AstraZeneca's Koselugo Receives Orphan Drug Designation in Japan for Neurofibromatosis Type 1

June 30, 2020 /Bio ValleyBIOON/ --AstraZeneca(AstraZeneca) recently announced that its targeted anticancer drug Koselugo (selumetinib) has been granted orphan drug designation (ODD) in Japan for the treatment of neurofibromatosis type 1 (NF1).

NF1 is a debilitating, progressive, often disfiguring, rareGeneticsneoplastic diseases, leading to tumor growth on the nerves, theseTumorIt can grow anywhere in the body, including the face, limbs, around the spine, and deep within the body in areas that may affect organs. This condition typically begins early in life and is caused by mutations or defects in specific genes.

NF1 is typically diagnosed in early childhood, affecting approximately 1 in 3,000 infants. It is characterized by changes in skin color (pigmentation), nerve and bone damage, and the development of both benign and malignant tumors throughout life.Tumorrisk. 30% to 50% of patients with NF1 develop one or more plexiform neurofibromas (PN).

Koselugo, co-developed and commercialized by AstraZeneca and Merck & Co., received U.S. approval in April this yearFDAApproved, it is the first drug approved for the treatment of NF1. The drug is a kinase inhibitor, meaning it works by targeting key enzymes, thereby blockingTumorCell Growth.

AstraZenecaTumorJosé Baselga, Executive Vice President of Research and Development, stated: “Neurofibromatosis type 1 (NF1) has a devastating impact on children, and there is an urgent need for new medications to help treat the resulting plexiform neurofibromas (PN) and associated clinical issues. Currently, therapeutic options in most countries are very limited. This orphan drug designation represents a significant step forward in providing the first NF1 medication to pediatric patients in Japan.”

Roy Baynes, Senior Vice President of Merck Research Laboratories and Global Head of Clinical Development, as well as Chief Medical Officer, stated: “Plexiform neurofibromas (PN) are one of the main manifestations of NF1, causing pain and disfigurement. In the Phase II SPRINT trial, selumetinib was shown to reduce pediatric”Tumor...size. We hope to bring this treatment to the underserved pediatric patient population in Japan.”

Plexiform Neurofibroma (PN) (Image source: cancerworld.info)

NF1 is a rare, incurable, and debilitating genetic disorder with an incidence of approximately 1 in 3,000 to 4,000 infants. The disease is caused by a spontaneous mutation in the NF1 gene orHeredityCaused by mutations and associated with various symptoms, including soft lumps on the skin surface and within the skin (cutaneous and subcutaneous neurofibromas), as well as skin pigmentation (café-au-lait macules). Approximately 30–50% of patients with NF1 develop plexiform neurofibromas (PN), which grow along the nerve sheath.Tumor. These PN can lead to clinical problems such as cosmetic defects, motor dysfunction, pain, airway dysfunction, visual impairment, and bowel/bladder dysfunction. PN begins in early childhood, varies greatly in severity, and can shorten life expectancy by 8–15 years.

Selumetinib is an oral, potent, and selective MEK1/2 kinase inhibitor. MEK1/2 proteins are upstream regulators of the extracellular signal-regulated kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is frequently activated in various types of cancer.

The NF1 gene encodes neurofibromin, a protein that negatively regulates the RAS/MEK pathway, thereby 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 development. Selumetinib potentially inhibits tumor growth by suppressing the MEK enzyme within this pathway. Currently, selumetinib is being evaluated in clinical studies as a monotherapy and in combination with other therapies for the treatment of various typesTumor。

In April this year, selumetinib received U.S.FDAApproved for marketing under the brand name Koselugo for pediatric patients aged ≥2 years with NF1, specifically indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) associated with NF1.

It is worth noting that Koselugo is the first drug approved for the treatment of NF1. Earlier this year, the European Medicines Agency (EMA) accepted the marketing authorization application (MAA) for selumetinib for the treatment of plexiform neurofibromas (PN) in patients with NF1, and further global regulatory submissions are underway. Previously, selumetinib was granted orphan drug designation in the United States, the European Union, and Switzerland. In the United States, it also received Rare Pediatric Disease Designation (RPDD) and Breakthrough Therapy Designation (BTD).

Selumetinib Molecular Structure (Image Source: Wikipedia)

Koselugo Received U.S.FDAApproved, based on the positive results from the SPRINT Phase II Stratum 1 trial sponsored by the Cancer Therapy Evaluation Program (CTEP) of the U.S. National Cancer Institute (NCI). The trial enrolled pediatric patients with NF1 and inoperable plexiform neurofibromas (PNs), defined as PNs that cannot be completely resected but do not pose a risk of severe morbidity to the patient. Efficacy outcomes were derived from 50 patients who received the recommended dose, with regular assessments of changes in tumor size and tumor-related symptoms conducted throughout the trial. During the trial, patients received Koselugo orally at a dose of 25 mg/m² twice daily until disease progression or unacceptableAdverse Reactions. ThisClinical TrialThe overall response rate (ORR) was determined, defined as: complete or partial response confirmed by MRI at 3–6 months (PNTumorProportion of patients with a volume reduction of ≥20%).

Data show that the overall response rate (ORR) for Koselugo as a twice-daily oral monotherapy was 66% (n=33/50), with all patients achieving partial response (PR). Among these patients, 82% experienced responses lasting 12 months or longer. Other clinical outcomes in patients during Koselugo treatment included changes in plexiform neurofibroma (PN)-related deficits, symptoms, and functional impairments. Although the sample sizes for evaluating each PN-related morbidity (such as deficits, pain, strength and mobility issues, airway compression, visual impairment, and bladder or bowel dysfunction) were small, there appeared to be a trend toward improvement in PN-related symptoms or functional deficits during treatment.

Common side effects in patients taking Koselugo include vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain (body pain affecting bones, muscles, ligaments, tendons, and nerves), fever, acneiform rash (acne), stomatitis (inflammation of the lips and mouth), headache, paronychia (infection of the skin around the toenails or fingernails), and pruritus (itching).

Koselugo can also cause serious side effects, including heart failure (manifested as reduced ejection fraction, or impaired contraction of the left ventricular myocardium) and ocular toxicity (acute and chronic eye injuries), including retinal vein occlusion, retinal pigment epithelium detachment, and visual impairment. Patients should undergo regular cardiac and ophthalmologic evaluations before initiating Koselugo therapy and during treatment. Koselugo can also lead to elevated creatine phosphokinase (CPK) levels, an enzyme found in the heart. (Bioon.com)

Original Source:Selumetinib granted orphan drug designation in Japan for neurofibromatosis type 1