EMEDZ.NET

Leniolisib (Joenja): Uses, Dose, MOA, Side effects

Drug Name: Leniolisib

Brand Name: Joenja

FDA Approval: 24th March 2023

Primary Indications: Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS)

Age group: 12 years of age or older

Leniolisib (Joenja) Indications:

JOENJA is a pharmaceutical product that has been specifically designed and recommended for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome.

It is indicated for the treatment of adults and children who are at least 12 years of age. PI3Kδ syndrome is a medical condition characterized by the activation of the PI3Kδ enzyme, which can cause various symptoms and complications, such as recurrent infections, lymphoproliferation, and autoimmune disorders.

The use of JOENJA has been clinically studied and proven to effectively reduce the severity of symptoms associated with APDS, making it a viable therapeutic option for patients suffering from this condition.

Leniolisib (Joenja) Dose:

Before initiating treatment with JOENJA, it is recommended to perform a pregnancy test in females of reproductive age groups.

This precautionary measure is necessary to ensure the safety of the patient, as well as any potential fetus that may be affected by the medication.

Dose recommendations:

Patient weight ≥45 kg:

The recommended dose is 70mg orally, twice daily with or without food, with an interval of 12 hours approximately.

Patient weight ≤45 kg:

No dosing recommendations have been advised in children and adults weighing less than 45 kgs.

Missed Dose:

If the time after the missed dose has been more than 6 hours, wait for the next dose and take it at the scheduled time.

If the patient vomits after taking the dose, the dose should be immediately repeated. If vomiting occurs after one hour of the dose, there is no need to take an extra dose.

It is crucial to comply with the recommended dosage and administration instructions and not to exceed the prescribed dose without the guidance of a qualified healthcare professional.

Contraindications to Leniolisib (Joenja):

There’s no contraindication available in the FDA prescribing information.

Warnings:

Embryo-Fetal Toxicity:

JOENJA may cause fetal harm. Confirm pregnancy in all females of reproductive ages before starting the treatment to avoid the risks.

Females should be instructed to practice an effective form of contraception during the treatment and at least one week after the last dose.

Vaccination:

It is important to note that live, attenuated vaccinations may have reduced effectiveness if they are administered during JOENJA treatment.

Side effects of Leniolisib (Joenja):

Common Side Effects (>= 20%):

Upper respiratory tract infection
Diarrhea
Fatigue
Nausea
Cough
Pyrexia (fever)
Headache
Decreased appetite
Rash
Abdominal pain
Arthralgia (joint pain)

Less common Side effects (1 - 10%):

Sinusitis
Bronchitis
Pharyngitis
Urinary tract infection
Influenza
Pneumonia
Herpes simplex infection
Viral infection
Gastroenteritis
Constipation
Dyspepsia (indigestion)
Vomiting
Dermatitis (skin inflammation)
Pruritus (itching)
Eczema (skin rash)
Back pain
Myalgia (muscle pain)
Pain in extremity
Asthenia (weakness)
Chills
Pain
Influenza-like illness
Edema peripheral (swelling in the limbs)
Abnormal liver function tests

Rare Side effects (<1%):

Anaphylaxis (severe allergic reaction)
Stevens-Johnson Syndrome
Toxic Epidermal Necrolysis
Lymphadenopathy (swollen lymph nodes)
Leukopenia (low white blood cell count)
Neutropenia (low neutrophil count)
Thrombocytopenia (low platelet count)
Hepatitis (liver inflammation)

Side Effects in Clinical Trials:

Adverse Reactions	JOENJA 70 mg (N=21)	Placebo (N=10)
Headache	6 (29%)	0
Sinusitis	4 (19%)	0
Atopic dermatitis	3 (14%)	0
Diarrhea	2 (10%)	0
Nasopharyngitis	2 (10%)	0

Drugs Interaction: Effect of Other Drugs on Joenja:

Drug Class	Effect on Joenja	Recommendation
Strong CYP3A4 Inhibitors	Increased exposure (2-fold)	Avoid concomitant use
Strong and Moderate CYP3A4 Inducers	Reduced exposure and efficacy	Avoid concomitant use
CYP1A2 Metabolized Drugs with a Narrow Therapeutic Index	Leniolisib inhibits CYP1A2	Avoid concomitant use with drugs that have a narrow therapeutic index
BCRP, OATP1B1, and OATP1B3 Substrates	Leniolisib inhibits BCRP, OATP1B1, and OATP1B3	Avoid concomitant use with drugs that are BCRP, OATP1B1, and OATP1B3 substrates

Use in Specific population:

Patient Population	Risks and Recommendation
Pregnancy	JOENJA can cause fetal harm.
Pregnancy	Avoid in pregnant women.
Lactation	Data is limited.
Lactation	Avoid breastfeeding during the treatment and for 1 week after the last dose.
Females and Males of Reproductive Potential	JOENJA is toxic for the fetus. Test for pregnancy before starting the treatment.
Females and Males of Reproductive Potential	Recommend an effective form of contraception during the treatment and one week after the last dose.
Pediatric Use	It is safe in children aged 12 years and older.
Pediatric Use	There are no dose recommendations in children younger than 12 years and those weighing less than 45 kg.
Geriatric Use	Not studied in patients older than 65 years of age.
Hepatic Impairment	Avoid in patients with moderate to severe hepatic impairment.

Mechanism of action of Leniolisib:

Leniolisib inhibits PI3K-delta by blocking its active binding site. Leniolisib is selective for PI3K-delta over other PI3K isoforms such as PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome, in cell-free isolated enzyme assays.

In cell-based assays, Leniolisib reduces the activity of the pAKT pathway and inhibits the proliferation and activation of B and T cell subsets.

Hyperactivity of PI3K-delta can be caused by 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.

By inhibiting the signaling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and dysregulation of B and T cells, leniolisib exerts its pharmacological effects.

Pharmacodynamics:

Property	Description
Absorption	Tmax is 1-hour post-dose and not affected by dose or food intake.
Distribution	Bi-exponential decay, indicating distribution delay towards peripheral tissues. Highly bound (94.5%) to plasma proteins.
Elimination	Feces: 67.0% Urin: 25.5%
Metabolism	60% metabolized by the liver, with CYP3A4 being the predominant enzyme involved (94.5%) in the primary oxidative metabolism. Minor contribution from other enzymes (3.5% CYP3A5, 0.7% CYP1A2, and 0.4% CYP2D6). Intestinal secretion by BCRP and extrahepatic CYP1A1 cannot be excluded as excretion routes.