publication date: Apr. 17, 2020

Drugs & Targets

FDA approves Koselugo for neurofibromatosis type 1

FDA has approved Koselugo (selumetinib) for the treatment of pediatric patients, two years and older, with neurofibromatosis type 1, a genetic disorder of the nervous system causing tumors to grow on nerves.

AstraZeneca and Merck sponsor the drug.

Koselugo is the first drug approved by FDA to treat this debilitating, progressive and often disfiguring rare disease that typically begins early in life.

“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. We continue to expedite product development for these patients,” 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, said in a statement.

Koselugo is approved specifically for patients who have symptomatic, inoperable plexiform neurofibromas, 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 one out of every 3,000 infants.  It is characterized by changes in skin coloring, 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 PNs.

“We are committed to regulatory flexibility and providing extensive guidance to industry in an effort to bring drugs forward that fulfill unmet medical needs. Koselugo represents this commitment,” Pazdur said. “For the first time, pediatric patients now have an FDA-approved drug to treat plexiform neurofibroma, a rare tumor associated with NF1.”

FDA approved Koselugo based on a clinical trial conducted by NCI of pediatric patients who had NF1 and inoperable PN (defined as a PN 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 , defined as the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on 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 PN-related disfigurement, symptoms and functional impairments. Although the sample sizes of patients assessed for each PN-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 PN-related symptoms or functional deficits during treatment.

FDA granted this application Priority Review and Breakthrough Therapy designation. Koselugo also received Orphan Drug designation and Rare Pediatric Disease Designation for the treatment of pediatric NF1. The application is awarded a Rare Pediatric Disease Priority Review Voucher.


FDA approves mitomycin for low-grade upper tract urothelial cancer

FDA has approved mitomycin (Jelmyto) for adult patients with low-grade upper tract urothelial cancer.

UroGen Pharma sponsors the drug.

“Although our nation’s emphasis is on the need to combat COVID-19, patients with cancer and their unique needs continue to be a top priority for the FDA,” 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, said in a statement. “We continue to expedite oncology product development in this critical time. Our staff is continuing to meet virtually with drug developers, academic investigators and patient advocates to push forward the coordinated review of drugs, biologics and devices for cancer.”

Efficacy determination was based on OLYMPUS (NCT02793128), an ongoing, single-arm, multicenter trial enrolling 71 patients with treatment-naïve or recurrent low-grade non-invasive UTUC with at least one measurable papillary tumor located above the ureteropelvic junction. Patients who had larger tumors could have had prior tumor debulking. Patients received weekly Jelmyto 4 mg per mL instillations via ureteral catheter or nephrostomy tube for 6 weeks. For patients with a complete response at 3 months, instillations were to be administered monthly for a maximum of 11 additional instillations.

While the majority of urothelial cancers occur in the bladder, UTUC corresponds to a subset of urothelial cancers that arise in the lining of the kidney or the ureter. UTUC can block the ureter or kidney, causing swelling, infections and impairment of kidney function in some patients. UTUCs can develop as low-grade or high-grade tumors. In general, low-grade tumors are not invasive and very rarely spread from the kidney or ureter.

However, they often recur and management involves treating visible tumors and trying to preserve the urinary tract, as these tumors are more likely to recur in the urinary system than they are to spread. Low-grade UTUC is rare, but affects 6,000-8,000 new patients in the United States every year.

“This is the first approval specifically for patients with low-grade UTUC and provides an option for some patients who may otherwise require a nephroureterectomy,” said Pazdur. “Due to substantial treatment challenges associated with the complex anatomy of the upper urinary tract, many patients need to be treated with radical surgery – usually complete removal of the affected kidney, ureter and bladder cuff. Jelmyto gives patients, for the first time, an alternative treatment option for low-grade UTUC.”

The major efficacy outcome measures were CR and CR durability. CR was defined as complete absence of tumor lesions 3 months after Jelmyto initiation and was assessed by urine cytology and ureteroscopy. If warranted, a biopsy was performed. Forty-one patients (58%) achieved a CR three months following treatment initiation and were continued in follow-up; 29 patients received at least one dose of maintenance therapy.

Durability of response in those with CRs was evaluated at 3, 6, 9 and 12 months, following the CR determination.Seven patients had documented recurrences and nineteen patients remained in CR at 12-months following CR determination. The median response duration had not been reached (range: 0, 18.8+ months).


Ontruzant, biosimilar of Herceptin, introduced in the U.S.

Merck April 15 introduced Ontruzant(trastuzumab-dttb), a biosimilar of the reference biologic medicine Herceptin, to the U.S. Ontruzant is available in both 150 mg single-dose vials and 420 mg multiple-dose vials.

Ontruzant will be introduced in the U.S. at a list price (wholesaler acquisition cost) of approximately $1,325 for the 150 mg single-dose vial and $3,709 for the 420 mg multiple-dose vial (prices are rounded), representing a 15% discount to the current list price of Herceptin.

Wholesaler acquisition costs do not include discounts to payers, providers, distributors and other purchasing organizations.

Ontruzant is indicated for adjuvant treatment of HER2 overexpressing nod- positive or node-negative (ER/PR negative or with one high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; as a single agent following multi-modality anthracycline based therapy.

Patients are selected for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

Merck launched Ontruzant in the U.S. as part of a development and commercialization agreement with Samsung Bioepis. Under the agreement between the companies, Samsung Bioepis is responsible for preclinical and clinical development, process development and manufacturing, clinical trials and regulatory registration. Merck will be responsible for all commercialization activities for products approved in its partnered territories, including the U.S.

FDA approved Ontruzant in January 2019 based on the review of Samsung Bioepis’ comprehensive data package, which included extensive structural and functional analytical data, nonclinical and clinical pharmacokinetic data, and a comparative clinical study demonstrating that Ontruzant is highly similar to its reference product, Herceptin, in terms of the safety, purity and potency of the product.

Copyright (c) 2020 The Cancer Letter Inc.