Mirdametinib

Mirdametinib is a selective, non-competitive inhibitor of the mitogen-activated protein kinase kinases MEK1 and MEK2. Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 tumour suppressor gene, which encodes neurofibromin. Loss of neurofibromin leads to dysregulated RAS signalling and overactivation of the downstream kinases MEK and ERK, which drives the growth of plexiform neurofibromas. Mirdametinib acts on this pathway by blocking MEK.

Mechanism of Action

• MEK inhibition: mirdametinib blocks the activity of MEK1 and MEK2 and with it the RAS–RAF–MEK pathway. In vitro it inhibited the kinase activity of both enzymes and the downstream phosphorylation of ERK.
• Effect on tumour cells: blocking MEK stops the proliferation and survival of tumour cells in which the RAF–MEK–ERK pathway is activated. This pathway regulates cell growth and senescence.
• Animal data: in a mouse model of NF1, oral mirdametinib reduced ERK phosphorylation, neurofibroma volume and tumour cell proliferation.
• Clinical study: efficacy was evaluated in ReNeu, a multicentre, open-label, single-arm phase 2 study of 114 patients aged 2 years and above (58 adults and 56 children) with symptomatic, inoperable NF1-related plexiform neurofibromas. Patients received 2 mg/m² twice daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

Pharmacokinetics

• Absorption: after repeated doses of 2 mg/m² twice daily in adults with NF1-related PN, the geometric mean steady-state Cmax was 188 ng/mL and the AUClast 431 ng × h/mL. Peak plasma concentrations occur about one hour after a dose. A high-fat, high-calorie meal lowered Cmax by 43% and delayed the peak by about 3 hours, but total exposure was essentially unchanged (AUCinf down 7%), so the effect is not considered clinically relevant.
• Distribution: the apparent volume of distribution was 255 L after a single radiolabelled 4 mg dose in healthy subjects. Plasma protein binding is above 99%, mainly to serum albumin, and the blood-to-plasma ratio is 0.61. Mirdametinib is reported to penetrate the central nervous system.
• Metabolism: extensive, by glucuronidation, hydrolysis and oxidation through UGT enzymes (mainly UGT1A6 and UGT2B7) and carboxylesterases, giving the O-glucuronide M22 and the carboxylic acid M15. Less than 10% is excreted unchanged. In vitro, neither mirdametinib nor its metabolites is expected to inhibit or induce CYP enzymes, UGT enzymes or the main drug transporters to a clinically relevant extent; the clinical relevance of the in vitro inhibition of BCRP, OATP1B1 and OATP2B1 by M22 could not be established.
• Elimination: after a single radiolabelled 4 mg dose in healthy adults, 68% of the dose was recovered in urine (0.7% unchanged) and 27% in faeces. The mean terminal half-life is 28 hours and the apparent clearance (CL/F) 6.34 L/h.
• Linearity and steady state: exposure rose in proportion to dose; the mean accumulation ratio was 1.1 to 1.9, and steady state is reached after about 6 days of repeated dosing.
• Special populations: age (2 to 86 years), sex and race do not significantly influence exposure, and the profile in children is similar to that in adults. Mild or moderate renal impairment does not affect exposure (population analysis); there are no data in severe renal impairment or end-stage renal disease. Mild hepatic impairment has no meaningful effect on exposure; there are no formal studies in hepatic impairment.

• Plexiform neurofibromas in NF1: monotherapy for symptomatic, inoperable plexiform neurofibromas (PN) in paediatric and adult patients with neurofibromatosis type 1 (NF1) aged 2 years and above.
• The indication is the same for the hard capsules (1 mg and 2 mg) and the dispersible tablets (1 mg).

• Hypersensitivity to mirdametinib or to any of the excipients.

The safety profile comes from a combined population of 75 adults and 58 children given 2 mg/m² twice daily for the first 21 days of each 28-day cycle. In adults the most common reactions of any grade were acneiform dermatitis (83%), diarrhoea (55%), nausea (55%), raised blood creatine phosphokinase (47%), musculoskeletal pain (41%), vomiting (37%) and fatigue (36%). In children they were raised creatine phosphokinase (59%), diarrhoea (53%), acneiform dermatitis (43%), musculoskeletal pain (41%), abdominal pain (40%), vomiting (40%) and headache (36%).

