Koselugo Becomes First-Ever Therapy Approved in the EU for Neurofibromatosis Type 1, Granted Conditional Approval for Pediatric Plexiform Neurofibromas

Plexiform neurofibroma (PN) (Image source: storytrender.com)

June 22, 2021 News /BioonBIOON/ --AstraZeneca(AstraZeneca) and Merck & Co. recently jointly announced that their targeted anticancer drug Koselugo (selumetinib) has received conditional approval from the European Commission (EC). The drug is a novel oral kinase inhibitor indicated for pediatric patients aged 3 years and older with neurofibromatosis type 1 (NF1) for the treatment of symptomatic, inoperable plexiform neurofibromas (PN). This approval,making Koselugo the first drug approved for the treatment of NF1 in Europe.Prior to this approval, surgery was the only treatment option for PN in children with NF1 in the EU. This approval marks a significant step in addressing theseTumor...has made a significant step forward in addressing the pro-aging effects of...

`NF1 is a debilitating nervous system disorder.`Geneticsdisease, with a global incidence of 1 in 3,000. In 30-50% of NF1 patients,TumorArising from the nerve sheath (plexiform neurofibroma [PN1]), it can cause clinical problems, such as: disfigurement, airway dysfunction, visual impairment, and bladder/bowel dysfunction.

In April 2020, Koselugo received U.S. FDA approval for pediatric patients aged ≥2 years with NF1 for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) associated with NF1. Notably,Koselugo is American.FDAThe first approved drug for the treatment of NF1.Previously, Koselugo was granted Orphan Drug Designation (ODD) and Breakthrough Therapy Designation (BTD) for the treatment of NF1. Koselugo is a kinase inhibitor, meaning it works by targeting key enzymes, thereby preventingTumorCell growth.

This approval is based on the results of the Phase II SPRINT Stratum 1 trial. This trial was sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI), and the relevant results have been published in the leading international medical journal *The New England Journal of Medicine* (NEJM). For details, see:Selumetinib in Children with Inoperable Plexiform。

The SPRINT Stratum 1 trial enrolled 50 pediatric patients (median age 10.2 years; range: 3.5–17.4) with NF1 and inoperable PN (defined as PN that could not be completely resected without causing severe morbidity to the patient). The most common neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33 patients), and pain (26 patients). In the trial, patients received oral Koselugo at 25 mg/m² twice daily (the approved recommended dose) until disease progression or unacceptableAdverse Reactions。During the trial, routine assessments of changes in patient tumor volume and tumor-related disease symptoms were conducted, and the overall response rate (ORR) was determined, defined as: complete response or partial response confirmed by MRI at 3–6 months (PN# Tumorproportion of patients with a volume reduction ≥20%).

Data shows,Koselugo (oral, twice daily) monotherapy provides significant clinical benefits for patients: sustained reduction in tumor volume, pain relief, improved daily function, and overall health-related quality of life.. In this trial,The objective response rate (ORR) for Koselugo treatment was 66%, with 33 out of 50 patients achieving a confirmed partial response.ORR refers to confirmed complete response (disappearance of PN) or partial response (PR,Tumorpercentage of patients with a volume reduction of at least 20%).

The efficacy and safety data obtained from extended follow-up of the SPRINT Stratum 1 trial are one of the conditions for the conditional approval of Koselugo in the European Union.

Molecular structure of selumetinib, the active pharmaceutical ingredient of Koselugo (Image source: lclabs.com)

NF1 is a debilitating, progressive, and often disfiguring rare disease that typically begins early in life and is caused by mutations or defects in a specific gene. NF1 is usually diagnosed in early childhood, affecting approximately 1 in 3,000 infants, and is characterized by changes in skin color (pigmentation), nerve and bone damage, and a lifelong risk of developing benign and malignant tumors. 30%–50% of NF1 patients develop one or more plexiform neurofibromas (PN). The primary treatment for PN is surgical resection. Unfortunately, due to theseTumorlocation or size, many patients are not suitable for surgery. Furthermore, NP typically recurs after optimal surgical resection, thus representing a significant area of unmet medical need.

The active pharmaceutical ingredient of Koselugo is selumetinib, an oral, potent, selective MEK1/2 kinase inhibitor. The NF1 gene encodes neurofibromin, a protein that negatively regulates the RAS/MAPK pathway, helping to control cell growth, differentiation, and survival. Mutations in the NF1 gene may lead to dysregulation of the RAS/RAF/MEK/ERK signaling pathway, which can result in uncontrolled cell growth, division, and replication, potentially leading to tumor growth. By inhibiting the MEK enzyme in this pathway, selumetinib has the potential to inhibit tumor growth. Currently, selumetinib is being evaluated in clinical studies as a monotherapy and in combination with other therapies for the treatment of various typesTumorpotential.

selumetinib was discovered by Array BioPharma, and AstraZeneca obtained exclusive global licensing rights to the compound in 2003. In July 2018, AstraZeneca and MSD reached# Tumorstrategic partnership to jointly develop and commercialize selumetinib and the PARP inhibitor Lynparza globally. Currently, both parties are conducting the Phase I/II SPRINT clinical trial to explore the potential benefits of selumetinib in pediatric patients with unresectable NF1-related plexiform neurofibromas (PN). Koselugo in adult patients with NF1-PNClinical Trial, and a clinical trial of an age-appropriate formulation for pediatric patients, is scheduled to commence this year. (Bioon.com)

Original Source:Koselugo approved in the EU for children with neurofibromatosis type 1 and plexiform neurofibromas