Leniolisib

Leniolisib inhibits BCRP, OATP1B1, and OATP1B3 in vitro. The effect of leniolisib on BCRP, OATP1B1, and OATP1B3 substrates has not been studied clinically. Due to a possible increase in systemic exposure of these substrates, avoid concomitant use of leniolisib with drugs that are BCRP, OATP1B1, and OATP1B3 substrates.

Live, attenuated vaccinations may be less effective if administered during leniolisib treatment.

Leniolisib inhibits CYP1A2 in a time-dependent manner in vitro. Avoid concomitant use of leniolisib with drugs that are primarily metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index.

Leniolisib is a substrate of CYP3A4. Leniolisib exposure was increased 2-fold when co-administered with itraconazole, a strong CYP3A4 inhibitor. Concomitant use of leniolisib with strong CYP3A4 inhibitors should be avoided.

Concomitant use of strong and moderate CYP3A4 inducers may result in reduced leniolisib exposure and thus reduced leniolisib efficacy. Therefore, concomitant use of leniolisib with strong and moderate CYP3A4 inducers should be avoided.

Leniolisib is extensively (60%) metabolized by the liver. The effect of hepatic impairment on the pharmacokinetics of leniolisib has not been studied. The use of leniolisib in patients with moderate to severe hepatic impairment is not recommended.

Risk Summary

Leniolisib can cause fetal harm based on findings from animal studies. There are no available data on leniolisib use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of leniolisib to pregnant rats and rabbits during the period of organogenesis at exposures approximately 2-6 times the MRHD on an AUC basis, produced embryofetal toxicity including malformations (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Leniolisib was administered orally to pregnant rats at doses of 10, 30, and 120 mg/kg/day during the period of organogenesis from gestation Day 6 to Day 17. Leniolisib at a dose of 120 mg/kg/day was associated with decreased fetal body weight, visceral and skeletal variations, and external, visceral, and skeletal malformations (eye bulge, microphthalmia, anophthalmia, and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 6 times the MRHD on an AUC basis. No developmental toxicity was observed in rats at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day).

Leniolisib was administered orally to pregnant rabbits at doses of 10, 30, and 100 mg/kg/day during the period of organogenesis from gestation Day 7 to Day 20. Leniolisib at a dose of 100 mg/kg/day was associated with skeletal variations as well as visceral and skeletal malformations (microphthalmia and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 2 times the MRHD on an AUC basis. No developmental toxicity was observed in rabbits at an exposure approximately 0.3 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day).

Pre- and post-natal development studies with leniolisib have not been conducted.

There are no data on the presence of leniolisib or its metabolites in human milk or the effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions from leniolisib in the breastfed child, advise women not to breastfeed during treatment with leniolisib and for 1 week after the last dose.

Carcinogenicity studies have not been conducted with leniolisib.

Leniolisib was not genotoxic in the in vitro Ames assay, in vitro chromosomal aberration assay in human lymphocytes, or micronucleus assays in TK6 cells (in vitro) and rats (in vivo).

In a fertility study, male rats had decreased round spermatids and decreased spermatocytes in the testis at an oral dose of 90 mg/kg/day (approximately 2 times the MRHD on an AUC basis). Leniolisib had no effect on fertility in female rats at oral doses up to 90 mg/kg/day (approximately 4 times the MRHD on an AUC basis). No effects on male or female fertility and reproductive performance indices were observed up to the maximum dose administered of 90 mg/kg/day (approximately 2-4 times the MRHD on an AUC basis).

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of leniolisib reflects exposure based on 38 adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) from the placebo-controlled portion of Study 2201 and additional open-label clinical safety data. Thirty-seven of 38 patients received leniolisib 70 mg orally twice daily for at least 25 weeks and 66% were exposed for 96 weeks or longer. Median duration of leniolisib treatment was approximately 2 years, and 4 patients had more than 5 years of leniolisib exposure.

The data below are based on the 12-week, placebo-controlled portion of Study 2201 in which either leniolisib 70 mg (N=21) or placebo (N=10) was administered twice daily to patients with APDS. Demographics of the patients who participated in this study are summarized in Clinical Studies. Table 1 presents the number of patients and incidence, rounded to the nearest percent, of adverse reactions that occurred in 2 or more patients treated with leniolisib and for which the incidence in patients treated with leniolisib was greater than the incidence in patients treated with placebo.

The most common adverse reactions (>10%) were headache, sinusitis, and atopic dermatitis.

Table 1. Adverse Reactions Reported by 2 or More Leniolisib-Treated Patients and More Frequently than Placebo:

¹ Dermatitis atopic: including dermatitis atopic and eczema
² Tachycardia: including tachycardia and sinus tachycardia

Laboratory Abnormalities

Seven (33%) patients receiving leniolisib developed an absolute neutrophil count (ANC) between 500 and 1500 cells/microL. No patients developed an ANC <500 cells/microL and there were no reports of infection associated with neutropenia.