Very common (≥1/10): in adults and children: headache, diarrhoea, nausea, vomiting, abdominal pain (including upper abdominal pain), constipation, acneiform dermatitis, rash, dry skin, pruritus, alopecia, musculoskeletal pain, fatigue, increased blood creatine phosphokinase, increased blood alkaline phosphatase, decreased ejection fraction. In children (common in adults): paronychia, stomatitis (including mouth ulceration), eczema, hair colour changes, decreased neutrophil count, decreased white blood cell count, increased alanine aminotransferase. In adults (common in children): peripheral oedema, increased aspartate aminotransferase.

Common (≥1/100 to <1/10): in adults and children: blurred vision, abnormal hair texture. In adults (very common in children): paronychia, stomatitis, eczema, hair colour changes, decreased neutrophil count, decreased white blood cell count, increased alanine aminotransferase. In children (very common in adults): peripheral oedema, increased aspartate aminotransferase. Reported in adults only: retinal vein occlusion, retinal pigment epithelial detachment, dry mouth.

Serious reactions reported in adults were abdominal pain (3%), musculoskeletal pain (1.3%) and retinal vein occlusion (1.3%); in children, musculoskeletal pain (1.7%). Grade 3 or higher decreased neutrophil count was very common in children (11%). Reactions that led to discontinuation in more than one adult were acneiform dermatitis, diarrhoea, nausea, rash and vomiting. Eye reactions and a fall in ejection fraction need specific monitoring (see Special Instructions).

No clinical interaction studies have been performed.

• UGT and carboxylesterase modulators: mirdametinib is metabolised by several UGT and carboxylesterase enzymes, and no study has tested a strong inducer or inhibitor of them. Caution is advised with probenecid and diclofenac (UGT inhibitors) and with rifampicin (a UGT inducer).
• Hormonal contraceptives: the effect of mirdametinib on systemically acting hormonal contraceptives has not been evaluated, so women using them should add a barrier method.
• Gastric acid reducers: proton-pump inhibitors, antacids and H2-receptor antagonists are not expected to matter, because dissolution does not depend on pH; they can be used without restriction.
• Food: can be taken with or without food. A fat-rich meal lowers the peak concentration but not overall exposure.

Treatment must be started by a physician experienced in the diagnosis and treatment of patients with NF1-related tumours. Ezmekly is taken by mouth, with or without food.

Recommended Dose

• Dose: 2 mg/m² of body surface area (BSA) twice daily (about every 12 hours) for the first 21 days of each 28-day cycle. The maximum dose is 4 mg twice daily.
• By body surface area: 0.40 to 0.69 m², 1 mg twice daily; 0.70 to 1.04 m², 2 mg twice daily; 1.05 to 1.49 m², 3 mg twice daily; 1.50 m² or more, 4 mg twice daily. A dose for a BSA below 0.40 m² has not been established.
• Duration: until the plexiform neurofibromas progress or toxicity becomes unacceptable.

Formulations and Method of Administration

• Hard capsules (1 mg, 2 mg): swallowed whole with drinking water. They must not be chewed, broken or opened, so that the full dose is delivered.
• Dispersible tablets (1 mg): recommended for patients aged 2 to under 6 years and for patients, including adults, who cannot swallow capsules whole. They can be swallowed whole or, when whole tablets cannot be given, dispersed in water and given from a dosing cup. The oral suspension can also be given through an enteral feeding tube. Preparation instructions are in section 6.6 of the SmPC.

Dose Reductions and Modifications

Interruption, dose reduction or permanent discontinuation may be needed according to safety and tolerability (grades follow NCI CTCAE version 5.0). Treatment is stopped permanently in patients who cannot tolerate it after one dose reduction.

• Reduced doses: BSA 0.40 to 0.69 m², 1 mg once daily; 0.70 to 1.04 m², 2 mg in the morning and 1 mg in the evening; 1.05 to 1.49 m², 2 mg twice daily; 1.50 m² or more, 3 mg twice daily.
• Ocular toxicity: grade 2 or lower, continue and consider ophthalmological examination every 2 to 4 weeks until improvement. Grade 3 or higher, interrupt until improvement; if recovery takes 14 days or less, resume at the reduced dose, and if it takes longer, consider discontinuation. Asymptomatic retinal pigment epithelial detachment (RPED), continue with ophthalmic assessment every 3 weeks until resolution. Symptomatic RPED, interrupt until resolution and resume at the reduced dose. Retinal vein occlusion, discontinue permanently.
• Decreased LVEF: asymptomatic absolute decrease of less than 20% from baseline with LVEF still above the lower limit of normal, continue. Asymptomatic absolute decrease of 10% or more from baseline with LVEF below the lower limit of normal, interrupt until improvement and resume at the reduced dose. Any absolute decrease of 20% or more from baseline, discontinue permanently.
• Skin toxicity: grade 1 or 2 acneiform dermatitis or non-acneiform rash, continue. Intolerable grade 2, or grade 3 or 4, interrupt until improvement and resume at the reduced dose.
• Other adverse reactions: intolerable grade 2 or grade 3, interrupt until improvement and resume at the reduced dose. Grade 4, interrupt until improvement, resume at the reduced dose and consider discontinuation.

