General Information

Rezlidhia (olutasidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor.

Rezlidhia is specifically indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.

Rezlidhia is supplied as capsules for oral administration. 

Select patients based on the presence of IDH1 mutations in blood or bone marrow.

• The recommended dosage of Rezlidhia is 150 mg taken orally twice daily until disease progression or unacceptable toxicity.
•  Administer Rezlidhia capsules orally about the same time each day. Do not administer 2 doses within 8 hours. Take on an empty stomach at least 1 hour before or 2 hours after a meal.
• Swallow Rezlidhia capsules whole. Do not break, open, or chew the capsules. If a dose of Rezlidhia is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of Rezlidhia is missed or not taken at the usual time, administer the dose as soon as possible and at least 8 hours prior to the next scheduled dose. Return to the normal schedule the following day.
• For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

Mechanism of Action

Rezlidhia (olutasidenib) is a small-molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1). In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of olutasidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions. In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited. Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models.

Side Effects

Adverse effects associated with the use of Rezlidhia (olutasidenib) may include, but are not limited to, the following:

• aspartate aminotransferase increased
• alanine aminotransferase increased
• potassium decreased
• sodium decreased
• alkaline phosphatase increased
• nausea
• creatinine increased
• fatigue/malaise
•  arthralgia
• constipation
• lymphocytes increased
• bilirubin increased
• leukocytosis
• uric acid increased
• dyspnea
•  pyrexia
• rash
• lipase increased
• mucositis
• diarrhea
• transaminitis

Rezlidhia comes with an increased risk of hepatotoxicity. 

The Rezlidhia (olutasidenib) drug label comes with the following Black Box Warning: • Differentiation syndrome, which can be fatal, can occur with Rezlidhia treatment. • If differentiation syndrome is suspected, withhold Rezlidhia and initiate corticosteroids and hemodynamic monitoring until symptom resolution.

Clinical Trial Results

The FDA approval of Rezlidhia was based on data from an open-label Phase 2 registrational study evaluating  Rezlidhia monotherapy at a dose of 150 mg twice daily in 153 patients with mIDH1 R/R AML. The efficacy-evaluable population was 147 patients who initiated  Rezlidhia at least six months prior to the interim analysis cutoff date of June 18, 2021, and who had a centrally confirmed IDH1 mutation. The primary endpoint was a composite of a complete remission (CR) plus a complete remission with partial hematological recovery (CRh). CRh is defined as less than 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and absolute neutrophil count >500/microliter). 

Results from the trial demonstrated a 35% (51/147) CR+CRh rate in mIDH1 R/R AML patients, with a median duration of response of 25.9 months. The median time to CR or CRh was 1.9 months. Of the patients who achieved the primary endpoint of CR+CRh, 92% (47/51) were CR with a median duration of response of 28.1 months.