On September 10, 2019 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, and Kyowa Kirin Co., Ltd., (Kyowa Kirin, TYO: 4151) reported plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for Crysvita (burosumab) for the treatment of FGF23-related hypophosphatemia associated with phosphaturic mesenchymal tumors (tumor-induced osteomalacia; TIO) that cannot be curatively resected or localized (Press release, Kyowa Hakko Kirin, SEP 10, 2019, View Source [SID1234539404]). The decision to submit follows the completion of a pre-sBLA meeting with the FDA and agreement on the filing package. The submission of the Crysvita sBLA is planned for the first half of 2020 and will be based on the current clinical data package.
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"Based on productive discussions with the FDA, we will be moving forward expeditiously with an sBLA filing for Crysvita in tumor-induced osteomalacia," said Camille L. Bedrosian, M.D., Chief Medical Officer of Ultragenyx. "We look forward to working with the agency during the review process, and we are committed to getting this therapy to patients with this serious disease with significant unmet medical need."
The BLA package will include data from two single-arm Phase 2 studies, a 144-week Phase 2 study in 14 adult patients conducted by Ultragenyx in the U.S. and an 88-week Phase 2 study in 13 adult patients conducted by Kyowa Kirin in Japan and South Korea. In both studies, Crysvita was associated with increases in serum phosphorus and serum 1,25-dihydroxyvitamin D levels. Increased phosphate levels led to improvements in osteomalacia, mobility, and vitality. Bone scans also demonstrated an increase in healed fractures and decrease in new fractures during Crysvita treatment. Adverse events generally reflected the patients’ underlying disease, and there were no serious treatment-related adverse events during the studies.
Crysvita is approved by the U.S. FDA, Health Canada, and Brazil’s National Health Surveillance Agency (ANVISA) for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients one year of age and older, and has received European conditional marketing authorization for the treatment of XLH with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons.
See below for Important Safety Information for Crysvita in X-linked hypophosphatemia.
About Tumor-Induced Osteomalacia (TIO)
TIO is caused by typically benign tumors that produce excess levels of fibroblast growth factor 23 (FGF23), causing phosphate wasting in the urine that leads to severe hypophosphatemia, osteomalacia, muscle weakness, fatigue, bone pain, and fractures. The symptoms rapidly resolve if the causal tumors or lesion can be resected; however, there are cases in which resection is not feasible or recurrence of the tumor occurs after resection. In patients for whom the tumor or lesion is inoperable, the current treatment consists of oral phosphate and/or vitamin D replacement. Efficacy of this management is often limited, as it does not treat the underlying disease and its benefits must be balanced with monitoring for potential risks such as nephrocalcinosis, hypercalciuria, and hyperparathyroidism. There are an estimated 500-1,000 patients with TIO in the United States, and approximately half of all cases are inoperable.
About Crysvita
Crysvita (burosumab-twza) is a recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Hakko Kirin, against the phosphaturic hormone FGF23. FGF23 is a hormone that reduces serum levels of phosphorus and active vitamin D by regulating phosphate excretion and active vitamin D production by the kidney. Phosphate wasting in TIO and other hypophosphatemic conditions, including XLH, is caused by excessive levels and activity of FGF23. Crysvita is designed to bind to and thereby inhibit the biological activity of FGF23. By blocking excess FGF23 in patients with TIO and XLH, Crysvita is intended to increase phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.
Kyowa Kirin and Ultragenyx have been collaborating in the development and commercialization of Crysvita globally based on the collaboration and license agreement between the parties.
Important Safety Information in X-Linked Hypophosphatemia
CONTRAINDICATIONS
Do not use CRYSVITA with oral phosphate and active vitamin D analogs.
Do not initiate CRYSVITA treatment if serum phosphorus is within or above the normal range for age.
CRYSVITA is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.
WARNINGS AND PRECAUTIONS
Hypersensitivity
Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with CRYSVITA. Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment.
Hyperphosphatemia and Risk of Nephrocalcinosis
Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.
Injection Site Reactions
Administration of CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment.
ADVERSE REACTIONS
Pediatric Patients
The most common adverse reactions (more than 10%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased, rash, toothache, myalgia, tooth abscess, and dizziness.
Adult Patients
The most common adverse reactions (more than 5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased.
Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression.
USE IN SPECIFIC POPULATIONS
There are no available data on CRYSVITA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657.
There is no information regarding the presence of CRYSVITA in human milk, or the effects of CRYSVITA on milk production or the breastfed infant. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRYSVITA and any potential adverse effects on the breastfed infant from CRYSVITA or from the underlying maternal condition.