Crysvita Drug Information
Generic name: BUROSUMAB
Uses of Crysvita
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.
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.
Dosage & Administration of Crysvita
| 10 – 14 | 10 |
|---|---|
| 15 – 18 | 10 |
| 19 – 31 | 20 |
| 32 – 43 | 30 |
| 44 – 56 | 40 |
| 57 – 68 | 50 |
| 69 – 80 | 60 |
| 81 – 93 | 70 |
| 94 – 105 | 80 |
| 106 and greater | 90 |
Side Effects of Crysvita
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 6 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 0 Cough Cough includes: cough and productive cough 15 6 Vomiting 12 8 Pain in extremity 11 10 Headache 10 6 Tooth abscess Tooth abscess includes: tooth abscess, tooth infection, toothache 10 4 Dental caries 9 2 Diarrhea 7 2 Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 7 1 Constipation 5 0 Rash Rash includes: rash, rash pruritic, rash maculopapular, rash erythematous, rash generalized and rash pustular 4 2 Nausea 3 1 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 1 39 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 3 38 Vomiting 25 6 31 Pyrexia 23 8 31 Pain in extremity 24 3 27 Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 19 2 21 Rash Rash includes: rash, rash pruritic, rash maculopapular, and rash pustular 14 1 15 Toothache 12 2 14 Myalgia 9 1 10 Tooth abscess 8 3 11 Dizziness Dizziness includes: dizziness, and dizziness exertional 8 0 8 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 6 Headache Headache includes: headache, and head discomfort 9 6 Tooth infection Tooth infection includes: tooth abscess, and tooth infection 9 6 Restless legs syndrome 8 5 Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 8 3 Dizziness 7 4 Muscle spasms 5 2 Constipation 6 0 Blood phosphorus increased Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia 4 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 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 Muscle spasms 5 Dizziness 4 Constipation 4 Injection site reaction Injection Site Reactions is defined by PTs "Injection Site Reaction", "Injection Site Pain" and "Injection Site Swelling" 4 Rash Rash is defined by PTs "Rash" and "Rash papular" 4 Headache 3 Vitamin D deficiency 2 Hyperphosphatemia 2 Restless legs syndrome 2 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.
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
Warnings & Cautions for Crysvita
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. Patients with tumor-induced osteomalacia who undergo treatment of the underlying tumor should have dosing interrupted and adjusted to prevent hyperphosphatemia .
Hypercalcemia Increases in serum calcium have been reported in patients treated with
CRYSVITA. Patients with risk factors such as, pre-existing hyperparathyroidism, prolonged immobilization, dehydration, hypervitaminosis D, or renal impairment, are at higher risk of hypercalcemia. Monitor these patients for serum calcium and parathyroid hormone levels before and during CRYSVITA treatment for moderate to severe hypercalcemia. In patients with moderate to severe hypercalcemia, CRYSVITA should not be administered until hypercalcemia is adequately managed.
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 .
Drug Interactions with Crysvita
Oral Phosphate and Active Vitamin D Analogs
Concomitant use of CRYSVITA with oral phosphate and/or active vitamin D analogs will increase phosphate concentrations greater than expected with CRYSVITA alone. This increase may result in hyperphosphatemia which can induce nephrocalcinosis. Concomitant use of CRYSVITA with oral phosphate and/or active vitamin D analogs is contraindicated.
Pregnancy Safety for Crysvita
Pregnancy Risk Summary There are no available data on CRYSVITA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to indicate clinical risk because they occurred at a drug exposure that was 15-fold higher, by AUC, than the human exposure at the maximum recommended human dose (MRHD) of 2 mg/kg every 2 weeks and were accompanied by maternal hyperphosphatemia and placental mineralization ( see Data ). Serum phosphorus levels should be monitored throughout pregnancy.
Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line at 1-844-768-3544. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In a reproductive toxicity study in pregnant cynomolgus monkeys, burosumab-twza was administered intravenously once every two weeks from Day 20 of pregnancy to parturition or cesarean section on Day 133, which includes the period of organogenesis, at doses of 0.2-, 2- and 15-fold human exposure at the adult MRHD of 2 mg/kg every 2 weeks.
