Neurofibromatosis Type 1

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Neurofibromatosis type 1 (NF1) is a genetic disorder that affects children and adults and that manifests in a variety of symptoms including abnormal pigmentation, skeletal deformities, non-malignant and malignant tumors, and neurological complications.

NF1 is characterized by mutations in the NF1 gene, which leads to over-activation of the MAPK pathway. NF1 has an estimated global birth incidence of approximately 1 in 3,000 individuals, and it is estimated that nearly 100,000 people are living with NF1 in the United States. The clinical course of NF1 is heterogeneous, and people with it have an 8 to 15-year shortened lifespan compared to the general population.

Watch Diane and Alex’s NF1-PN story

What causes NF1?

NF1 is caused by mutations in the gene that controls the production of a protein called neurofibromin (neurofibromin 1). In about 50% of people with NF1, the disorder results from gene mutations that occur for unknown reasons (spontaneous mutation). In others with the disorder, NF1 is inherited.

Does NF1 progress?

Throughout their lifetime, patients with NF1 display a progression of different clinical manifestations. Almost everyone will experience a skin tumor called cutaneous neurofibroma at some point, 50-80% will exhibit a behavioral or cognitive deficit and about 30-50% of patients will develop plexiform neurofibromas (PN), which are peripheral nerve sheath tumors that cause severe disfigurement, pain and functional impairment. In rare cases, NF1-PN can transform into malignant peripheral nerve sheath tumors (MPNST), a diagnosis that has a 12-month survival rate of under 50%. NF1-PNs are most often diagnosed in the first two decades of life.

Are there treatments?

GOMEKLI (mirdametinib) is approved in the U.S. for the treatment of adult and pediatric patients 2 years of age and older with NF1 who have symptomatic plexiform PN not amenable to complete resection. The FDA (2020) and EMA (2021) also approved another drug from the MEK inhibitor class for the treatment of children with NF1-PN.

INDICATION  

GOMEKLI (mirdametinib) is indicated for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection. 

IMPORTANT SAFETY INFORMATION  

WARNINGS AND PRECAUTIONS  

Ocular Toxicity: GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision. In the adult pooled safety population, ocular toxicity occurred in 28% of patients treated with GOMEKLI: 21% were Grade 1, 5% were Grade 2 and 1.3% were Grade 3. RVO occurred in 2.7%, RPED occurred in 1.3%, and blurred vision occurred in 9% of adult patients. In the pediatric pooled safety population, ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2. Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI as clinically indicated. 

Left Ventricular Dysfunction: GOMEKLI can cause left ventricular dysfunction. GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or LVEF <55% prior to initiation of treatment. In the ReNeu study, decreased LVEF of 10 to <20% occurred in 16% of adult patients treated with GOMEKLI. Five patients (9%) required dose interruption, one patient (1.7%) required a dose reduction, and one patient required permanent discontinuation of GOMEKLI. The median time to first onset of decreased LVEF in adult patients was 70 days. Decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% occurred in 1.8% of pediatric patients treated with GOMEKLI. One patient (1.8%) required dose interruption of GOMEKLI. The median time to first onset of decreased LVEF in pediatric patients was 132 days. All patients with decreased LVEF were identified during routine echocardiography, and decreased LVEF resolved in 75% of patients. Before initiating GOMEKLI, assess ejection fraction (EF) by echocardiogram. Monitor EF every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction. 

Dermatologic Adverse Reactions: GOMEKLI can cause dermatologic adverse reactions including rash. The most frequent rashes included dermatitis acneiform, rash, eczema, maculo-papular rash and pustular rash. In the pooled adult safety population, rash occurred in 92% of patients treated with GOMEKLI (37% were Grade 2 and 8% were Grade 3) and resulted in permanent discontinuation in 11% of patients. In the pooled pediatric safety population, rash occurred in 72% of patients treated with GOMEKLI (22% were Grade 2 and 3.4% were Grade 3) and resulted in permanent discontinuation in 3.4% of patients. Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction. 

Embryo-Fetal Toxicity: GOMEKLI can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of GOMEKLI. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Also advise patients to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose (females) or 3 months after the last dose (males).  

ADVERSE REACTIONS 

The most common adverse reactions (>25%) in adult patients were rash (90%), diarrhea (59%), nausea (52%), musculoskeletal pain (41%), vomiting (38%), and fatigue (29%). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase. 

The most common adverse reactions (>25%) in pediatric patients were rash (73%), diarrhea (55%), musculoskeletal pain (41%), abdominal pain (39%), vomiting (39%), headache (34%), paronychia (32%), left ventricular dysfunction (27%), and nausea (27%). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase.  

USE IN SPECIFIC POPULATIONS 

Verify the pregnancy status of patients of reproductive potential prior to initiating GOMEKLI. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.  

To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics Inc. at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 

Please see full Prescribing Information including Patient Information and Instructions for Use.