JOENJA® (leniolisib) tablets, for oral use Initial U.S. Approval: 2023
Application Number: N217759
Approval Date: Mar 24, 2023
Applicant Holder Full Name: PHARMING TECHNOLOGIES BV
MECHANISM
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.
INDICATION
JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older.
DOSAGE ADMINSTRATION
Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing ≥45kg.
DOSAGE FORM AND STRENGTH
Tablets: 70 mg leniolisib
API
Leniolisib phosphate is a white to yellowish to yellowish-greenish powder. The aqueous solubility of leniolisib phosphate is pH dependent with decreasing solubility observed with increasing pH.
COMPOSITION/EXCIPIENTS
JOENJA film-coated tablets are for oral administration. Each tablet contains 70 mg of leniolisib (equivalent to 85 mg leniolisib phosphate) with the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet film-coating contains hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, polyethylene glycol, talc, and titanium dioxide.
PK
The systemic drug exposure (AUC and Cmax) 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 (t1/2) of approximately 7 hours. Steady state drug concentrations can be expected to be reached after approximately 2 to 3 days of JOENJA treatment.
In a placebo controlled, single and multiple ascending dose study in healthy participants, leniolisib median time to maximum plasma concentration (Tmax) occurred at about 1 hour postdose. Tmax 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 JOENJA treatment.
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.
Leniolisib was 60% metabolized by the liver, with CYP3A4 being the most predominant enzyme involved (94.5%) 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.
ADVERSE REACTIONS
Most common adverse reactions (incidence >10%) were headache, sinusitis, and atopic dermatitis.
Orange Book
8653092 - a chemical patent
