Enasinib

Enasinib is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.

Dosage & Administration

The recommended starting dose of Enasidenib is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Do not split or crush Enasidenib tablets. Administer Enasidenib tablets orally about the same time each day. If a dose of Enasidenib is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day.
Recommended Monitoring for Safety
: Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of Enasidenib and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. Interrupt dosing or reduce dose for toxicities.

Differentiation Syndrome. Differentiation syndrome is a condition that affects your blood cells which may be life-threatening or lead to death if not treated. Differentiation syndrome has happened within 10 days and up to 5 months after starting Enasinib. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome while taking Enasinib:
Fever
Cough
Shortness of Breath
Swelling of Arms and Legs
Swelling Around Neck, Groin, Or Underarm Area
Fast Weight Gain
Bone Pain

Differentiation Syndrome
: In the clinical trial, 14% of patients treated with Enasinib experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with Enasinib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after Enasinib initiation.
Embryo-Fetal Toxicity
: Based on animal embryo-fetal toxicity studies, Enasinib can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, Enasinib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive potential to use effective contraception during treatment with Enasinib and for at least 1 month after the last dose of Enasinib. Advise males with female partners of reproductive potential to use effective contraception
during treatment with Enasinib and for at least 1 month after the last dose of Enasinib. Pregnant women, patients becoming pregnant while receiving Enasinib, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2 hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells.