$idhifa (enasidenib) for patients with relapsed refractory aml and an idh2 mutation$

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WATCH THE MECHANISM OF ACTION OF ENASIDENIB

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TAKE A DIFFERENT APPROACH—RELEASE THE BLOCK ON MYELOID DIFFERENTIATION

IDHIFA, the only non-cytotoxic, targeted inhibitor of the mutant IDH2 enzyme, releases the block on myeloid differentiation.

Myeloblast

White blood cell (WBC)

Red blood cell (RBC)

Platelet

The normal IDH2 enzyme converts isocitrate to alpha-ketoglutarate (α-KG), a substrate for enzymes essential to gene expression and myeloid differentiation.^1-5

mutated idh2 enzyme Mutated IDH2 converts α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to a block on myeloid differentiation and results in myeloblast proliferation.^1-5

In preclinical studies, IDHIFA blocked the conversion of α-KG to 2-HG. In patient blood samples, IDHIFA decreased 2-HG levels and induced myeloid differentiation.⁶

NORMAL MARROW

DIFFERENTIATION BLOCKED

DIFFERENTIATION RESTORED

Myeloblast

White blood cell (WBC)

Red blood cell (RBC)

Platelet

NORMAL MARROW

The normal IDH2 enzyme converts isocitrate to alpha-ketoglutarate (α-KG), a substrate for enzymes essential to gene expression and myeloid differentiation.^1-5

DIFFERENTIATION BLOCKED

mutated idh2 enzyme Mutated IDH2 converts α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to a block on myeloid differentiation and results in myeloblast proliferation.^1-5

DIFFERENTIATION RESTORED

In preclinical studies, IDHIFA blocked the conversion of α-KG to 2-HG. In patient blood samples, IDHIFA decreased 2-HG levels and induced myeloid differentiation.⁶

NORMAL MARROW

DIFFERENTIATION BLOCKED

DIFFERENTIATION RESTORED

Next: Idhifa Efficacy

Indication

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

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Important Safety Information

WARNING: DIFFERENTIATION SYNDROME

Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

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WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

References:

1. McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9):3672-3677.
2. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52-60.
3. Yang H, Ye D, Guan K, et al. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562-5571.
4. Genetics Home Reference. Your guide to understanding genetic conditions: IDH2 gene. NIH US National Library of Medicine website. https://ghr.nlm.nih.gov/gene/IDH2. Published February 2016. Accessed May 10, 2017.
5. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553-567.
6. Data on file, Celgene Corporation. Summit, New Jersey.

Celgene Commercial Co-pay Program Terms and Conditions

Eligibility

Patients must meet the following criteria to enroll:

Covered by commercial or private insurance
Reside in the United States or US territory
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Program Benefits

For Celgene oral hematology products, Celgene provides assistance to reduce the co-pay of eligible patients to $25 per prescription with a maximum benefit of $10,000 per enrollment period
For Celgene IV products, the Program will cover the co-pay for each prescription of a Celgene product up to a maximum of $10,000 per enrollment period
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Patients are responsible for any costs that exceed the Program’s $10,000 maximum
The Program will not cover, and shall not be applied toward, the cost of any dosing procedure, any other healthcare provider service or supply charges or other treatment costs, or any costs associated with a hospital stay

Program Timing

If eligible, patients will be enrolled from the date of enrollment through the end of the then current calendar year

Additional Terms and Conditions of the Celgene Commercial Co-pay Programs

Patients, pharmacists, and healthcare providers must not seek reimbursement from health insurance or any third party for any part of the benefit received by the patient through this Program. Patients must not seek reimbursement from any health savings, flexible spending, or other healthcare reimbursement accounts for the amount of assistance received from the Program
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