Leniolisib

Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAkt pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/Akt pathway, and to the dysregulation of B and T cells.

Ex vivo pharmacodynamics of leniolisib [proportion of phosphorylated Akt (pAkt)-positive B cells] were assessed intra-individually at 10, 30, and 70 mg twice daily for 4 weeks at each dose level in patients with APDS. Within the explored dose range, higher leniolisib plasma concentrations were generally associated with higher reduction of pAkt-positive B cells and higher doses were associated with a slightly higher peak reduction as well as more sustained reduction. Treatment with leniolisib 70 mg twice a day at steady state is estimated to produce time-averaged reduction of pAkt-positive B cells by approximately 80%.

The systemic drug exposure (AUC and C_max) of leniolisib increased dose proportionally within the studied range of doses (20 to 140 mg twice a day dosing and single doses of 10 to 400 mg). During twice daily dosing approximately 12 hours apart, leniolisib accumulates approximately 1.4-fold (range of 1.0 to 2.2) in achieving steady-state, consistent with an effective half-life (t_1/2) of approximately 7 hours. Steady state drug concentrations can be expected to be reached after approximately 2 to 3 days of leniolisib treatment. The pharmacokinetics of leniolisib are similar between healthy participants and APDS patients.

Gastric Acid Reducing Agents: Leniolisib exhibits pH-dependent solubility (pH range of 1.2 to 4), with low solubility at higher pH values (≥ 5). However, PK results from APDS patients did not indicate that acid reducing agents (e.g., H2-antagonists, proton pump inhibitors) have a clinically relevant effect on leniolisib systemic exposure.

CYP1A2 Substrates with Narrow Therapeutic Indices: Time-dependent (irreversible) inhibition of CYP1A2 was observed in the presence of leniolisib in vitro.

Transporters: In vitro, leniolisib is a substrate and an inhibitor of the hepatic efflux transporter BCRP and a substrate of P-gp. Leniolisib was identified in vitro as a potential inhibitor of the hepatic uptake and efflux transporters OATP1B1/B3 and BCRP.

Absorption

In a placebo controlled, single and multiple ascending dose study in healthy participants, leniolisib median time to maximum plasma concentration (T_max) occurred at about 1 hour postdose. T_max appeared independent of dose and was not altered after multiple oral doses. Food is unlikely to have a clinically meaningful effect on the systemic exposure of leniolisib during leniolisib treatment.

Distribution

The systemic decay in leniolisib plasma concentration over time is bi-exponential, indicating a distribution delay towards peripheral tissues. The apparent terminal elimination t_1/2 is approximately 10 hours. The volume of distribution of leniolisib is estimated to be 28.5 L in patients with APDS. Leniolisib was highly bound (94.5%) to plasma proteins.

Elimination

The mean recovery of total ¹⁴C-radioactivity following a single oral dose of 70 mg ¹⁴C-leniolisib was 92.5% (67.0% and 25.5% recovered via feces and urine, respectively) 168 hours postdose. Unchanged leniolisib (6.32%) was the predominant drug-related material recovered in urine.

Metabolism

Leniolisib was 60% metabolized by the liver, with CYP3A4 being the most predominant enzyme involved (95.4%) in the primary oxidative metabolism of leniolisib with minor contribution from other enzymes (3.5% CYP3A5, 0.7% CYP1A2 and 0.4% CYP2D6). Intestinal secretion by BCRP as well as extrahepatic CYP1A1 cannot be excluded as excretion routes.

Specific Populations

Pediatric Patients

Following a single 70 mg oral dose of leniolisib in APDS patients, leniolisib systemic exposures were comparable between pediatric patients (12 to 17 years of age) and adults (≥ 18 years of age), with median T_max (ranging from 1 to 5 hours) reached approximately 3 hours post-dose in patients 12 to 17 years of age. The observed difference in the median T_max between pediatric patients (12 to 17 years of age) and adults (≥ 18 years of age) is not clinically relevant given the PK variability and comparable concentration-time profiles between the two age groups.

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of leniolisib has not been evaluated. As leniolisib is metabolized to a large extent by the liver (60%), use of leniolisib is not recommended in patients with moderate to severe hepatic impairment.

Drug Interaction Studies

Strong CYP3A4 Inhibitors: Leniolisib-exposure was increased approximately 2 fold when administered with itraconazole (strong CYP3A4 inhibitor).

Moderate CYP3A4 Inhibitors: Physiological based pharmacokinetic (PBPK) model-based simulations predicted a maximum increase of 75% in leniolisib AUC_0-12 with erythromycin (moderate CYP3A4 inhibitor).

CYP3A4 Inducers: PBPK model-based simulations predicted a maximum decrease of 78% and 58% in leniolisib AUC_0-12 with rifampin (strong CYP3A4 inducer) and efavirenz (moderate CYP3A4 inducer), respectively.

CYP2D6 and P-gp inhibitors: Quinidine (strong P-gp and CYP2D6 inhibitor) had no effect on leniolisib systemic exposure. Leniolisib is not a sensitive substrate of P-gp and CYP2D6.

Oral Contraceptives: When combined with a monophasic oral contraceptive containing levonorgestrel and ethinylestradiol, leniolisib increased ethinylestradiol exposure by approximately 25 to 30% in terms of both AUC and C_max, but did not affect the C_max or AUC of levonorgestrel. Efficacy of a combined oral contraceptive composed of ethinylestradiol and levonorgestrel is not expected to be compromised by concomitant use with leniolisib.