CLINICAL SAFETY
CRYSVITA® (burosumab-twza) safety was studied in 65 pediatric patients with XLH treated over 40 weeks
Adverse reactions
CRYSVITA was evaluated in 3 clinical studies of pediatric patients with XLH.
Study 1 was a Phase 3 randomized, open-label study in children aged 1 to 12 years in which patients (N=61) received CRYSVITA or conventional therapy for at least 64 weeks.
| Adverse Reactions Reported in 10% or More of CRYSVITA-treated Pediatric Patients and With Higher Frequency Than Conventional Therapy–treated Patients in Study 1 | |||
|---|---|---|---|
| Adverse Reaction |
CRYSVITA (N=29) n (%) |
Conventional Therapy (N=32) n (%) |
|
| Pyrexia | 16 (55) | 6 (19) | |
| Injection site reactiona | 15 (52) | 0 (0) | |
| Coughb | 15 (52) | 6 (19) | |
| Vomiting | 12 (41) | 8 (25) | |
| Pain in extremity | 11 (38) | 10 (31) | |
| Headache | 10 (34) | 6 (19) | |
| Tooth abscessc | 10 (34) | 4 (13) | |
| Dental caries | 9 (31) | 2 (6) | |
| Diarrhea | 7 (24) | 2 (6) | |
| Vitamin D decreasedd | 7 (24) | 1 (3) | |
| Constipation | 5 (17) | 0 (0) | |
| Rasha | 4 (14) | 2 (6) | |
| Nausea | 3 (10) | 1 (3) | |
FOOTNOTES
n, number of patients with an event; N, total number of patients who received at least 1 dose of CRYSVITA or conventional therapy.
aInjection 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.
bCough includes: cough and productive cough.
cTooth abscess includes: tooth abscess, tooth infection, and toothache.
dVitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased.
eRash includes: rash, rash pruritic, rash maculopapular, rash erythematous, rash generalized, and rash pustular.
Study 2 was a Phase 2 open-label study in children aged 5 to 12 years in which patients (N=52) received CRYSVITA for at least 64 weeks. Study 3 was a Phase 2 open-label study in children aged 1 to 4 years in which patients (N=13) received CRYSVITA for at least 40 weeks.1
| 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) (%) |
| Headache | 38 (73) | 1 (8) | 39 (60) |
| Injection site reactiona | 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 decreasedb | 19 (37) | 2 (15) | 21 (32) |
| Rashc | 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) |
| Dizzinessd | 8 (15) | 0 (0) | 8 (12) |
FOOTNOTES
n, number of patients with an event; N, total number of patients who received at least one dose of CRYSVITA.
aInjection 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.bVitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased.
cRash includes: rash, rash pruritic, rash maculopapular, and rash pustular.
dDizziness includes: dizziness, and dizziness exertional.
Hypersen–
sitivity 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%).1
Hyperphos–
phatemia
In pediatric studies, there were no events of hyperphosphatemia reported.1
Injection site reaction (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 (e.g., injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) 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.1
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to CRYSVITA in the studies described in this website with the incidence of antibodies in other studies or to other products may be misleading.
In XLH clinical studies, none (0/13) of the 1- to 4-year-old patients, 19% (10/52) of the 5- to 12-year-old patients, and 15% (20/131) of the adult patients tested positive for anti-drug antibodies (ADA) after receiving CRYSVITA. Among these, three 5- to 12-year-old patients tested positive for neutralizing antibodies. The presence of ADA was not associated with clinically relevant changes in pharmacokinetics, pharmacodynamics, efficacy, and safety of burosumab in patients with XLH.
Reference
-
CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.
CLINICAL SAFETY
CRYSVITA® (burosumab-twza) safety was studied in 134 adults with XLH treated over 24 weeks
Adverse reactions
CRYSVITA was evaluated in a randomized, double-blind, placebo-controlled Phase 3 study in adults with XLH. Patients were randomized to receive CRYSVITA (N=68) or placebo (N=66) for 24 weeks, followed by a 24-week open-label period during which all patients continued on CRYSVITA.1
| Adverse Reactions Reported in >5% of CRYSVITA-treated Adult Patients and in at Least 2 Patients More Than With Placebo in the 24-week Placebo-controlled Phase 3 Study | |||
|---|---|---|---|
| Adverse Reaction |
CRYSVITA (N=68) n (%) |
Placebo (N=66) n (%) |
|
| Back pain | 10 (15) | 6 (9) | |
| Headachea | 9 (13) | 6 (9) | |
| Tooth infectionb | 9 (13) | 6 (9) | |
| Restless leg syndrome | 8 (12) | 5 (8) | |
| Vitamin D decreasedc | 8 (12) | 3 (5) | |
| Dizziness | 7 (10) | 4 (6) | |
| Muscle spasms | 5 (7) | 2 (3) | |
| Constipation | 6 (9) | 0 (0) | |
| Blood phosphorus increasedd | 4 (6) | 0 (0) | |
FOOTNOTES
n, number of patients with an event; N, total number of patients who received at least 1 dose of CRYSVITA or placebo.
aHeadache includes: headache and head discomfort.
bTooth infection includes: tooth abscess and tooth infection.
cVitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased.
dBlood phosphorus increased includes: blood phosphorus increased and hyperphosphatemia.
Hypersen-
sitivity 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.1
Hyperphos-
phatemia
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 2 occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced by 50%. One patient required a second dose reduction for continued hyperphosphatemia.1
Injection site reaction (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.1
Restless leg syndrome (RLS)
In the double-blind period of Study 4, approximately 12% of the CRYSVITA treatment group had worsening of baseline 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 1 case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event.1
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 (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.1
No new adverse reactions were identified in the open-label extension period.
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to CRYSVITA in the studies described in this website with the incidence of antibodies in other studies or to other products may be misleading.
In XLH clinical studies, none (0/13) of the 1- to 4-year-old patients, 19% (10/52) of the 5- to 12-year-old patients, and 15% (20/131) of the adult patients tested positive for anti-drug antibodies (ADA) after receiving CRYSVITA. Among these, three 5- to 12-year-old patients tested positive for neutralizing antibodies. The presence of ADA was not associated with clinically relevant changes in pharmacokinetics, pharmacodynamics, efficacy, and safety of burosumab in patients with XLH.
Reference
-
CRYSVITA (burosumab-twza) US Prescribing Information; June 2020.
