Leniolisib

Leniolisib selectively inhibits PI3Kδ by blocking the active binding site of PI3Kδ. Gain-of-function variants in the gene encoding p110δ catalytic subunit (resulting in APDS1) or loss-of-function variants in the p85α regulatory subunit (resulting in APDS2) both lead to hyperactive PI3Kδ signalling leading to increased production of phosphatidylinositol 3,4,5 trisphosphate and downstream phosphorylated protein kinase B (pAkt). Through inhibiting PI3Kδ thus decreasing production of PIP3, hyperactivity of the downstream Akt/mammalian target of rapamycin (mTOR) pathway is reduced, subsequent deficiencies and dysregulation of B and T cell populations normalise.

The pharmacokinetics of leniolisib have been studied in healthy subjects and adult and adolescent patients with APDS. 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.

Absorption

In a placebo-controlled, ascending single and multiple dose study in healthy participants, leniolisib was rapidly absorbed in the fasted state, with median time to maximum plasma concentration (t_max) at about 1 hour post dose. T_max appeared independent of dose and was not altered after multiple oral doses.

Food effect

Co-administration of a single 70 mg dose of leniolisib with a high fat meal delayed the rate of absorption (T_max) by 3 hours (0.64 h [fasting] to 3.51 h [fed]) and decreased C_max on average by 41% but not the extent of absorption (area under the curve [AUC]). The impact of food on the absorption of leniolisib is not expected to be clinically relevant.

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 (estimate from steady-state drug washout). The median oral volume of distribution during the terminal phase ranged from 33 L to 57 L, indicating that leniolisib has a moderate-to-low volume of distribution. In humans, the in vitro blood/plasma ratio is 0.643.

Biotransformation

Leniolisib was 60% metabolized by the liver, with CYP3A4 as 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). The strong activity of recombinant CYP1A1 suggests a possible involvement of this enzyme in the biotransformation of leniolisib in extra-hepatic tissues. Intestinal secretion by BCRP and extrahepatic CYP1A1 cannot be excluded as excretion routes.

Elimination

The mass balance of an oral dose of 70 mg ¹⁴C-leniolisib was 92.5% (standard deviation: 2.3%) 168 hours post dose (morning of Day 8).

¹⁴C-leniolisib was excreted predominately via faeces (67.0%), while excretion via urine was approximately 25.5%. Approximately 70% of the ¹⁴C-leniolisib was recovered within 48 hours. During twice daily dosing approximately 12 hours apart, leniolisib accumulates approximately 1.4-fold in achieving steady state (range of 1.0 to 2.2), consistent with an effective half-life (t_1/2) of approximately 7 hours.

Linearity/non-linearity

Dose proportionality analysis of systemic drug exposure (AUC and maximum plasma concentration [C_max]) indicates that the pharmacokinetics of leniolisib are linear with respect to both dose (20 to 140 mg twice a day dosing and single doses of 10 to 400 mg/day) and time.

Pharmacokinetic/pharmacodynamic relationship(s)

Ex vivo pharmacodynamics of leniolisib (proportion 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%.

Repeated dose toxicity

The effects observed in the repeat dose toxicity studies were primarily in the haemolymphopoietic system related to the immunomodulatory properties of leniolisib and the gastrointestinal tract in mice, rats, and monkeys. Leniolisib caused depletion/decreased activity in lymphoid tissues and inhibited the T cell dependent antibody response (TDAR) in rats. As a result of immunosuppression, an increase in opportunistic skin infections (in rats) and gastrointestinal toxicity (i.e., inflammation/infections in mice and monkeys) were observed, leading to severe diarrhoea and emesis (monkeys only). At the NOAELs of rats and monkeys in the chronic toxicity studies, the combined male/female plasma exposure (AUC_0-24h,u) was similar to the human exposure at the therapeutic dose.

Genotoxicity and carcinogenicity

Leniolisib did not show mutagenic, clastogenic, or aneugenic potential in the genotoxicity studies. No signs of carcinogenic potential (e.g., hyperplasia/neoplasia) were found in repeated dose toxicity studies. Long-term animal studies to evaluate the carcinogenic potential of leniolisib have not been conducted.

Reproductive and developmental toxicity

In the 26-week rat study, lower prostate weights correlated with a decreased secretion seen microscopically. In this study and the 10-week juvenile rat study, lower testes and epididymis weights and lower sperm counts were linked to decreases in the germinal epithelium and round spermatids and loss of spermatocytes. These histological findings occurred at 90 and ≥40 mg/kg/day, respectively (corresponding to 2.4- and 1.5-fold the maximum human recommended dose based on AUC). No effects on male or female fertility or reproductive performance was noted in rats up to 90 mg/kg/day (corresponding to 2.4- to 3.8-fold the maximum human recommended dose based on AUC).

Embryonic and foetal development studies in rats and rabbits showed microphthalmia as well as reduced orbital socket size (rats and rabbits) and anophthalmia (rats only) at the highest dose levels (120 and 100 mg/kg/day, respectively). In rabbits, aglossia was also reported from 30 mg/kg/day. The NOAELs for embryo-foetal development were 30 mg/kg/day in rats and 10 mg/kg/day in rabbits corresponding to approximately 1.7- and 0.1-fold, respectively, the maximum recommended human dose based on AUC. Therefore, based on submitted data, it can be concluded that leniolisib is teratogenic in rats and rabbits and it could represent a clinical potential risk.

In the pre- and postnatal developmental rat toxicity study, adverse reactions on the progeny during the preweaning period, manifested as reduced pup survival and persistently lower pup weight during postweaning, were seen at maternal doses of 90 mg/kg/day. Leniolisib was detected in all lactation study samples, with leniolisib concentrations increasing in a dose-dependent manner resulting in a concentration that was approximately 2- to 3-fold higher than the maternal plasma concentration at 10 to 30 mg/kg/day.

In the 10-week juvenile rat study initiated in 7 days old animals, an increase in mortality rate was reported during the preweaning period at 90 mg/kg/day (AUC levels measured after the first dose were 9.5-fold those at the maximum human recommended dose).