The treatment did not result in teratogenic effects in fetuses or offspring. An increase in late fetal loss, a shortened gestation period, and an increased incidence of preterm births were observed at 15-fold human exposure at the adult MRHD of 2 mg/kg every 2 weeks, concomitant with maternal hyperphosphatemia and placental mineralization. Burosumab-twza was detected in serum from fetuses indicating transport across the placenta.
Hyperphosphatemia but no ectopic mineralization was present in fetuses and offspring of dams exposed to 15-fold human exposure at the MRHD of 2 mg/kg dose every 2 weeks. Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring.
Pediatric Use of Crysvita
Pediatric Use Safety and effectiveness of CRYSVITA have been established in pediatric patients 6 months and older. Safety and effectiveness in pediatric patients 1 year and older with XLH are based on one phase 3, open-label, active control study and two open-label studies evaluating serum phosphorus and radiographic findings. Safety and effectiveness in patients 6 months to 1 year and adolescents are supported by evidence from the studies in pediatric patients 1 year to less than 13 years of age with additional modeling and simulation of adult and pediatric pharmacokinetic (PK) and pharmacodynamic (PD) data to inform dosing . Safety and effectiveness for CRYSVITA in pediatric patients with XLH below the age of 6 months have not been established.
Safety and effectiveness of CRYSVITA in pediatric patients 2 years and older with TIO are supported by evidence from the studies in adult patients with TIO with additional modeling and simulation of PK data from adult and pediatric XLH patients and adult TIO patients to inform dosing. Safety and effectiveness for CRYSVITA in pediatric patients with TIO below the age of 2 years have not been established.
Contraindications for Crysvita
is contraindicated: In concomitant use with oral phosphate and/or active vitamin D analogs (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) due to the risk of hyperphosphatemia . When serum phosphorus is within or above the normal range for age . In patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism . With oral phosphate and/or active vitamin D analogs. When serum phosphorus is within or above the normal range for age. In patients with severe renal impairment or end stage renal disease.
Overdosage Information for Crysvita
There have been no reports of overdose with CRYSVITA. CRYSVITA has been administered in pediatric clinical trials without dose limiting toxicity using doses up to 2 mg/kg body weight with a maximal dose of 90 mg, administered every two weeks. In XLH adult clinical trials, no dose limiting toxicity has been observed using doses up to 1 mg/kg or a maximal total dose of 128 mg every 4 weeks. In non-XLH rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels.
Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were also observed at exposure greater than human exposure. In case of overdose, it is recommended that serum phosphorus levels, serum calcium levels and renal function be measured immediately and monitored periodically until resolution to normal/baseline levels. In case of hyperphosphatemia, withhold CRYSVITA and initiate appropriate medical treatment.
Clinical Studies of Crysvita
Pediatric X-linked Hypophosphatemia
CRYSVITA has been evaluated in three studies enrolling a total of 126 pediatric patients with XLH. Study 1 (NCT 02915705) is a 64-week randomized, open-label study in 61 pediatric XLH patients, 1 to 12 years old that compared treatment with CRYSVITA to active control (oral phosphate and active vitamin D). At time of first dose the mean age of patients was 6.3 years and 44% were male. All patients had radiographic evidence of rickets at baseline, with an RSS score of ≥ 2.0 and had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 4 years. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment for a 7-day washout period and then reinitiated for patients in the active control group.
Patients were randomized to receive either CRYSVITA at a starting dose of 0.8 mg/kg every two weeks or oral phosphate (recommended dose 20-60 mg/kg/day) and active vitamin D (recommended doses calcitriol 20-30 ng/kg/day or alfacalcidol 40-60 ng/kg/day). Patients randomized to active control received a mean oral phosphate dose of approximately 41 mg/kg/day (range 18 to 110 mg/kg/day) at Week 40 and approximately 46 mg/kg/day (range 18 mg/kg/day to 166 mg/kg/day) at Week 64. They also received either a mean oral calcitriol dose of 26 ng/kg/day at Week 40 and 27 ng/kg/day at Week 64 or a therapeutically equivalent amount of alfacalcidol. Eight patients in the CRYSVITA arm titrated up to 1.2 mg/kg based on serum phosphorus measurements. All patients completed at least 64 weeks on study.
