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Koselugo, the first therapy for children with neurofibromatosis type 1, a debilitating and disfiguring rare disease, FDA approved

The FDA ( U.S. Food and Drug Administration ) has approved Koselugo ( Selumetinib ) for the treatment of pediatric patients, 2 years of age and older, with neurofibromatosis type 1 ( NF1 ), a genetic disorder of the nervous system causing tumors to grow on nerves.
Koselugo is the first drug approved by the FDA to treat this debilitating, progressive and often disfiguring rare disease that typically begins early in life.

Koselugo is approved specifically for patients who have symptomatic, inoperable plexiform neurofibromas ( PN ), which are tumors involving the nerve sheaths ( coating around nerve fibers ) and can grow anywhere in the body, including the face, extremities, areas around the spine and deep in the body where they may affect organs.
Koselugo is a kinase inhibitor, meaning it functions by blocking a key enzyme, which results in helping to stop the tumor cells from growing.

NF1 is a rare, progressive condition caused by a mutation or flaw in a particular gene. NF1 is usually diagnosed in early childhood and appears in an estimated 1 out of every 3,000 infants. It is characterized by changes in pigmentation, neurologic and skeletal impairments and risk for development of benign and malignant tumors throughout life. Between 30% and 50% of patients born with NF1 develop one or more plexiform neurofibromas.

The FDA approved Koselugo based on a clinical trial conducted by the National Cancer Institute ( NCI ) of pediatric patients who had NF1 and inoperable plexiform neurofibroma ( defined as a plexiform neurofibroma that could not be completely removed without risk for substantial morbidity to the patient ).
The efficacy results were from 50 of the patients who received the recommended dose and had routine evaluations of changes in tumor size and tumor-related morbidities during the trial.
Patients received Koselugo 25 mg/m2 orally twice a day until disease progression or until they experienced unacceptable adverse reactions.
The clinical trial measured the overall response rate ( ORR ), defined as the percentage of patients with a complete response and those who experienced more than a 20% reduction in plexiform neurofibroma volume on magnetic resonance imaging ( MRI ) that was confirmed on a subsequent MRI within 3-6 months.
The ORR was 66% and all patients had a partial response, meaning that no patients had complete disappearance of the tumor. Of these patients, 82% had a response lasting 12 months or longer.

Other clinical outcomes for patients during Koselugo treatment including changes in plexiform neurofibroma-related disfigurement, symptoms and functional impairments.
Although the sample sizes of patients assessed for each plexiform neurofibroma-related morbidity ( such as disfigurement, pain, strength and mobility problems, airway compression, visual impairment and bladder or bowel dysfunction ) were small, there appeared to be a trend of improvement in plexiform neurofibroma-related symptoms or functional deficits during treatment.

Common side effects for patients taking Koselugo were vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acneiform rash, stomatitis, headache, paronychia and pruritus.

Koselugo can also cause serious side effects including heart failure ( manifested as ejection fraction decrease ) and ocular toxicity (acute and chronic damage to the eye) including retinal vein occlusion, retinal pigment epithelial detachment and impaired vision.
Patients should have cardiac and ophthalmic assessments performed prior to initiating Koselugo and at regular intervals during treatment.

Koselugo can also cause increased creatinine phosphokinase ( CPK ), an enzyme found in the heart, brain and skeletal muscles. When muscle tissue is damaged, CPK leaks into a person’s blood. CPK elevation in a patient receiving Koselugo should prompt an evaluation for rhabdomyolysis.

Koselugo should be withheld, dosage reduced or dosage permanently discontinued based on the severity of adverse reactions.

Further, Koselugo contains Vitamin-E, and patients are at an increased risk of bleeding if their daily intake of Vitamin-E exceeds the recommended or safe limits.

Based on findings from animal studies, Koselugo may cause harm to a newborn baby when administered to a pregnant woman. ( Xagena )

Source: FDA, 2020