The FDA has approved burosumab-twza (Crysvita®, Ultragenyx Pharmaceutical, Inc.), a fully human monoclonal antibody, for the treatment of patients aged two and older with tumor-induced osteomalacia (TIO) whose tumors are unable to be located or removed.
A rare condition, TIO develops when tumors secrete high levels of fibroblast growth factor 23 (FGF23), a peptide hormone–like substance which lowers phosphate levels, thereby weakening and softening the bones. Patients with TIO can experience bone pain, fractures, muscle weakness, and general debilitation. The most common tumors associated with TIO are mesenchymal tumors, which can develop in the bone, cartilage, or other soft or connective tissues.
The approval was based on two phase 2 clinical trials: Study 6 (NCT02304367), which enrolled patients with FGF23-related hypophosphatemia, and Study 7 (NCT02722798), which enrolled adult patients with TIO. Patients in both trials received a 0.3 mg/kg starting injection of burosumab-twza once every 4 weeks, with treatment titrated to achieve a fasting serum phosphorus level between 2.5 and 4.0 mg/dL. Patients enrolled in Study 6 received a mean dose of 0.83 mg/kg at Week 20, 0.87 mg/kg at Week 48, 0.77 mg/kg at Week 96, and 0.71 mg/kg at Week 144; patients enrolled in Study 7 received a mean dose of 0.91 mg/kg at Week 48 and 0.96 mg/kg at Week 88.
In Study 6, 50% of 14 evaluable patients achieved a mean serum phosphorus level above the lower limit of normal through Week 24 of treatment and maintained the increase through Week 144. Burosumab-twza increased mean serum phosphorus levels from 1.60 mg/dL at baseline to 2.64 mg/dL at Week 24. Healing of TIO-related bone lesions was suggested by the results of bone scans. Burosumab-twza was also associated with improved quality of life and physical functioning, with mean Global Fatigue Scores decreasing from a baseline value of 5.3 to 3.6 at Week 48 and 3.3 at Week 48.
In Study 7, 69% of 13 patients achieved a mean serum phosphorus level above the lower limit of normal through Week 24 and maintained normal levels through Week 88. Mean serum phosphorus levels increased from 1.62 mg/dL at baseline to 2.63 mg/dL at Week 24 of treatment.
The most common adverse events occurring in patients in both trials included hypersensitivity (22%), tooth abscess (19%), muscle spasms (19%), dizziness (15%), constipation (15%), injection site reaction (15%), rash (15%), headache (11%), vitamin D deficiency (7%), hyperphosphatemia (7%), and restless leg syndrome (7%).
Burosumab-twza is contraindicated in patients taking oral phosphate or active vitamin D analogs, those with normal or high serum phosphate levels, and those with severe kidney impairment or end-stage renal disease. In the case of serious hypersensitivity events, treatment with burosumab-twza should be interrupted.
"Treatment for TIO focuses on identifying and removing the tumor that causes the disease. However, when that is not possible, burosumab-twza can help increase the levels of phosphate in the blood," commented Theresa E. Kehoe, MD, Acting Director of the Division of General Endocrinology in the FDA's Center for Drug Evaluation and Research. "As the first FDA-approved therapy to treat this debilitating disease, today's action is an important step in finding treatment options for patients living with TIO whose tumor cannot be found or removed."
The recommended starting dose of burosumab-twza is 0.4 mg/kg rounded to the nearest 10 mg every two weeks for pediatric patients aged two and older and 0.5 mg/kg administered every four weeks for adult patients. In both pediatric and adult patients, the dose may be increased to 2 mg/kg, with a maximum dosage of 180 mg administered every two weeks.
For More Information
Jan de Beur S, Miller P, Weber T, et al (2019). OR13-1 burosumab improves the biochemical, skeletal, and clinical symptoms of tumor-induced osteomalacia syndrome. J Endocr Soc, 3(suppl_1):OR13-1. DOI:10.1210/js.2019-OR13-1
US Food and Drug Administration (2020). FDA approves first therapy for rare disease that causes low phosphate blood levels, bone softening. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-disease-causes-low-phosphate-blood-levels-bone-softening?utm_campaign=061820_PR_FDA%20Approves%20First%20Therapy%20for%20Rare%20Disease%20that%20Bone%20Softening&utm_medium=email&utm_source=Eloqua
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