Serum Phosphorus In Study 1, CRYSVITA increased mean (SD) serum phosphorus levels from 2.4 mg/dL at baseline to 3.3 mg/dL at Week 40 and to 3.3 mg/dL at Week 64. In the active control group, mean (SD) serum phosphorus concentrations increased from 2.3 mg/dL at baseline to 2.5 mg/dL at Week 40 and to 2.5 mg/dL at Week 64. The renal phosphate reabsorptive capacity as assessed by TmP/GFR increased in the CRYSVITA-treated patients from a mean (SD) of 2.2 mg/dL at baseline to 3.4 mg/dL and 3.3 mg/dL at Week 40 and Week 64, respectively. In the active control group, mean (SD) TmP/GFR decreased from 2.0 mg/dL at Baseline to 1.8 mg/dL at Week 40, and remained below baseline at Week 64 at 1.9 mg/dL. Figure 1: Serum Phosphorus Concentration and Change from Baseline (mg/dL) (Mean ± SD) by Treatment Group in Children 1-12 Years in Study 1 The dotted line represents the lower limit of normal (3.2 mg/dL) for patients in Study 1. Radiographic Evaluation of Rickets Radiographs were examined to assess XLH-related rickets using the 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C). The RSS score is assigned based on images of the wrist and knee from a single timepoint, with higher scores indicating greater rickets severity. The RGI-C score is assigned based on side-by-side comparisons of wrist and knee radiographs from two timepoints, with higher scores indicating greater improvement in radiographic evidence of rickets.
A RGI-C score of +2.0 was defined as radiographic evidence of substantial healing. In Study 1, baseline mean (SD) total RSS was 3.2 in the CRYSVITA group and 3.2 in the active control group. After 40 weeks of treatment with CRYSVITA, mean total RSS decreased from 3.2 to 1.1 and from 3.2 to 2.5 in the active control group.
LS mean (SE) RGI-C Global score was +1.9 in the CRYSVITA group and +0.8 in the active control group at Week 40 (see Table 10 ). At Week 40, 21 of the 29 patients in the CRYSVITA group and 2 of the 32 patients in the active control arm achieved a RGI-C global score ≥ +2.0. These findings were maintained at Week 64 as shown in Table 10. Table 10: Rickets Response in Children 1-12 Years Receiving CRYSVITA Every 2 Weeks in Study 1 Endpoint Timepoint CRYSVITA Every 2 Weeks (N=29) Active Control (N=32) RSS Total Score Baseline Mean (SD) 3.2
LS Mean change from baseline in total score
The estimates of LS mean and 95% CI for Week 40 are from an ANCOVA model accounting for treatment group, baseline RSS and baseline age stratification factor; the estimates for Week 64 are from a generalized estimating equation (GEE) model accounting for treatment group, visit, treatment by visit interaction, baseline RSS and baseline age stratification factor. (reduction indicates improvement) with 95% CI Week 40 -2.0 (-2.33, -1.75) -0.7 (-0.98, -0.43) Week 64 -2.2 (-2.46, -2.00) -1.0 (-1.31, -0.72) RGI-C Global Score RGI-C at Week 40 is the primary endpoint of Study 1 LS Mean score (positive indicates healing) with 95% CI Week 40 +1.9 (+1.70, +2.14) +0.8 (+0.56, +0.99) Week 64 +2.06 (+1.91, +2.20) +1.03 (+0.77, +1.30) Lower Extremity Skeletal Abnormality In Study 1, lower extremity skeletal abnormalities were assessed by RGI-C in standing long leg radiographs. At Week 64, the CRYSVITA group maintained greater improvement compared with the active control group (LS mean : +1.25 versus +0.29 ; difference of +0.97 (95% CI: +0.57, +1.37, GEE model)). Serum Alkaline Phosphatase Activity For Study 1, mean (SD) serum total alkaline phosphatase activity decreased from 511 at baseline to 337 U/L in the CRYSVITA group (mean change: -33%) and from 523 at baseline to 495 U/L in the active control group (mean change: -5%) at Week 64. Growth In Study 1, CRYSVITA treatment for 64 weeks increased standing mean (SD) height Z score from -2.32 at baseline to -2.11 at Week 64 (LS mean change (SE) of +0.17 ). In the active control group, mean (SD) height Z score increased from -2.05 at baseline to -2.03 at Week 64 (LS mean (SE) change of +0.02 ). The difference between the treatment groups at Week 64 was +0.14 (95% CI: 0.00, +0.29). Study 2 (NCT 02163577) is a randomized, open-label study in 52 prepubescent XLH patients, 5 to 12 years old, which compared treatment with CRYSVITA administered every 2 weeks versus every 4 weeks. Following an initial 16-week dose titration phase, patients completed 48-weeks of treatment with CRYSVITA every 2 weeks.
