United Therapeutics announces FDA approval of dinutuximab for treatment of high-risk neuroblastoma

United Therapeutics Corporation (NASDAQ: UTHR) announced today that the United States Food and Drug Administration (FDA) has approved Unituxin™ (dinutuximab) Injection (formerly called ch14.18), in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the United States of approximately 700 patients, of whom 50% are diagnosed as having high-risk disease. Unituxin is a chimeric biologic antibody that induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytoxicity (ADCC) and complement-dependent cytoxicity (CDC) and is part of an immunotherapeutic regimen to treat pediatric high-risk neuroblastoma.

The approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) conducted by the Children's Oncology Group (COG). The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. At the seventh interim analysis, an improvement in EFS [HR 0.57 (95% CI: 0.37, 0.89); p = 0.01, log-rank test] was demonstrated and four remaining patients undergoing treatment on the RA arm crossed over to receive Unituxin/RA. The median EFS was not reached (3.4 years, NR) in the Unituxin/RA arm and was 1.9 years (1.3, NR) in the RA arm. An analysis of overall survival (OS) conducted three years later documented an improvement in OS in the Unituxin/RA arm compared to the RA arm [HR 0.58 (95% CI: 0.37, 0.91)]. At the time of this survival analysis, median OS had not been reached in either arm.

The most common serious adverse reactions (greater than or equal to 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

The most common adverse drug reactions (greater than or equal to 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%).

"This approval has been a collaborative effort between the National Cancer Institute (NCI), the Children's Oncology Group and United Therapeutics for the first approved therapy for pediatric high-risk neuroblastoma," said Roger Jeffs, Ph.D., United Therapeutics' President and Co-Chief Executive Officer. "We are grateful for the FDA's thorough review and collaboration on this program, and we look forward to expanding our research efforts in the area of pediatric oncology."

"The FDA approval of dinutuximab represents the culmination of a remarkably productive collaboration between researchers of the NCI-supported Children's Oncology Group, the manufacturing and clinical research groups of NCI, and the oncology team at United Therapeutics," said Malcolm Smith, MD, Ph.D., Associate Branch Chief, Pediatrics in the Cancer Therapy Evaluation Program at NCI. Children with neuroblastoma will benefit from this collaboration, and the drug development pathway blazed by dinutuximab will likely be followed in the future to develop other novel agents directed against pediatric cancer therapeutic targets."

"After decades of pursuits, I am pleased to see that dinutuximab has received FDA approval and may now benefit high risk neuroblastoma patients," said Alice Yu, M.D., Ph.D., University of California San Diego and Principle Investigator of the registration study conducted by the COG. "This is not only the first successful immunotherapeutic to target a non-protein antigen, but also to be developed from an Investigational New Drug application through phase 3 trials largely through investigator-initiated effort and NCI support."

The recommended dose and schedule for Unituxin is 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Patients require intravenous treatment with opioids prior to, during, and for 2 hours following the Unituxin infusion to mitigate neuropathic pain. Prior to each Unituxin dose, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics.

In connection with the Unituxin approval, United Therapeutics agreed to certain postmarketing requirements (PMRs) and certain postmarketing commitments (PMCs). PMRs and PMCs are studies that sponsors conduct after FDA approval to gather additional information about a product's safety, efficacy, or optimal use. PMRs are required studies, whereas a sponsor voluntarily commits to conduct PMCs.

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United Therapeutics Corporation

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