Gomekli mirdametinib 1 mg Tablet, For Suspension, 42-count — NDC 82448-134-42 (Billing 82448-0134-42)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Mirdametinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK. In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.

12.2Pharmacodynamics 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/m 2 , clinically significant QTc interval prolongation was not observed.

12.3Pharmacokinetics GOMEKLI pharmacokinetic parameters are summarized in Table 6. Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib General Information Steady-state [mean (%CV)] Cmax Adult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL AUC Adult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio (AUC) [mean] 1.1 to

1.9Absorption Tmax [median (min, max)] Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose Absolute bioavailability No data are available in humans Food effect [GMR% (90% CI)] (high-fat, high-calorie meal) Cmax 57% (54%, 61%) AUCinf 93% (90%, 96%) Distribution Human plasma protein binding Greater than 99% Apparent volume of distribution [mean (%CV)] 255 L (13%) Elimination Apparent systemic clearance [mean (%CV)]

6.3L/h (13%) Terminal elimination half-life [mean (%CV)] 28 h (12%) Metabolism Primary pathway Metabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes. Excretion Radioactivity In urine: 68% In feces: 27% Unchanged mirdametinib In urine and feces: 9% In urine: 0.7% Abbreviations: AUC: area under the plasma concentration-time curve; AUCinf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; Cmax: 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.

12.1Mechanism of Action Mirdametinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK. In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.

12.3Pharmacokinetics GOMEKLI pharmacokinetic parameters are summarized in Table 6. Table 6: Pharmacokinetic Parameters and Characteristics of Mirdametinib General Information Steady-state [mean (%CV)] Cmax Adult patients (≥18 years): 188 (52%) ng/mL Pediatric patients (2 to17 years): 191 (62%) ng/mL AUC Adult patients (≥18 years): 431 (43%) ng·h/mL Pediatric patients (2 to 17 years): 459 (46%) ng·h/mL Time to steady-state Approximately 6 days Accumulation ratio (AUC) [mean] 1.1 to

1.9Absorption Tmax [median (min, max)] Tablet: 0.8 (0.4-3) hours post-dose Capsule: 1.1 (0-4) hours post-dose Absolute bioavailability No data are available in humans Food effect [GMR% (90% CI)] (high-fat, high-calorie meal) Cmax 57% (54%, 61%) AUCinf 93% (90%, 96%) Distribution Human plasma protein binding Greater than 99% Apparent volume of distribution [mean (%CV)] 255 L (13%) Elimination Apparent systemic clearance [mean (%CV)]

6.3L/h (13%) Terminal elimination half-life [mean (%CV)] 28 h (12%) Metabolism Primary pathway Metabolism involves glucuronidation and oxidation via UGT (primarily UGT1A6 and UGT2B7) and CES enzymes. Excretion Radioactivity In urine: 68% In feces: 27% Unchanged mirdametinib In urine and feces: 9% In urine: 0.7% Abbreviations: AUC: area under the plasma concentration-time curve; AUCinf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; Cmax: 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.

12.2Pharmacodynamics 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/m 2 , clinically significant QTc interval prolongation was not observed.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to GOMEKLI in 133 patients (75 adults and 58 pediatric patients) in the ReNeu study [see Clinical Studies (14) ] (n=114) and Study NF-106 (n=19) [NCT-02096471].

Patients received GOMEKLI 2 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Among 133 patients who received GOMEKLI, 62% were exposed for one year or longer, 38% were exposed for 2 years or longer, and 12% were exposed for 3 years or longer. Neurofibromatosis Type 1-Associated Plexiform Neurofibromas The safety of GOMEKLI was evaluated in the ReNeu study [see Clinical Studies (14) ] .

Eligible patients were 2 years of age and older with neurofibromatosis type 1 (NF1) who had symptomatic plexiform neurofibromas (PN). Patients were excluded for abnormal left ventricular ejection fraction (LVEF), uncontrolled hypertension, alanine transaminase (ALT) value of >2 × upper limit of normal (ULN), any current or history of retinal vein occlusion (RVO) or retinal pigment epithelium detachment (RPED), intraocular pressure >21 mmHg (or upper limit of normal adjusted by age), and history of glaucoma. 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.

Adult Patients The median age of adult patients (age ≥18) who received GOMEKLI was 35 years (range: 18-69); 64% were female; 85% were White, 9% were Black or African American, 3.4% were Asian, 3.4% were other races or race not reported; and 1.7% were Hispanic or Latino. For adult patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 0.4 to 46 months). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI.

Serious adverse reactions occurring in ≥1% of patients were COVID-19 (3.4%), nephrolithiasis (3.4%), and in 1 patient each: acute kidney injury, abdominal pain, ischemic colitis, urinary tract infection, retinal vein occlusion, scoliosis, squamous cell carcinoma of skin, cerebrovascular accident and chronic obstructive pulmonary disease. One fatal adverse reaction occurred in an adult patient (1.7%) who received GOMEKLI, due to COVID-19. Permanent discontinuation of GOMEKLI due to an adverse reaction occurred in 22% of adult patients.

Adverse reactions which resulted in permanent discontinuation of GOMEKLI in ≥1% of adult patients were rash, diarrhea, nausea, abdominal pain, alopecia, dry skin, left ventricular dysfunction, cough, wheezing, COVID-19, peripheral swelling, RVO, dizziness, and vomiting. Dosage interruptions of GOMEKLI due to an adverse reaction occurred in 31% of adult patients. Adverse reactions which required dosage interruption in ≥5% of patients included left ventricular dysfunction and COVID-19.

Dose reductions of GOMEKLI due to an adverse reaction occurred in 17% of adult patients. Adverse reactions which required dose reductions in ≥5% of patients included rash. The most common adverse reactions (>25%) were rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.

The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. Pediatric Patients The median age of pediatric patients (age ≤17 years) who received GOMEKLI was 10 years (range: 2 to 17); 54% were female; 66% were White, 20% were Black or African American, 9% were other races or race not reported, 3.6% were Asian, 1.8% were American Indian or Alaska Native; and 14% were Hispanic or Latino. For pediatric patients treated with GOMEKLI, the median duration of treatment was 22 months (range: 1.6 to 40 months).

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13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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/m 2 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/m 2 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/m 2 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/m 2 based on AUC).

The reversibility of effects on ovary and male reproductive organs was not assessed.