All 52 patients completed at least 64 weeks on study; no patient discontinued. Burosumab-twza dose was adjusted to target a fasting serum phosphorus concentration of 3.5 to 5.0 mg/dL based on the fasting phosphorus level the day of dosing. Twenty-six of 52 patients received CRYSVITA every two weeks up to a maximum dose of 2 mg/kg.
The average dose was 0.73 mg/kg (range: 0.3, 1.5) at Week 16, 0.98 mg/kg (range: 0.4, 2.0) at Week 40 and 1.04 mg/kg (range: 0.4, 2.0) at Week 60. The remaining 26 patients received CRYSVITA every four weeks. At study entry, the mean age of patients was 8.5 years and 46% were male. Ninety-six percent had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 7 years.
Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Ninety-four percent of patients had radiographic evidence of rickets at baseline. Study 3 (NCT 02750618) is a 64-week open-label study in 13 pediatric XLH patients, 1 to 4 years old.
Patients received CRYSVITA at a dose of 0.8 mg/kg every two weeks with 3 patients titrating up to 1.2 mg/kg based on serum phosphorus measurements. All patients completed at least 40 weeks on study; no patients discontinued. At study entry, the mean age of patients was 2.9 years and 69% were male.
All patients had radiographic evidence of rickets at baseline and 12 patients had received oral phosphate and active vitamin D analogs for a mean (SD) duration of 16.7 months. Oral phosphate and active vitamin D analogs were discontinued prior to study enrollment. Serum Phosphorus In Study 2, CRYSVITA increased mean (SD) serum phosphorus levels from 2.4 at baseline to 3.3 and 3.4 mg/dL at Week 40 and Week 64 in the patients who received CRYSVITA every 2 weeks.
The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean (SD) of 2.2 at baseline to 3.3 and 3.4 mg/dL at Week 40 and Week 64. In Study 3, CRYSVITA increased mean (SD) serum phosphorus levels from 2.5 mg/dL at baseline to 3.5 mg/dL at Week 40. Radiographic Evaluation of Rickets In Study 2, baseline mean (SD) RSS total score was 1.9 in patients receiving CRYSVITA every two weeks. After 40 weeks of treatment with CRYSVITA, mean total RSS decreased from 1.9 to 0.8 (see Table 11 ). After 40 weeks of treatment with CRYSVITA, the mean RGI-C Global score was +1.7 in patients receiving CRYSVITA every two weeks. Eighteen out of 26 patients achieved an RGI-C score of ≥ +2.0. These findings were maintained at Week 64 as shown in Table 11. In Study 3, baseline mean (SD) total RSS was 2.9 in 13 patients.
