RARE Daily

FDA Approves First Therapy to Treat Rare Tumor Disorder NF1

April 13, 2020

Rare Daily Staff

The U.S. Food and Drug Administration approved AstraZeneca and Merck’s Koselugo for the treatment of pediatric patients, 2 years of age and older, with neurofibromatosis type 1, a genetic disorder of the nervous system that causes 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.

Neurofibromatosis type 1 (NF1) is caused by a spontaneous or inherited mutation in the NF1 gene. In 20 to 50 percent of patients, tumors develop on the nerve sheaths (plexiform neurofibromas, or PNs). These PNs can cause clinical issues, such as pain, motor dysfunction, airway dysfunction, bowel/bladder dysfunction and disfigurement as well as having the potential to transform into malignant peripheral nerve sheath tumors.

People with NF1 may experience a number of complications such as learning difficulties, visual impairment, twisting and curvature of the spine, high blood pressure, and epilepsy. NF1 also increases a person’s risk of developing other cancers, including malignant brain tumors, malignant peripheral nerve sheath tumor, and leukemia. Symptoms begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.

Koselugo (selumetinib) is approved specifically for patients who have symptomatic, inoperable PNs, which can grow on nerves 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 that blocks the MEK enzyme and results in helping to stop the tumor cells from growing.

“For the first time, pediatric patients now have an FDA-approved drug to treat plexiform neurofibroma, a rare tumor associated with NF1,” said Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

Koselugo was approved based on a clinical trial conducted by the National Cancer Institute of pediatric patients who had NF1 and inoperable PN. 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 overall response rate, defined as the percentage of patients with a complete response and those who experienced more than a 20 percent reduction in PN volume on MRI, was 66 percent, and all patients had a partial response, meaning that no patients had complete disappearance of the tumor. Of these patients, 82 percent had a response lasting 12 months or longer.

Although the sample sizes of patients assessed for each PN-related morbidity were small, there appeared to be a trend of improvement in PN-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, acne, inflammation of the mouth and lips, headache, infection in the skin that surrounds a toenail or fingernail, and itching. Koselugo can also cause serious side effects including heart failure and damage to the eyes.

AstraZeneca licensed selumetinib in 2003 from Array BioPharma, and in 2017, entered into a co-development and co-commercialization agreement for the compound with Merck as part of their collaboration around the PARP inhibitor Lynparza. Working together, the companies agreed to develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies agreed to develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

Koselugo had received the FDA’s Priority Review and Breakthrough Therapy designations. Koselugo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, and Rare Pediatric Disease Designation for the treatment of pediatric NF1, which is given for serious or life-threatening diseases in individuals aged from birth to 18 years. It includes access to the FDA’s expedited review and approval process, and a priority review voucher if approved.

The vouchers can be used to reduce the time of an FDA new drug approval review to six months from ten months. The vouchers are potentially lucrative because they are transferable. Most recently, Swedish Orphan Biovitrum sold its Priority Review voucher to AstraZeneca for $95 million. AstraZeneca received a voucher for Koselugo.

The FDA’s Pazdur said that advancing rare and orphan therapies remains a top priority during the current pandemic.

“Everyone’s daily lives have been disrupted during the COVID-19 pandemic, and in this critical time we want patients to know that the FDA remains committed to making patients with rare tumors and life threatening diseases, and their unique needs, a top priority,” he said. “We continue to expedite product development for these patients.”


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