while mild neutropenia, with spontaneous resolution, was recorded in 4 of 21 leniolisib-treated patients 29. Subsequently, the patients involved in part I (dose-finding trial, DFT) and part II (fixed-dose, randomized controlled trial, RCT) (NCT02435173) were involved in an extension trial (NCT02859727), currently ongoing, involving monitoring of patients with maximum exposure to leniolisib for 5 years (open-label extension, single arm extension study; n = 37 patients with APDS) 30. Adverse events were reported in 32 of the 37 patients, and the majority (85.3%) were grade 1 or 2. The most common events were respiratory tract infection (9 patients), migraine (6 patients), external otitis (5 patients), COVID-19 (5 patients), pyrexia (6 patients) and weight gain (5 patients). Additionally, 15 patients reported gastrointestinal problems, 10 of whom had an history of gastrointestinal disorder. Serious adverse events (SAEs) such as vomiting, colitis, sinusitis and abdominal pain were also reported during the trial, but none of these were definitively associated with leniolisib treatment 30.

The causes of the serious adverse events, related to therapy with the PI3K inhibitor class, have been attributed to excessive inhibition of the activity of the PI3K isoforms. This inhibition may result in the disruption of the immune system and PI3K/AKT/mTOR signaling pathways, leading to SAEs 42, as reported in hematoncological patients treated with PI3K inhibitors. An ex vivo study on human cells showed that some adverse events related to PI3K inhibition, linked to autoimmune conditions such as colitis or hepatotoxicity, can be determined by the reduced activity of regulatory T cells (Treg), leading to an increased activation and response of CD8+ T cells (Tkiller) 46. Another ex vivo study, performed in mouse B lymphocytes, demonstrated a relationship between total inhibition of PI3Kδ and the over-expression of the AID enzyme (activation-induced cytidine deaminase), a specific enzyme which is crucial for the appropriate production of functional antibodies. A preclinical study has shown that some PI3Kδ inhibitors (idelalisib, duvelisib) may increase genomic instability of B cells due to AID upregulation, leading to an increased risk of lymphoma 47. However, no data regarding the long-term use of leniolisib are available, but it may lead to low grade adverse events, given its lower potency toward the PI3Kδ isoform (IC50 = 11 nM), compared to high potency PI3Kδ inhibitors such as idelalisib (IC50 = 2.5 nM) and duvelisib (IC50 = 2.5 nM) (Tab. I).

Leniolisib and comparison with other PI3K inhibitors

Idelasilib was one of the first PI3K inhibitors whose activity was evaluated both in vitro (leukemic patient samples) and in vivo, patients with lymphoma. The data demonstrated effective inhibition of all PI3K isoforms, with a poor safety profile characterized by drug-associated adverse events, such as severe neutropenia and increased risk of infections, in oncological patients 48-50. Other inhibitors have been evaluated in the context of APDS, such as nemiralisib. This molecule showed interesting results in animal models, reducing S. pneumoniae-induced mortality 51. However, an open-label, phase II study (NCT02593539) in patients with APDS showed no efficacy and some adverse events that were considered tolerable; accordingly, no further studies were carried out 52. In contrast, seletalisib (UCB5857) showed encouraging results, with significant efficacy in APDS, but serious adverse events (liver and kidney dysfunction) were reported in a phase 1b trial (7 recruited APDS patients; European Clinical Trials Database 2015-002900-10) and in the extension study (4 recruited patients, of which 3 completed the study; European Clinical Trials Database 2015-005541) 53,54.

In conclusion, looking at the efficacy and safety profile of leniolisib, the clinical reports on this drug are promising. Both the first clinical trial (NCT02435173) and the extension study (NCT02859727) showed significant efficacy and good tolerability in all patients exposed to the treatment. Typical disease symptoms and clinical signs, such as infection, lymphoproliferation (lymphadenopathy, splenomegaly), cytopenia and immune system alterations were significantly reduced in leniolisib treated APDS patients, along with reduction of lymph node and spleen size. Moreover, reduced levels of CD8+ senescent T cells and IgM were detected in leniolisib treated APDS patients 30.

Pharmacodynamic profile of leniolisib and other PI3K inhibitors

As hypothesized by Cant et al., 2024 42, the good tolerability and safety profile of leniolisib observed in clinical trials in APDS may be accounted to: (i) its high selectivity for PI3Kδ, compared to the other PI3K isoforms expressed in T- and B-lymphocytes; (ii) modulation of kinase enzyme activity which is restored to a physiological range, due to its low potency (Tab. I). In this light, leniolisib’s safety and tolerability profile appears to be better than that of inhibitors used in hemato-oncological patients. Furthermore, PI3K inhibitors studied in clinical trials for treatment of hematological neoplasms were used at high dosages, in order to obtain an antiproliferative effect through complete kinase activity inhibition. Indeed, a comparison between leniolisib and other inhibitors (idelalisib and duvelisib, FDA approved for chronic lymphocytic leukemia) is not useful to infer or predict SAEs in different populations treated with different drug doses and regimens.

