Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Pharming Technologies B.V., Darwinweg 24, 2333 CR Leiden, The Netherlands
Pharmacotherapeutic group: Immunostimulants, other immunostimulants
ATC code: L03AX22
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 efficacy of leniolisib was assessed in Study 2201, a 12-week randomised, blinded, placebo-controlled phase ⅔ study in 31 patients with confirmed APDS-associated pathogenic variant in either PIK3CD or PIK3R1. Patients were randomized 2:1 to receive either leniolisib 70 mg or placebo twice a day. Patient demographics at baseline are presented in Table 2.
Table 2. Baseline demographic and disease characteristics (Study 2201):
| Demographics and disease characteristics | Leniolisib 70 mg (N=21) | Placebo (N=10) |
| Demographics | ||
| Age1 (Years) mean (SD) | 22.2 (10.00) | 26.7 (13.43) |
| Age Categories <18, n (%) (Min, Max) ≥18, n (%) (Min, Max) | 8 (38) (12, 17) 13 (62) (18, 54) | 4 (40) (15, 17) 6 (60) (18, 48) |
| Sex, n (%) Male Female | 11 (52) 10 (48) | 4 (40) 6 (60) |
| Race, n (%) Asian Black White Other | 1 (5) 1 (5) 18 (86) 1 (5) | 1 (10) 1 (10) 7 (70) 1 (10) |
| Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Not reported | 0 14 (67) 7 (33) | 1 (10) 7 (70) 2 (20) |
| Disease characteristics | ||
| APDS 1 (PIK3CD variant), n (%) | 16 (76) | 9 (90) |
| APDS 2 (PIK3R1 variant), n (%) | 5 (24) | 1 (10) |
| Concomitant glucocorticoids, n (%) | 12 (57) | 6 (60) |
| Concomitant immunoglobulin G (IgG), n (%) | 14 (67) | 7 (70) |
| Previous rapamycin/sirolimus use, n (%) | 4 (19) | 3 (30) |
SD – standard deviation
1 Patient age from study Day -4 up to initial dosing
Patients had nodal and/or extranodal lymphoproliferation, as measured by index nodal lesion selected by the Cheson methodology on CT or MRI and clinical findings and manifestations compatible with APDS (e.g., history of repeated oto-sino-pulmonary infections, organ dysfunction). mTOR inhibitors and PI3Kδ inhibitors (selective or non-selective) were prohibited within 6 weeks of baseline and throughout the study. In addition, patients treated with previous or concurrent B cell depleting agents (e.g., rituximab) within 6 months of baseline were excluded from the study, unless absolute B lymphocytes in the blood were normal. B cell depleting agents were prohibited throughout the study.
The co-primary efficacy endpoints were improvement in lymphoproliferation as measured by a change from baseline in lymphadenopathy measured by the log10-transformed sum of product diameters (SPD) of index lesions, and the normalisation of immunophenotype as measured by the percentage of naïve B cells out of total B cells. Table 3 presents the results for the co-primary endpoints.
Table 3. Primary analysis of change from baseline at Week 12 (Day 85):
| Leniolisib (N=21) | Placebo (N=10) | |
| Log10-transformed SPD of index lesions (excluding patients with 0 lesions at baseline)a | ||
| nb | 18 | 8 |
| Baseline mean (SD) | 3.03 (0.42) | 3.05 (0.39) |
| Change from baseline, LS mean (SE) | -0.30 (0.04) | -0.06 (0.06) |
| Difference vs. placebo (95% CI) | -0.24 (-0.37, -0.11) | |
| p-value | 0.0012 | |
| Percentage of naïve B cells out of total B cells (patients with <48% of naïve B cells at baseline)c | ||
| nd | 8 | 5 |
| Baselinee mean (SD) | 27.16 (13.16) | 30.51 (7.97) |
| Change from baseline, LS mean (SE) | 34.76 (3.08) | -5.37 (3.95) |
| Difference vs. placebo (95% CI) | 40.13 (28.51, 51.75) | |
| p-value | <0.0001 | |
CI=confidence interval; SD=standard deviation; SE=standard error; SPD=sum of product diameters; vs=versus; LS Mean=least-squares mean
Note: The LS mean change from baseline, difference in LS mean change from baseline between leniolisib and placebo, and its p-value were obtained from an Analysis of Covariance model with treatment as a fixed effect and log10-transformed baseline SPD as a covariate. The use of both glucocorticoids and IV Ig at baseline was included as categorical (yes/no) covariates.
a Change in index lesion size was measured using the log10 transformed SPD of the largest lymph nodes (maximum of 6) identified as per the Cheson criteria on CT/MRI.
b The analysis excluded 2 patients from each treatment group due to protocol deviations and 1 patient on leniolisib having complete resolution of the index lesion identified at baseline.
c Only patients with a reduced percentage of naïve B cells at baseline (defined as below 48% being the lowest value across all ages in literature) were included in the analysis.
d The analysis excluded 2 patients from each treatment group due to protocol deviations, 5 patients on leniolisib and 3 patients on placebo with more than or equal to 48% naïve B cells at baseline, 5 patients on leniolisib with no Day 85 measurement, and 1 patient on leniolisib with no baseline measurement.
e Baseline is defined as the arithmetic mean of the Baseline and Day 1 values when both were available, and if either value was missing, the existing value was used.
The European Medicines Agency has deferred the obligation to submit the results of studies with leniolisib in one or more subsets of the paediatric population in APDS (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
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.
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 (tmax) at about 1 hour post dose. Tmax appeared independent of dose and was not altered after multiple oral doses.
Co-administration of a single 70 mg dose of leniolisib with a high fat meal delayed the rate of absorption (Tmax) by 3 hours (0.64 h [fasting] to 3.51 h [fed]) and decreased Cmax 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 (see section 4.2).
The systemic decay in leniolisib plasma concentration over time is bi-exponential, indicating a distribution delay towards peripheral tissues. The apparent terminal elimination t1/2 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.
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.
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 (t1/2) of approximately 7 hours.
Dose proportionality analysis of systemic drug exposure (AUC and maximum plasma concentration [Cmax]) 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.
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%.
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 (AUC0-24h,u) was similar to the human exposure at the therapeutic dose.
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.
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).
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