Revumenib

Revumenib is a menin inhibitor that blocks the interaction of both wild-type lysine methyltransferase 2A (KMT2A) and KMT2A fusion proteins with menin. The binding of wild-type KMT2A or KMT2A fusion proteins with menin is involved in NPM1 mutated acute myeloid leukemias and KMT2A-rearranged acute leukemias, respectively, through activation of a leukemogenic transcriptional pathway. Susceptible NPM1 mutations are defined as those that result in loss of the nucleolar localization signal and the insertion of a new nuclear export signal leading to the accumulation of mutant NPM1 in the cytoplasm of AML cells. The most common of such NPM1 mutations in patients with AML are Types A, B, and D.

In nonclinical studies using cells that express KMT2A fusions, inhibition of the menin-KMT2A interaction with revumenib altered the transcription of multiple genes including differentiation markers. In nonclinical in vitro and in vivo studies, revumenib demonstrated antiproliferative and antitumor activity in leukemia cells harboring KMT2A fusion proteins. Revumenib also showed antiproliferative activity in vitro in leukemia cells with an NPM1 mutation.

Revumenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown.

Cardiac Electrophysiology

The effect of REVUFORJ on the QTc interval was evaluated across a dose range of 113 mg to 339 mg twice daily (1.2 times the highest adult approved recommended dosage) with and without strong CYP3A4 inhibitors in patients with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation.

The increase in QTc interval was concentration dependent with an increase in QTc predicted to be 23 msec (upper bound of 90% confidence interval: 25 msec) at the mean steady-state maximum concentration (C_max) observed in patients at the highest approved recommended dosage without strong CYP3A4 inhibitors. The increase in QTc interval was predicted to be 20 msec (upper bound of 90% confidence interval: 21 msec) at steady-state C_max after administration of 160 mg twice daily with strong CYP3A4 inhibitors.

The pharmacokinetics of revumenib were characterized in patients with relapsed or refractory acute leukemia with a KMT2A translocation or an NPM1 mutation following single and multiple oral administration of revumenib with or without strong CYP3A4 inhibitors. Steady-state pharmacokinetic parameters are presented as geometric mean [coefficient of variation (%CV)] unless otherwise specified.

Revumenib Pharmacokinetics in Patients with R/R Acute Leukemia with a KMT2A translocation or an NPM1 mutation:

Abbreviations: C_max = maximum plasma concentration; AUC = area under the time concentration curve; T_max = time to peak concentration
^a - Steady-state
^b - Dosage range of 113 mg to 339 mg (1.26 times the highest adult approved recommended dosage)
^c - Approximately 400-500 calories, 25% of calories from fat
^d - Independent of concentration
^e - M1 contributes to revumenib's clinically significant effects on QTc [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)] but does not contribute to its efficacy at the approved recommended dosage
^f - A single dose of radiolabeled revumenib 276 mg (1.02 times the highest adult approved recommended dosage) to adult patients with relapsed/refractory acute leukemia

Specific Populations

No clinically significant differences in the pharmacokinetics of revumenib were observed based on age (1 to 84 years), race (67% White, 7% Asian, 8% Black), sex, mild to moderate (CLcr 30 to 89 mL/min) renal impairment, and mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr less than 30 mL/min), end-stage renal disease (CLcr less than 15 mL/min), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment is unknown.

Body weight (6-151 kg) has a significant effect on the pharmacokinetics of revumenib, with higher revumenib exposures in patients with lower body weight (less than 40 kg). This supports the use of BSA-based dosage in patients weighing less than 40 kg.

Pediatric Patients

Revumenib geometric mean (CV%) steady-state C_max was 3137 (39%) ng/mL and AUC_0-tau was 14,630 (55%) ng·hr/mL following 95 mg/m² twice daily with strong CYP3A4 inhibitors.

Revumenib predicted geometric mean (%CV) steady-state C_max was 1597 (70%) ng/mL and AUC_0-tau was 12,570 (56%) ng·hr/mL following 160 mg/m² twice daily without strong CYP3A4 inhibitors.

Drug Interaction Studies

Clinical Studies

Strong CYP3A4 Inhibitors: Revumenib AUC and C_max is increased by 2-fold following concomitant use of multiple doses of revumenib with certain azole antifungals that are strong CYP3A4 inhibitors (i.e., posaconazole, itraconazole, and voriconazole). Similarly, revumenib AUC and C_max is increased by 2.5-fold following concomitant use of multiple doses of revumenib with cobicistat (strong CYP3A4 inhibitor).

Strong and Moderate CYP3A4 Inducers: Revumenib exposure is expected to decrease and M1 exposure is expected to increase with strong and moderate CYP3A4 inducers.

Other Drugs: No clinically significant differences in revumenib pharmacokinetics were observed when used concomitantly with fluconazole (moderate CYP3A4 inhibitor), isavuconazole (moderate CYP3A4 inhibitor).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Revumenib inhibits CYP3A4, but does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

Revumenib does not induce CYP1A2, CYP2B6, and CYP3A4.

Transporter Systems: Revumenib is a substrate of OCT1, OCT2, OAT1, OAT3, and MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, MATE2-K, or BSEP. M1 is a substrate of OATP1B1, but is not a substrate of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B3, MATE1, or MATE2-K.

Revumenib inhibits MATE1, but does not inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MATE2-K. M1 inhibits MATE1, but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and MATE2-K.

In a repeat dose toxicity study in dogs treated with revumenib at 12.5, 25, or 40 mg/kg/day for 13 weeks, microscopic findings of nerve fiber degeneration in the brain, sciatic nerves, and spinal cord segments were observed at ≥12.5 mg/kg/day and were not reversed at the end of a 13-week recovery period.

In a repeat dose toxicity study in rats treated with revumenib at 75, 150, 300 mg/kg/day for 13 weeks, dose dependent ocular findings of lens opacities were observed at ≥75 mg/kg/day; the findings progressed during the dosing and recovery periods and were not reversed.

Hyperplasia was observed in multiple organs including the testes, mammary gland, uterus, pancreas, and kidney in rats treated at ≥75 mg/kg/day for up to 13 weeks. The findings were irreversible in the testes, mammary gland, and pancreas. Revumenib exposures at 75 mg/kg/day in rats are approximately 2 times the human exposure (AUC) at the recommended dose.