DISCUSSION

Before leniolisib’s approval by the FDA, APDS patients were treated only with antibiotics, antivirals, immunosuppressants and Immunoglobulin Replacement Therapy (IRT), in order to control infectious symptoms and immunodisregulation 16,18,24,25. However, these therapies are insufficient to control and reduce the symptoms of APDS, and research has focused on PI3Kδ inhibitors, which reduce the activation of the PI3K/AKT/mTOR signaling pathway, (hyperactivated in APDS patients due to mutated PI3Kδ) thus acting against alterations of immune system functions 13,25. Several inhibitors have been evaluated in clinical trials for APDS management; only leniolisib achieved FDA designation as an orphan drug for APDS, based on an initial blinded, randomized, placebo-controlled, 12-week study (NCT02435173) 28-30. Other PI3Kδ inhibitors have been evaluated in clinical trials for the treatment of various lymphomas and different forms of leukemia. However, as mentioned above, the high levels of kinase activity inhibition led to several SAEs 49,50,52,53. Leniolisib improved several clinical conditions related to PI3Kδ activity such as lymphoproliferation and subsequent differentiation of mature and activated lymphocytes, and also reduced the level of activation of the AKT signaling pathway in T-lymphocytes in patients with APDS, by about 80% 55. This evidence suggests that leniolisib may have a crucial role preventing the onset of lymphoma in APDS patients. In fact, as reported by Rao et al., 2024 30, none of the 3 patients with lymphoma included in the dose-finding trial had relapses or new lymphomas up to the interim analysis cut off. Treatment with leniolisib has also been proposed for other chronic autoimmune diseases, such as Sjögren’s syndrome, a connective tissue disease in which the immune system destroys mucous membrane glands (salivary or ocular) 56,57. Leniolisib has already been approved for patients with APDS by the FDA in 2023 and is awaiting approval by the EMA. Preliminary results from the open-label extension trial NCT02859727 confirm data on the safety and tolerability of leniolisib in patients with APDS 29. Analysis of pharmacodynamic and pharmacokinetic data suggests that leniolisib, compared to other PI3K inhibitors, is safe and well tolerated in APDS patients due to: low PI3Kδ potency (high IC50), high selectivity for the mutated PI3Kδ expressed in lymphocytes of APDS patients 42 and low apparent distribution volume that reduce would reduce the risk of drug accumulation and adverse events.

Acknowledgements

The authors acknowledge the Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network. CC was supported by grants PNRRMR1-2022-12376594 and by the Italian Ministry of Health (5x1000 202205_INFETT). CBMP was supported by the funding PON Ricerca e Innovazione D.M. 1062/21–Contratti di ricerca, from the Italian Ministry of University (MUR). [Contract #: 08-I-17629-2]. FL was supported by the funding Missione 4 “Istruzione e Ricerca” - “Dalla ricerca all’impresa”- NextGenerationUE - “ANTHEM: AdvaNced Technologies for Human-centrEd Medicine”, Spoke 4, PNC0000003.

Conflicts of interest statement

CC has received consulting fees from Pharminger.

Ethical consideration

Not applicable.

Funding

This research has not been supported by external funding.

Author’s contribution

CC: contributed to design the manuscript draft and to write and finalize it; AT: contributed to draw the manuscript draft and finalization. All authors revised the manuscript and approved the final version.

History

Received: July 23, 2024

Published: January 21, 2025

Figures and tables

FIGURE 1. Mechanism of action of leniolisib. The APDS1 syndrome (GOF mutations of the p110δ catalytic subunit of PI3Kδ), APDS2 syndrome (LOF mutations of the p85α subunit, which regulates PI3Kδ activity) and APDS-like syndrome (LOF mutations at the PTEN phosphatase that hydrolyses PIP3) are associated with overactivation of the PI3Kδ/AKT pathway. Leniolisib, a selective PI3Kδ inhibitor, is able to inhibit the PI3Kδ/AKT pathway. PIP2, phosphatidylinositol 4,5-bisphosphate. PIP3, phosphatidylinositol (3,4,5)-triphosphate. PTEN, deletion homologue of phosphatase and tensin. PI3Kδ, phosphoinositide 3-kinase or phosphatidylinositol 3-kinase delta (catalytic subunit p110δ). AKT, protein kinase B. LOF, mutation with loss of function. GOF, mutation with increased functionality. Created with BioRender.com.

IC50(nM)
Inhibitors PI3Kα PI3Kβ PI3Kγ PI3Kδ δ/γ ratio
Copanlisib 0.5 3.7 6.4 0.7 0.1094
Idelalisib 820 565 89 2.5 0.0281
Duvelisib 1602 85 27 2.5 0.0926
Umbralisib > 10,000 1116 1065 22 0.0207
Leniolisib 244 424 2230 11 0.0049
IC50 : Inhibitory Concentration 50.
TABLE I. PI3K isoform selectivity of leniolisib vs other PI3Kδ inhibitors 41.

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Authors

Alberto Tommasini - Department of Medical Sciences, University of Trieste, Trieste, Italy

Caterina Cancrini - Research Unit of Primary Immunodeficiency, IRCCS Bambino Gesù Children Hospital, Rome, Italy

Antonino Trizzino - Department of Pediatric Hematology and Oncology, ARNAS Ospedali Civico Di Cristina Benfratelli Hospital, Palermo, Italy

Valentina Drago - S.C.F. Studio di Consulenza Farmacologica s.r.l. unipersonale, Catania, Italy

Francesca Lazzara - Department of Biomedical and Biotechnological Sciences, University of Catania, Italy

Chiara Bianca Maria Platania - Department of Biomedical and Biotechnological Sciences, University of Catania, Italy

Vassilios Lougaris - Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia, Brescia, Italy

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How to Cite
Tommasini, A. ., Cancrini, C., Trizzino, A. ., Drago, V., Lazzara, F. ., Platania, C. B. M., & Lougaris, V. (2025). PI3Kδ inhibition treatment of APDS: efficacy, safety and tolerability of targeted therapy with leniolisib. Italian Journal of Pediatric Allergy and Immunology, 38(4). https://doi.org/10.53151/2531-3916/2024-588
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