Leniolisib: a novel treatment for activated phosphoinositide-3 kinase delta syndrome

Graphical Abstract IC50 = 11 nM (PI3Kδ); 244 nM (PI3Kα); 424 nM (PI3Kβ), 2,230 nM (PI3Kγ).

The approved PI3K kinase inhibitors are idelalisib, duvelisib, copanlisib, alpelisib, and umbralisib (Hoegenauer et al., 2016;Rao et al., 2017;Bloomfield et al., 2021;Bou Zeid and Yazbeck, 2023).Idelalisib, a purine-quinazolin-4-one derivative was approved in 2014 for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL).It is a first-in-class PI3K-δ selective inhibitor.It also inhibits AKT, MAPK, TNFα, CXCR4, and CXCR5 in cellbased assays.Replacing one N-atom with carbon in the quinazoline ring and changing F to Cl yielded duvelisib, which is a selective PI3K-γ and PI3K-δ inhibitor.Duvelisib was approved in 2018 for the treatment of adult patients with relapsed or refractory CLL or SLL and relapsed or refractory FL after at least two prior therapies.Duvelisib also inhibits several cell-signaling pathways such as B-cell receptor signaling, CXCR12-mediated chemotaxis of malignant B cells, and CXCL12-induced T cell migration.Copanlisib, a-2,3-dihydroimidazo[1,2-c]quinazolin-5yl-pyrimidine derivative was approved in 2017 as a PI3K-α and PI3K-δ inhibitor for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.Alpelisib, a small molecule was approved in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced, or metastatic breast cancer as determined by an FDA-approved test.It is a selective PI3Kα inhibitor.Umbralisib, a 4 H-chromen-4-one derivative was approved in 2021 for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen.Umbralisib selectively inhibits PI3K-delta and casein kinase 1-epsilon.Most PI3K inhibitors have been approved based on single-arm studies but were later withdrawn due to severe adverse effects.There is an urgent need for a new PI3K inhibitor with a good safety profile.Leniolisib was approved on 26 March 2023, based on a 12-week blinded, randomized, placebo-controlled study in adult and pediatric patients 12 years of age and older with an APDS-associated PI3Kδ genetic mutation [NCT02435173].Chemical structure, PI3K isoform selectivity, primary disease indications, and serious adverse events of approved PI3K inhibitors are summarized in Table 1.

Development of leniolisib
Investigators from Novartis discovered novel 4,6-diaryl quinazolines (Hoegenauer et al., 2016;Hoegenauer et al., 2017) such as compound 8 (Figure 1).It is a potent and isoformselective PI3Kδ inhibitor in vitro and in vivo.However, the poor water solubility of this compound leads to an unfavorable PK profile in rats (Hoegenauer et al., 2016).They modified the core structure to partially saturated bicyclic systems resulting in compound 9. Compound 9 is also an isoform-selective potent PI3δ inhibitor but the cellular potency decreased 54 times compared to compound 8 due to low cellular permeability.Researchers introduced a spacer moiety such as ether or NH at the 4-position of the core structure, improving solubility, membrane permeability, and biochemical activity in cellular assays.By introducing a CF3 group at the 3position of the methoxypyridine ring and at the 4-position with pyrrolidinyl-1-propanone with an NH spacer, a clinical candidate, leniolisib, was obtained.Lenilisib shows an optimal profile, good solubility (500 times better than the initial compound), metabolic stability, membrane permeability, and favorable PK properties (Hoegenauer et al., 2017).

Dosage and administration
The recommended dosage is 70 mg orally twice daily approximately 12 h apart, with or without food in adult and pediatric patients 12 years of age and older and weighing ≥45 kg.

Mechanism of action of leniolisib
APDS is linked with gain-of-function variants in the gene encoding p110δ PIK3CD or loss of function variants in the gene encoding p85α PIK3R1, each of which causes hyperactivity of PI3Kdelta (Fresno Vara et al., 2004;Hoegenauer et al., 2016  Adverse events (Grade ≥3) resulting in inhibition of proliferation and activation of B and T cell subsets (Brown et al., 2022).The primary endpoint of leniolisib is safety and tolerability in patients with APDS.Leniolisib met the primary endpoint with all adverse events being mild and grades 1-3 (Rao et al., 2023).
The secondary endpoint of leniolisib is the efficacy in APDS patients.From the clinical trial, leniolisib for the treatment of patients with APDS showed rapid normalization of the PI3Kδ signaling pathway, reduction of lymphoproliferation, and improvement of key immune cell subsets (Cant et al., 2023;Rao et al., 2023).A significant reduction in lymphadenopathy was observed in patients treated with leniolisib (62.7% reduction in lymph node size and 37.6% reduction in spleen volume) compared to placebo (5%).

