GOMEKLI Capsule / Tablet Ref.[114757] Active ingredients: Mirdametinib

Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.

Cardiac Electrophysiology

At approximately six times the steady-state exposure associated with the recommended dose of 2 mg/m², clinically significant QTc interval prolongation was not observed.

GOMEKLI pharmacokinetic parameters are summarized in Table 6.

Table 6. Pharmacokinetic Parameters and Characteristics of Mirdametinib:

Abbreviations: AUC: area under the plasma concentration-time curve; AUC_inf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; C_max: maximum plasma concentration; CV: coefficient of variation; GMR: geometric least squares mean ratio; UGT: uridine diphosphate (UDP)-glycosyltransferase

Specific Populations

Effects of Age, Sex, and Race

No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White).

The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown.

Drug Interaction Studies

No clinical DDI studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is currently unknown.

In Vitro Studies

CYP Enzymes: Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4.

Transporter Systems: Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

Mirdametinib is a substrate of BCRP and P-gp transporters.

Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day (approximately 15 times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC).

Mirdametinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.

In a dedicated fertility study, male rats were treated with mirdametinib for 28 days before mating with untreated females to Gestational Day 1. Female rats were treated with mirdametinib for 14 days before mating with untreated males to Gestational Day 7. No effects on mating performance or fertility in males or females were observed at doses up to 1 mg/kg/day (approximately 2 times the human clinical dose of 2 mg/m² twice daily based on BSA). In a 3-month repeat-dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses ≥0.3 mg/kg/day (approximately 2 times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC). Findings in male rats included hypoplasia of the spermatogenic epithelium in the testis, decreased content in the epididymis, and inflammation of the prostate at 1 mg/kg (approximately 8-times the human exposure at the clinical dose of 2 mg/m² based on AUC). The reversibility of effects on ovary and male reproductive organs was not assessed.

14.1 Neurofibromatosis Type 1 Associated Plexiform Neurofibromas

The efficacy of GOMEKLI was evaluated in the ReNeu study (NCT03962543), a multicenter, single-arm study in 114 patients ≥2 years of age with symptomatic, inoperable neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) causing significant morbidity. An inoperable PN was defined as a PN that cannot be completely surgically removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN. Patients received GOMEKLI 2 mg/m² orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

The major efficacy outcome measure was confirmed overall response rate (ORR), defined as the percentage of patients with complete response (disappearance of the target PN) or partial response (≥20% reduction in PN volume). Responses were assessed by blinded independent central review (BICR) using volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria modified to be confirmed at a subsequent tumor assessment within 2 to 6 months during the 24-cycle treatment phase. A secondary efficacy outcome measure was duration of response for patients who achieved a confirmed response.

Adults

A total of 58 adult patients received GOMEKLI. The median age was 35 years (range 18 to 69 years); 64% were female, 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races; and 1.7% were Hispanic or Latino. Approximately half of the patients (53%) had a progressing PN at study entry, 7% had prior treatment with a MEK inhibitor and 69% had prior surgery. Morbidities reported in >25% of patients were pain (90%), disfigurement or major deformity (52%), and motor dysfunction (40%).

Pediatric Patients

A total of 56 pediatric patients received GOMEKLI. The median age was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. Most patients (63%) had a progressing PN at study entry, 11% had prior treatment with a MEK inhibitor and 36% had prior surgery. Morbidities reported in >25% of patients were pain (70%), disfigurement or major deformity (50%), and motor dysfunction (27%).

Efficacy results are provided in Table 7. The median time to onset of response was 7.8 months (range: 4 months to 19 months) for the adult cohort and 7.9 months (range: 4.1 months to 18.8 months) for the pediatric cohort.

Table 7. Efficacy Results by BICR from ReNeu:

Abbreviations: CI: confidence interval.

^a Confirmed overall response was defined as two consecutive assessments of PR or CR assessed within 2-6 months during the Treatment Phase.
^b Patients who had no post-baseline MRI assessment or no confirmed overall response were treated as non-responders.
^c All partial responses.
^d Obtained using the Clopper-Pearson approach.
^e Duration of response was assessed based on observed time.