After 40 weeks of treatment with CRYSVITA, mean total RSS decreased from 2.9 to 1.2 and the mean (SE) RGI-C Global score was +2.3 (see Table 11 ). All 13 patients achieved a RGI-C global score ≥ +2.0. Table 11: Rickets Response in Children 1-12 Years Receiving CRYSVITA Every 2 Weeks in Study 2 and Study 3 Endpoint Timepoint CRYSVITA Every 2 Weeks Study 2 The estimates of LS mean and 95% CI are from a generalized estimating equation (GEE) model accounting for regimen, visit, regimen by visit interaction, baseline RSS for study 2. (N=26) Study 3 The estimates of LS mean and 95% CI for Week 40 are from an ANCOVA model accounting for age and baseline RSS for study 3. (N=13) RSS Total Score Baseline Mean (SD) 1.9
LS Mean change from baseline in total score (reduction indicates improvement) with
95% CI Week 40 -1.1 (-1.28, -0.85) -1.7 (-2.03, -1.44) Week 64 -1.0 (-1.2, -0.79) RGI-C Global Score LS Mean score (positive indicates healing) with 95% CI Week 40 +1.7 (+1.48, +1.84) +2.3 (+2.16, +2.51) Week 64 +1.6 (+1.34, +1.78) Lower Extremity Skeletal Abnormality In Study 3, the mean (SE) change in lower limb deformity as assessed by RGI-C, using standing long leg radiographs, was +1.3 at Week 40. Serum Alkaline Phosphatase Activity For Study 2, mean (SD) serum total alkaline phosphatase activity was 462 U/L at baseline and decreased to 354 U/L at Week 64 (-23%) in the patients who received CRYSVITA every 2 weeks. For Study 3, mean (SD) serum total alkaline phosphatase activity was 549 U/L at baseline and decreased to 335 U/L at Week 40 (mean change: -36%). Growth In Study 2, CRYSVITA treatment for 64 weeks increased standing mean (SD) height Z score from -1.72 at baseline to -1.54 in the patients who received CRYSVITA every two weeks (LS mean change of +0.19 (95% CI: 0.09 to 0.29). Figure 1
Adult X-linked Hypophosphatemia Study 4 (NCT 02526160) is a randomized, double-blind, placebo-controlled
study in 134 adult XLH patients. The study comprises a 24-week placebo-controlled treatment phase followed by a 24-week open-label treatment period in which all patients received CRYSVITA. CRYSVITA was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% were male.
All patients had skeletal pain associated with XLH/osteomalacia at baseline. The baseline mean (SD) serum phosphorus concentration was below the lower limit of normal at 1.98 mg/dL. Oral phosphate and active vitamin D analogs were not allowed during the study. Out of the 134 patients enrolled in the study, one patient in the CRYSVITA group discontinued treatment during the 24-week placebo-controlled treatment period, and 7 patients discontinued CRYSVITA during the open-label treatment period.
Study 5 (NCT 02537431) is a 48-week, open-label, single-arm study in 14 adult XLH patients to assess the effects of CRYSVITA on improvement of osteomalacia as determined by histologic and histomorphometric evaluation of iliac crest bone biopsies. Patients received 1 mg/kg CRYSVITA every four weeks. At study entry, the mean age of patients was 40 years (range 25 to 52 years) and 43% were male.
Oral phosphate and active vitamin D analogs were not allowed during the study. Serum Phosphorus In Study 4 at baseline, mean (SD) serum phosphorus was 1.9 and 2.0 mg/dL in the placebo and CRYSVITA groups respectively. During the initial 24-week double-blind, placebo-controlled period, mean (SD) serum phosphorus across the midpoints of dose intervals (2 weeks post dose) was 2.1 and 3.2 mg/dL in the placebo and CRYSVITA groups, and mean (SD) serum phosphorus across the ends of dose intervals was 2.0 and 2.7 mg/dL in the placebo and CRYSVITA groups.
