Introduction
Joenja (leniolisib) is an oral phosphoinositide 3-kinase delta (PI3Kδ) inhibitor developed by Pharming Pharmaceuticals. It received FDA approval in March 2023 as the first targeted treatment for activated phosphoinositide 3-kinase delta syndrome (APDS), a rare primary immunodeficiency disorder. Joenja represents a significant advancement in the management of this genetic condition by targeting the underlying molecular pathway dysfunction.
Mechanism of Action
Joenja works through selective inhibition of phosphoinositide 3-kinase delta (PI3Kδ), a key enzyme in the PI3K-AKT signaling pathway. In APDS, gain-of-function mutations in PIK3CD or PIK3R1 genes lead to overactivation of PI3Kδ signaling, resulting in immune dysregulation, impaired lymphocyte maturation, and increased susceptibility to infections. Leniolisib binds reversibly to the ATP-binding pocket of PI3Kδ, inhibiting the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3) and downstream signaling. This modulation helps restore normal immune function by reducing aberrant lymphocyte activation and promoting proper immune cell development.
Indications
Joenja is indicated for the treatment of activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and pediatric patients 12 years of age and older.
Dosage and Administration
Standard dosing: 70 mg orally twice daily with or without food Administration:- Tablets should be swallowed whole with water
- Missed dose: Take as soon as remembered unless it's almost time for the next dose
- No dosage adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73m²)
- No dosage adjustment required for mild hepatic impairment (Child-Pugh A)
- Use in severe hepatic impairment (Child-Pugh C) is not recommended
- Pediatric patients <12 years: Safety and effectiveness not established
Pharmacokinetics
Absorption: Median Tmax approximately 2 hours post-dose; bioavailability ~25% Distribution: Mean apparent volume of distribution ~105 L; protein binding ~84% Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8 Elimination: Mean terminal half-life ~10 hours; primarily excreted in feces (78%) with minor renal excretion (12%)Contraindications
- Hypersensitivity to leniolisib or any component of the formulation
- Concurrent use with strong CYP3A inducers
Warnings and Precautions
Serious Infections: May increase risk of infections; monitor for signs and symptoms of infection Hepatic Toxicity: Elevations in liver enzymes reported; monitor liver function tests periodically Pregnancy and Lactation: Based on mechanism of action, may cause fetal harm; advise effective contraception during treatment and for 1 week after discontinuation CYP3A Interactions: Avoid concomitant use with strong CYP3A inducers; dose adjustment may be needed with strong CYP3A inhibitorsDrug Interactions
Strong CYP3A Inducers (rifampin, carbamazepine, St. John's wort): Contraindicated - may decrease leniolisib exposure Strong CYP3A Inhibitors (clarithromycin, itraconazole, ritonavir): May increase leniolisib exposure; consider dose reduction Moderate CYP3A Inhibitors (fluconazole, diltiazem): Monitor for increased adverse reactions CYP3A Substrates: Leniolisib may increase exposure of sensitive CYP3A substratesAdverse Effects
Most common adverse reactions (≥10%):- Headache (32%)
- Fatigue (24%)
- Nausea (15%)
- Diarrhea (12%)
- Dizziness (10%)
- Serious infections (pneumonia, COVID-19)
- Elevated liver enzymes
- Hypertension
Monitoring Parameters
- Complete blood count with differential at baseline and periodically
- Liver function tests at baseline and periodically
- Signs and symptoms of infection
- Blood pressure monitoring
- Clinical response assessment (reduction in lymphoproliferation, improvement in immune function)
- Growth parameters in pediatric patients
Patient Education
- Take Joenja exactly as prescribed, approximately every 12 hours
- Report any signs of infection (fever, chills, cough) immediately
- Inform all healthcare providers about Joenja use before starting new medications
- Use effective contraception during treatment and for 1 week after discontinuation
- Do not stop taking Joenja without consulting your healthcare provider
- Store at room temperature (20-25°C/68-77°F)
- Report any side effects, particularly severe headaches, dizziness, or gastrointestinal symptoms
References
1. FDA Approval Letter: Joenja (leniolisib). March 2023 2. Rao VK, et al. A randomized, placebo-controlled phase 3 trial of leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-983 3. Lucas CL, et al. Dominant-activating germline mutations in the gene encoding the PI3K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97 4. Joenja [package insert]. Leiden, The Netherlands: Pharming Pharmaceuticals; 2023 5. Coulter TI, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606 6. Maccari ME, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543