Pharmacodynamics
Leniolisib reduced PI3Kδ pathway hyperactivation in cell lines overexpressing p110δ mutants and primary cells.Within the recommended dose ranges, higher leniolisib plasma concentrations were associated with greater reductions in pAkt-positive B cells.Treatment with leniolisib 70 mg twice daily doses at steady state was estimated to produce a time-averaged reduction in pAkt-positive B cells of almost 80% (Hoegenauer et al., 2016;Hoegenauer et al., 2017;Rao et al., 2017;Bou Zeid and Yazbeck, 2023).

Pharmacokinetics (PK)
Steady-state drug concentrations were reached after approximately 2-3 days of treatment.The pharmacokinetics of leniolisib are similar in both healthy participants and APDS patients (De Buck et al., 2018;Pearson et al., 2019).

Absorption
The systemic drug exposure (AUC and C max ) of leniolisib increases in a dose-dependent manner.
The median time to maximum plasma concentration (T max ) of leniolisib is 1 h and is independent of dose.Food has no significant effect.

Distribution
The volume distribution of leniolisib is almost 28.5 L in patients with APDS and 94.5% of it binds to human plasma proteins.

Elimination
The terminal elimination half-life of leniolisib is 10 h and the apparent oral clearance is 4 L/h (De Buck et al., 2018;Pearson et al., 2019).

Metabolism
Leniolisib is primarily metabolized in the liver by CYP3A4 (94.5%) in the oxidative metabolism pathway with minor contributions from other enzymes (3.5% CYP3A5, 0.7% CYP1A2 and 0.4% CYP2D6).The main circulating species is the parent drug (Fresno Vara et al., 2004;Hoegenauer et al., 2016;Hoegenauer et al., 2017;Cant et al., 2023).It undergoes O-demethylation to form the M1 metabolite as shown in Scheme 2. The N-dealkylation gives the M43 metabolite.Oxidation of the N-atom on the pyrimidine forms the M9 metabolite.Several oxidations of leniolisib yield M6/M7 and M10 metabolites, which have not been fully characterized (De Buck et al., 2018;Pearson et al., 2019).

Drug interaction studies 9.1 Effect of other drugs on leniolisib
Leniolisib is a substrate of CYP3A4.Concomitant use of leniolisib with any strong CYP3A4 inhibitors (NCT02435173) should be avoided.

Effect of leniolisib on other drugs
Leniolisib is an inhibitor of CYP1A2.Concomitant use of leniolisib with any strong CYP1A2 inhibitors should be avoided.Leniolisib is an inhibitor of BCRP, OATP1B1, and OATP1B3.Concomitant use of leniolisib with these inhibitors may reduce the efficacy of leniolisib (NCT02435173).

Conclusion
The first generation of clinical PI3Kδ and/or PI3Kγδ-selective inhibitors such as idelalisib (PI3Kδ), duvelisib (PI3Kγδ), and umbralisib (PI3Kδ) have demonstrated antitumor activity in R/R iNHL, CLL, and FL from single-arm clinical trials.Initially, these agents showed favorable results in terms of overall response rate (ORR) and progression-free survival (PFS).However, in doubleblind randomized clinical trials, these agents showed a decrease in overall survival (OS) and an increase in fatal and severe adverse reactions compared with patients in the control arms.Leniolisib has demonstrated a good safety profile due to its significant chemical and structural differences from the previous PI3K inhibitors.It is approved for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome.Previously, Activated Phosphoinositide-3 Kinase Delta Syndrome was treated based on anti-infective prophylaxis, including antibiotics, immunoglobulin replacement, and immunomodulatory agents, such as sirolimus but inborn errors of immunity cannot be prevented by antibiotic/antiviral therapy -only hematopoietic stem cell transplantation (HSCT).HSCT therapy can improve some clinical symptoms of APDS, but patients are at high risk of engraftment failure and need unplanned donor cell infusions.This method is associated with adverse events such as graft-versus-host disease, organ toxicity, severe infectious complications, and death (Coulter et al., 2017;Maccari et al., 2018;Durandy and Kracker, 2020).
Leniolisib is the first approved drug for this disease that directly targets a cell signaling pathway.GSK has developed a new clinical candidate, Nemiralisib (GSK2269557) as a competitor of lenilisib and has entered it into clinical trials.However, this drug for APDS 1 has now been withdrawn due to toxicity.Nemiralisib is in clinical trials for Chronic Obstructive Pulmonary Disease (COPD) and asthma.Leniolisib is the only standalone approved drug for patients with APDS1.
Currently, leniolisib is also undergoing a clinical trial in patients with primary Sjögren's Syndrome.Sjögren's syndrome is a chronic (long-lasting) autoimmune disorder.It occurs when the immune system damages the glands that produce and control moisture in the eyes, mouth, and other parts of the body.The main symptoms are dry eyes and mouths.Sjögren's syndrome is associated with high PI3Kδ activity (Yin et al., 2022).Leniolisib alone or in combination with other drugs may be beneficial in patients with autoimmune diseases such as rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus where PI3Kδ is overactive.

TABLE 1
Chemical structure, biological data, disease indications, and adverse events of Approved PI3K inhibitors.