A total of 94% of patients treated with CRYSVITA achieved a serum phosphorus level above the lower limit of normal (LLN) compared to 8% in the placebo group through Week 24 (see Table 12 ). Table 12: Proportion of Adult Patients Achieving Mean Serum Phosphorus Levels Above the LLN at the Midpoint of the Dose Interval During the 24-Week Placebo-Controlled Period of Study 4 Placebo (N = 66) CRYSVITA (N = 68) The 95% CIs are calculated using the Wilson score method. Achieved Mean Serum Phosphorus > LLN Across Midpoints of Dose Intervals Through Week 24 - n (%) 5 (8%) 64 (94%) 95% CI p-value P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratifications. < 0.0001 During the open-label treatment period, serum phosphorus was maintained during continued CRYSVITA therapy, with no evidence of loss of effect through Week 48. Figure 2: Mean (± SD) Serum Phosphorus Peak Concentrations (mg/dL) in Study 4 Placebo subjects cross over to receive open-label CRYSVITA treatment at Week 24, The dotted lines represent the upper limit of normal (4.5 mg/dL) and lower limit of normal (2.5 mg/dL) for patients in Study 4 At baseline, the mean (SD) ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 1.60 and 1.68 mg/dL in the placebo and CRYSVITA groups respectively. At Week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 1.69 and 2.73 mg/dL in the placebo and CRYSVITA groups.
At Week 24 (end of a dose interval), mean (SD) TmP/GFR was 1.73 and 2.21 mg/dL in the placebo and CRYSVITA groups. During the open-label treatment period, TmP/GFR remained stable during continued CRYSVITA therapy through Week 48. Radiographic Evaluation of Osteomalacia In Study 4, a skeletal survey was conducted at baseline to identify osteomalacia-related fractures and pseudofractures. Osteomalacia-related fractures are defined as atraumatic lucencies extending across both bone cortices and pseudofractures are defined as atraumatic lucencies extending across one cortex.
There were 52% of patients who had either active (unhealed) fractures (12%) or active pseudofractures (47%) at baseline. The active fractures and pseudofractures were predominantly located in the femurs, tibia/fibula, and metatarsals of the feet. Assessment of these active fracture/pseudofracture sites at Week 24 demonstrated a higher rate of complete healing in the CRYSVITA group compared to placebo as shown in Table 13. During the double-blind, placebo-controlled treatment period through Week 24, a total of 6 new fractures or pseudofractures appeared in 68 patients receiving CRYSVITA, compared to 8 new abnormalities in 66 patients receiving placebo (see Table 13 ). Table 13: Comparison of Fracture Healing with CRYSVITA vs Placebo in Study 4 Double Blind Period Active Fractures Active Pseudofractures Total Fractures Placebo n (%) CRYSVITA n (%) Placebo n (%) CRYSVITA n (%) Placebo n (%) CRYSVITA n (%) No. of fractures at baseline 13 14 78 51 91 65 Healed at Week 24 0 (0%) 7 (50%) 7 (9%) 21 (41%) 7 (8%) 28 (43%) During the open-label treatment period, the patients who continued receiving CRYSVITA showed continued healing of fractures at Week 48. In the 'placebo to CRYSVITA' group, fracture healing at Week 48 was observed for active fractures (n = 6, 46%), and active pseudofractures (n = 26, 33%). Patient Reported Outcomes Study 4 evaluated patient-reported XLH-related symptoms (pain, joint stiffness, and physical function). At 24 weeks, the CRYSVITA arm showed a mean improvement from baseline (-7.9) compared to the placebo arm (+0.3) in the stiffness severity score (range 0 to 100; lower scores are reflective of symptom improvement). At 24 weeks, no significant difference between CRYSVITA and placebo was demonstrated in patient-reported pain intensity or physical function score.
Bone Histomorphometry In Study 5, after 48 weeks of treatment, healing of osteomalacia was observed in ten patients as demonstrated by decreases in Osteoid volume/Bone volume (OV/BV) from a mean (SD) score of 26% at baseline to 11%, a change of -57%. Osteoid thickness (O.Th) declined in eleven patients from a mean (SD) of 17 micrometers to 12 micrometers, a change of -33%. Mineralization lag time (MLt) declined in 6 patients from a mean (SD) of 594 days to 156 days, a mean change of -74%. Figure 2
Tumor-induced Osteomalacia
CRYSVITA has been evaluated in two studies enrolling a total of 27 patients with TIO. Study 6 (NCT 02304367) is a single-arm open-label study that enrolled 14 adult patients with a confirmed diagnosis of FGF23-related hypophosphatemia produced by an underlying tumor that was not amenable to surgical excision or could not be located. Of the 14 TIO patients enrolled in Study 6, eight were male, and patients ranged from 33 years to 68 years of age (Median 59.5 years). Oral phosphate and active vitamin D analogs were discontinued two weeks prior to study enrollment. Patients received CRYSVITA every 4 weeks at a weight based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. The mean dose was 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. Study 7 (NCT 02722798) is a single-arm open-label study.
