The U.S. Food and Drug Administration (FDA) has approved Koselugo (selumetinib) for the treatment of patients, 2 years of age and older, who have neurofibromatosis type 1 (NF1) with inoperable plexiform neurofibromas.
NFI is a genetic disorder due to mutations in the NF1 gene that leads to a plethora of symptoms and those symptoms can further categorize the disease.
Persons with cutaneous neurofibromas have soft lumps on and under the skin and possibly so ‘cafe au lait’ spots.
Persons with plexiform neurofibromas have tumors that develop on the nerve sheaths that can cause symptoms such as pain, motor dysfunction, airway dysfunction, bowel/bladder dysfunction and disfigurement. Learning difficulties, visual impairment, twisting and curvature of the spine, hypertension, and epilepsy are also common.
Selumetinib is approved specifically for patients who have symptomatic, inoperable plexiform neurofibromas. Selumetinib is a kinase inhibitor that attenuates tumor cells from growing.
The approval is largely based on an open-label, phase 2 clinical trial recently published in the New England Journal of Medicine. In the study, 50 children (median age, 10.2 years; range, 3.5 to 17.4) with inoperable plexiform neurofibromas were given oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients had a confirmed partial response to treatment and 28 of those had a durable response (i.e., lasting more than 1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. Other symptoms also showed improvement in some patients(quality of life, strength, range of motion).
Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and six patients had disease progression.
The most common side effects were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain. fever, acne, stomatitis, headache, paronychia, and pruritus.
Selumetinib can also cause serious side effects including heart failure and ocular toxicity. Patients should have cardiac and ophthalmic assessments performed prior to starting treatment and at regular intervals during treatment. Selumetinib may also cause harm to a newborn baby when administered to a pregnant woman. The FDA advises health care professionals to tell females of reproductive age, and males with female partners of reproductive potential, to use effective contraception during treatment with selumetinib.
Since the drug is applicable for pediatric patients, the company sponsor (AstraZeneca) was awarded a Rare Pediatric Disease Priority Review Voucher which allows the company to use that voucher on any future drug to give it a ‘priority review’ by the FDA (i.e., reduce the review process from approximately ten months to six months).