Special Populations

• Elderly: no dose adjustment for patients aged 65 or over; clinical data in this age group are limited.
• Renal impairment: no adjustment in mild or moderate impairment. Not studied in severe impairment (creatinine clearance 15 to under 30 mL/min) or end-stage renal disease, so no dose recommendation can be made.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above the upper limit of normal up to 1.5 times that limit, or normal bilirubin with AST above the limit). Not studied in moderate or severe impairment, so no recommendation can be made.
• Children: safety and efficacy below 2 years of age have not been established; no data are available.

Missed or Vomited Dose

If a dose is missed, or if vomiting occurs after a dose, an additional dose must not be taken; the patient continues with the next scheduled dose. Vomiting is managed as clinically indicated, including with anti-emetics.

Ocular Toxicity

Patients should be told to report any new visual disturbance. Retinal vein occlusion and RPED were reported commonly in adults in clinical studies. A comprehensive ophthalmological evaluation is needed before treatment starts, at regular intervals during treatment, and whenever a patient reports new or worsening visual changes such as blurred vision, in children, adolescents and adults alike. Treatment is interrupted and then reduced or stopped permanently according to severity (see Administration and Dosage).

Decreased Left Ventricular Ejection Fraction

An asymptomatic fall in LVEF of 10% or more from baseline occurred in 16% of adults and 27% of children in the ReNeu study; all cases were asymptomatic. Patients with a history of impaired LVEF, or a baseline ejection fraction below the institutional lower limit of normal, have not been studied, and the ejection fraction should be above that limit before treatment. LVEF is evaluated by echocardiogram before treatment, every 3 months during the first year and then as clinically indicated. A decrease is managed by interruption, dose reduction or discontinuation.

Skin Toxicity

Rash (acneiform and non-acneiform), dry skin, pruritus, eczema and hair changes were reported in the ReNeu study. Patients should contact their doctor or nurse if they notice a skin reaction. Supportive care such as emollient creams starts at the first signs, and treatment is interrupted, reduced or stopped according to severity.

Carcinogenicity Risk

A potential carcinogenicity risk in humans could not be excluded within the clinical exposure range.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception and pregnancy test: women of childbearing potential should be advised that mirdametinib may cause foetal harm and to avoid becoming pregnant. A pregnancy test is recommended before treatment starts. Female and male patients of reproductive potential should use effective contraception during treatment and for 6 months (females) and 3 months (males) after the last dose. Women using systemic hormonal contraceptives should add a barrier method. Treatment is not recommended in women of childbearing potential who are not using contraception.
• Pregnancy: data are limited and animal studies showed reproductive toxicity. Ezmekly should not be used during pregnancy. If a patient, or the female partner of a male patient, becomes pregnant, she should be told of the potential risk to the foetus.
• Breastfeeding: it is not known whether mirdametinib or its metabolites pass into human milk, and a risk to the infant cannot be excluded. Breastfeeding should stop during treatment and not restart until 1 week after the last dose.
• Fertility: based on animal findings, mirdametinib may impair fertility in males and females of reproductive potential; whether the effects are reversible is unknown, and there are no human data.

Excipients

Each hard capsule contains less than 1 mmol sodium (23 mg) per dose, that is, it is essentially sodium-free. For the dispersible tablets, see the SmPC of that formulation.

Effect on Driving

Ezmekly may have a moderate influence on the ability to drive and use machines. Fatigue and blurred vision have been reported, and patients with these symptoms should take care.

Both the hard capsules and the dispersible tablets: store below 30 °C in the original package to protect from light. No cold chain is needed. The capsules come in HDPE bottles with a child-resistant closure and an aluminium foil induction seal: 42 capsules of 1 mg, or 42 or 84 capsules of 2 mg. Not all pack sizes may be marketed.

• Hard capsules: 4 years.
• Dispersible tablets: 42 months. After the tablet(s) are dispersed in water the in-use period is 6 hours.

Prescription only (Rx). Ezmekly is a medicinal product subject to restricted medical prescription (Annex II B), and treatment must be started by a physician experienced in the diagnosis and treatment of NF1-related tumours. It is taken at home as capsules or dispersible tablets and stored at room temperature, so it is supplied to the patient or to the treating clinic on prescription.