CRYSVITA

1 INDICATIONS AND USAGE CRYSVITA is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for: The treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older. ( 1.1 ) The treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. ( 1.2 ) 1.1 X-linked Hypophosphatemia CRYSVITA is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older. 1.2 Tumor-induced Osteomalacia CRYSVITA is indicated for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Hyperphosphatemia and Risk of Nephrocalcinosis [see Warnings and Precautions (5.2) ] Hypercalcemia [see Warnings and Precautions (5.3) Injection Site Reactions [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥25% in the CRYSVITA group and > Active Control) in pediatric XLH patients are: pyrexia, injection site reaction, cough, vomiting, pain in extremity, headache, tooth abscess, dental caries. ( 6.1 ) Most common adverse reactions (>5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless legs syndrome, vitamin D decreased, dizziness, constipation, muscle spasms, blood phosphorus increased. ( 6.1 ) Most common adverse reactions (>10%) in TIO patients are: tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Pediatric Patients with XLH CRYSVITA was studied in three pediatric XLH studies. Study 1 is a randomized, open-label phase 3 study in XLH patients ages 1 to 12 years, who were randomized to treatment with CRYSVITA or treatment with active control of oral phosphate and active vitamin D (CRYSVITA N = 29, Active Control N = 32). Study 2 is an open-label phase 2 study in XLH patients ages 5 to 12 years (N = 52). Study 3 is an open-label phase 2 study in XLH patients ages 1 to less than 5 years (N = 13). Overall, the patient population was 1-12 years (mean age 7.0 years), 49% male, and 88% white. In Study 1, patients randomized to CRYSVITA received a mean dose of approximately 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks. All patients in this group and the active control group completed 64 weeks of treatment. Adverse reactions occurring in ≥ 10% of subjects in the CRYSVITA group, with higher frequency than in the subjects in the active control group, through the 64-week treatment period in Study 1 are shown in Table 6 . Table 6: Adverse Reactions Reported in 10% or More of CRYSVITA-Treated Pediatric Patients and with Higher Frequency Than the Active Control Group in Study 1 Adverse Reaction CRYSVITA (N=29) n (%) Active Control (N=32) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or active control Pyrexia 16 (55) 6 (19) Injection site reaction Injection site reaction includes: injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 15 (52) 0 (0) Cough Cough includes: cough and productive cough 15 (52) 6 (19) Vomiting 12 (41) 8 (25) Pain in extremity 11 (38) 10 (31) Headache 10 (34) 6 (19) Tooth abscess Tooth abscess includes: tooth abscess, tooth infection, toothache 10 (34) 4 (13) Dental caries 9 (31) 2 (6) Diarrhea 7 (24) 2 (6) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 7 (24) 1 (3) Constipation 5 (17) 0 (0) Rash Rash includes: rash, rash pruritic, rash maculopapular, rash erythematous, rash generalized and rash pustular 4 (14) 2 (6) Nausea 3 (10) 1 (3) In Study 2, 26 of the patients received CRYSVITA at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received CRYSVITA every 4 weeks. The mean duration of exposure in Study 2 was 124 weeks. In Study 3, patients received CRYSVITA at a mean dose of 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks at Week 40. The mean duration of exposure in Study 3 was 45 weeks. Adverse reactions occurring in more than 10% of CRYSVITA-treated patients from Studies 2 and 3 are shown in Table 7 . Table 7: Adverse Reactions Reported in More Than 10% of Pediatric Patients Receiving CRYSVITA in Studies 2 and 3 Adverse Reaction Study 2 (N=52) n (%) Study 3 (N=13) n (%) Overall (N=65) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA Headache 38 (73) 1 (8) 39 (60) Injection site reaction Injection site reaction includes: injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 35 (67) 3 (23) 38 (59) Vomiting 25 (48) 6 (46) 31 (48) Pyrexia 23 (44) 8 (62) 31 (48) Pain in extremity 24 (46) 3 (23) 27 (42) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 19 (37) 2 (15) 21 (32) Rash Rash includes: rash, rash pruritic, rash maculopapular, and rash pustular 14 (27) 1 (8) 15 (23) Toothache 12 (23) 2 (15) 14 (22) Myalgia 9 (17) 1 (8) 10 (15) Tooth abscess 8 (15) 3 (23) 11 (17) Dizziness Dizziness includes: dizziness, and dizziness exertional 8 (15) 0 (0) 8 (12) Hypersensitivity Reactions In Study 1 (N=29 for CRYSVITA arm), the most frequent hypersensitivity reactions were rash (10%), injection site rash (10%) and injection site urticaria (7%). In Studies 2 and 3 (N=65), the most frequent hypersensitivity reactions were rash (22%), injection site rash (6%), and urticaria (5%). Hyperphosphatemia In pediatric studies, no events of hyperphosphatemia were reported. Injection Site Reactions (ISR) In Study 1 (N=29 for CRYSVITA arm), 52% of the patients had a local injection site reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of CRYSVITA injection. In Studies 2 and 3 (N=65), approximately 58% of the patients had a local injection site reaction at the site of CRYSVITA injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. Adverse Reactions in Adult Patients with XLH The safety of CRYSVITA in adult patients with XLH was demonstrated in a randomized, double-blind, placebo-controlled study (Study 4) of 134 patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%). A total of 68 and 66 patients received at least one dose of CRYSVITA or placebo, respectively. The mean dose of CRYSVITA was 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks. Adverse reactions reported in more than 5% of CRYSVITA-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 4 are shown in Table 8 . Table 8: Adverse Reactions Occurring in More Than 5% of CRYSVITA-Treated Adult Patients and in at Least 2 Patients More Than with Placebo in the 24-Week Placebo-Controlled Period of Study 4 Adverse Reaction CRYSVITA (N=68) n (%) Placebo (N=66) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or placebo Back pain 10 (15) 6 (9) Headache Headache includes: headache, and head discomfort 9 (13) 6 (9) Tooth infection Tooth infection includes: tooth abscess, and tooth infection 9 (13) 6 (9) Restless legs syndrome 8 (12) 5 (8) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 8 (12) 3 (5) Dizziness 7 (10) 4 (6) Muscle spasms 5 (7) 2 (3) Constipation 6 (9) 0 (0) Blood phosphorus increased Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia 4 (6) 0 (0) The 24-week placebo controlled study was followed by a 24-week open-label treatment period in which all patients received CRYSVITA subcutaneously every 4 weeks. No new adverse reactions were identified in the open-label extension period. Hypersensitivity Reactions In the double-blind period of Study 4, approximately 6% of patients in both the CRYSVITA and placebo treatment groups experienced a hypersensitivity event. The events were mild or moderate and did not require discontinuation. Hyperphosphatemia In the double-blind period of Study 4, 7% of patients in the CRYSVITA treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL [the upper limit of normal] on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent. A single patient required a second dose reduction for continued hyperphosphatemia. Injection Site Reactions (ISR) In the double-blind period of Study 4, approximately 12% of patients in both the CRYSVITA and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. Restless Legs Syndrome (RLS) In the double-blind period of Study 4, approximately 12% of the CRYSVITA treatment group had worsening of baseline restless legs syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation. Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event. Spinal Stenosis Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. In the CRYSVITA phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 7 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression. Adverse Reactions in Patients with TIO The safety of CRYSVITA in patients with TIO was demonstrated in two single-arm clinical studies (Study 6 and Study 7) that enrolled a total of 27 patients. Fourteen patients were male, and patients ranged from 33 to 73 years of age. The mean dose of CRYSVITA was 0.77 mg/kg every 4 weeks and the mean duration of exposure was 121 weeks. Adverse reactions reported in adult TIO patients in the pooled data from Study 6 and Study 7 are shown in Table 9 . Table 9: Adverse Reactions Reported in Adult Patients with TIO Based on Study 6 and Study 7 (N=27) Adverse Reaction Overall (N=27) n (%) Tooth abscess Tooth abscess is defined by PTs "Tooth abscess" and "Tooth ache" 5 (19) Muscle spasms 5 (19) Dizziness 4 (15) Constipation 4 (15) Injection site reaction Injection Site Reactions is defined by PTs "Injection Site Reaction", "Injection Site Pain" and "Injection Site Swelling" 4 (15) Rash Rash is defined by PTs "Rash" and "Rash papular" 4 (15) Headache 3 (11) Vitamin D deficiency 2 (7) Hyperphosphatemia 2 (7) Restless legs syndrome 2 (7) Hypersensitivity reactions In the pooled data for Studies 6 and 7, 22% of patients experienced a hypersensitivity reaction. The most frequent hypersensitivity reactions were eczema (11%) and rash (11%). The events were mild or moderate in severity. Hyperphosphatemia In the pooled data for Studies 6 and 7, 2 patients (7%) experienced hyperphosphatemia which was managed with dose reduction. Injection site reactions The frequency of injection site reactions was 15% (injection site reaction, injection site pain, and injection site swelling). The injection site reactions were generally mild in severity, required no treatment and resolved in all cases. Restless Legs Syndrome In the pooled data for Studies 6 and 7, 2 patients (7%) experienced symptoms of restless legs syndrome, which were mild and did not require treatment interruption. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of CRYSVITA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and nutrition disorders: Hypercalcemia Skin and subcutaneous tissue disorders: Urticaria Investigations: Blood phosphorus increased in pediatric XLH patients, blood parathyroid hormone increased