In Study 7, 13 adult patients with a confirmed diagnosis of TIO received CRYSVITA. Of the 13 TIO patients who received treatment in Study 7, six were male, and patients ranged from 41 years to 73 years of age (Median 58.0 years). Oral phosphate and active vitamin D analogs were discontinued two weeks prior to study enrollment. Patients received CRYSVITA every 4 weeks at a weight based starting dose of 0.3 mg/kg that was titrated to achieve a fasting serum phosphorus level of 2.5 to 4.0 mg/dL. The mean (SD) dose was 0.91 mg/kg at Week 48, and 0.96 mg/kg at Week 88. Serum Phosphorus In Study 6, CRYSVITA increased mean (SD) serum phosphorus levels from 1.60 mg/dL at baseline to 2.64 mg/dL averaged across the midpoint of dose intervals through Week 24 with 50% of patients (7/14) achieving a mean serum phosphorus level above the LLN averaged across the midpoint of dose intervals through Week 24. Increase in the mean serum phosphorus concentrations was sustained near or above the LLN through Week 144 (Figure 3). The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from a mean (SD) of 1.12 mg/dL at baseline to 2.12 mg/dL at Week 48, and remained stable through Week 144. Figure 3: Serum Phosphorus Concentration and Change from Baseline in Study 6 (mg/dL) The dotted line represents the lower limit of normal (2.5 mg/dL) for patients in study 6. In Study 7, CRYSVITA increased mean (SD) serum phosphorus levels from 1.62 mg/dL at baseline to 2.63 mg/dL averaged across the midpoint of dose intervals through Week 24 with 69% of patients (9/13) achieving a mean serum phosphorus level above the LLN averaged across the midpoint on dose interval through Week 24. Mean serum phosphorus concentrations were sustained above LLN through Week 88. The renal phosphate reabsorptive capacity, as assessed by TmP/GFR, increased from a mean (SD) of 1.15 mg/dL at baseline to 2.30 mg/dL mg/dL at Week 48. Bone Histomorphometry In Study 6, osteomalacia was present at baseline in nine out of 11 patients with paired bone biopsies, and healing was assessed after 48 weeks of treatment. In these 9 patients with osteomalacia at baseline, OV/BV decreased from a mean (SD) score of 21.2% at baseline to 13.9%, a change of -34%. O.Th declined from a mean (SD) of 18.9 micrometers to 12.1 micrometers, a change of -36%. MLt declined in 3 patients from a mean (SD) of 667 days to 331 days, a change of -50%. In Study 7, osteomalacia was present at baseline in all 3 patients with paired bone biopsies, and healing was assessed after 48 weeks of treatment.
In these 3 patients, OV/BV decreased from a mean (SD) score of 14.0% at baseline to 9.2%, a change of -34%. O.Th declined from a mean (SD) of 16.0 micrometers to 13.5 micrometers, a change of -16%. Radiographic Evaluation of Osteomalacia In Study 6, 99m technetium-labelled whole body bone scans were performed at baseline and subsequent timepoints during the study on all 14 patients. Bone scans allow for assessment of sites of increased tracer uptake in a wide range of bone conditions, including osteomalacia. In patients with TIO, increased tracer uptake on bone scan is presumed to be nontraumatic fractures and pseudofractures.
At baseline, all patients had areas of tracer uptake with a total of 249 bone abnormalities across 14 patients. The number of areas of tracer uptake decreased from Week 48 through Week 144, suggesting healing of the bone abnormalities. Figure 3
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
Ready to save on Crysvita?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Crysvita Prices