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Drug Trials Snapshots: CRYSVITA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the CRYSVITA Package Insert for complete information.

CRYSVITA (burosamab-twza)
Kris-VEE-tuh
Ultragenyx Pharmaceutical
Approval date: April 17, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

CRYSVITA is a drug for the treatment of a genetic form of rickets called X-linked hypophosphatemia, in patients 1 year of age and older.

X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by low levels of phosphate in the blood which causes soft, weak bones (rickets).

How is this drug used?

CRYSVITA is an injection given under the skin by a healthcare provider. The dose is based on body weight. In pediatric patients, CRYSVITA is given every 2 weeks. In adults, CRYSVITA is given every 4 weeks.

What are the benefits of this drug?

In children with X-linked hypophosphatemia, treatment with CRYSVITA increased phosphate levels in the blood and improved bone abnormalities of rickets at the knee and wrist. In adults, CRYSVITA increased the phosphate levels in the blood.

What are the benefits of this drug (results of trials used to assess efficacy)?

CRYSVITA efficacy was assessed using the radiographic Thacher Rickets Severity Scale (RSS) endpoints and mean serum phosphorus levels. The RSS evaluates the metaphyseal and growth plate abnormalities of rickets at the knee and wrist. A total RSS score is assigned from 0 (no rickets) to 10 (worst possible). Results are presented using efficacy or ITT (Intent to Treat) population.

Table 2. Rickets Response in Children 1-12 Years Receiving CRYSVITA Every 2 Weeks in Trials 1 and 2

Endpoint
Timepoint
CRYSVITA Every 2 Weeks
Trial 1
 (5-12 years old)
(N=26)
Trial 2
(1-4 years old)
(N=13)
Rickets Severity Scale (RSS) Total Score
Baseline Mean (SD)1.9 (1.17)2.9 (1.37)
LS Mean change from baseline in total scorea (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) 

a The estimates of LS means and 95% CI (confidence interval) are from the generalized estimation equation model accounting for baseline RSS, visits and regimen and its interaction for Trial 1 and from ANCOVA model accounting for age and baseline RSS for Trial 2.

In Trial 1, CRYSVITA increased mean serum (SD) phosphorus levels from 2.4 (0.40) at baseline to 3.3 (0.40) and 3.4 (0.45) mg/dL at week 40 and week 64.

In Trial 2 CRYSVITA increased mean (SD) serum phosphorus levels from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at week 40.

Table 3 below summarizes efficacy results for Trial 3. Efficacy was assessed on the mean serum phosphorus level endpoint. Results are presented using efficacy or ITT (Intent to Treat) population.

Table 3. Proportion of Adult Patients Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN) at the Midpoint of the Dose Interval in Trial 3

 Placebo
(N = 66)
CRYSVITA
(N = 68)
Achieved Mean Serum Phosphorus > LLN Across Midpoints of Dose Intervals Through Week 24 - n (%)5 (8%)64 (94%)
95% CI(3.3, 16.5)(85.8, 97.7)
p-valuea <>

The 95% CIs are calculated using the Wilson score method.
aP-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratifications.

CRYSVITA Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: CRYSVITA worked similarly in males and females.
  • Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in response among races could not be determined.
  • Age: CRYSVITA worked similarly in patients younger and older than 50 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 4 below summarizes the results for the primary efficacy endpoint, RSS, by sex and age in pediatric patients.

Table 4. RSS Total Score, Change from Baseline By Sex and Age Group (Trial 1)

VisitSubgroupQ2W
(N=26)
Sex
  Baseline nMean (SD)
Male121.67 (0.89)
Female142.14 (1.37)
  Week 40 nLS Mean Change (SE)
(95% CI)
Male12-0.70 (0.17)
(-1.03, -0.37)
Female14-1.37 (0.13)
(-1.63, -1.11)
Week 64Male12-0.45 (0.10)
(-0.65, -0.25)
Female14-1.48 (0.12)
-(1.72, -1.24)
Age Group
Baseline 


5 to <9>

9 to 12 years
nMean (SD)

10

16

1.40 (1.02)

2.25 (1.17)
Week 405 to <9 years="">

9 to 12 years
10

16
-0.93 (0.16)
(-1.24, -0.62)
-1.09 (0.15)
(-1.38, -0.80)
Week 645 to <9 years="">

9 to 12 years
10

16
-0.78 (0.15)
(-1.08, -0.49)
-1.09 (0.15)
(-1.38, -0.80)

LS mean and 95% CI for change from baseline per GEE model, which included visit, regimen, visit by regimen as factors, and RSS total score at baseline as a covariate, with exchangeable covariance structure

Adapted from FDA Review

Table 5 below summarizes the results for the primary efficacy endpoint, mean serum phosphorus, by sex, age, and race in adult patients.

Table 5. Proportion of Adult Patients Who Achieved a Mean Serum Phosphorus > LLN Across Midpoints of dose Intervals Through Week 24 by Subgroups (Trial 3)

Achieved Mean Serum Phosphorus > LLNPlacebo
(N =66)
n/N1 (%) [CI]
CRYSVITA
(N = 68)
n/N1 (%) [CI]
Sex
Male1/23 (4.3) [0.8, 21.0]22/24 (91.7) [74.2, 97.7]
Female4/43 (9.3) [3.7, 21.6]42/44 (95.5) [84.9, 98.7]
Race
White5/53 (9.4) [4.1, 20.3]53/55 (96.4) [87.7, 99.0]
All Others0/13 (0.0) [0, 22.8]11/13 (84.6) [57.8, 95.7]
Age Group
50 years3/54 (5.6) [1.2, 15.4]49/52 (94.2) [84.6, 98.8]
> 50 years2/12 (16.7) [2.1, 48.4]15/16 (93.8) [69.8, 99.8]

N1 is the number of subjects in the subgroup; n is the number of subjects, who Achieved Mean Serum Phosphorus > LLN Across Midpoints of Dose Intervals Through week 24

Adapted from FDA Review

What are the possible side effects?

CRYSVITA may cause serious side effects including allergic reactions and injection site reactions.

The most common side effects of CRYSVITA in children are headache, injection site reaction, vomiting, fever, pain in extremity, and decreased vitamin D.

The most common side effects of CRYSVITA in adults are back pain, headache, tooth infection, restless leg syndrome, decreased vitamin D, dizziness, constipation, and increased blood phosphorus.

What are the possible side effects (results of trials used to assess safety)?

The tables below summarize adverse reactions, in pediatric (Trials 1 and 2) and adult patients (Trial 3) with X-linked hypophosphatemia, who received at least one dose of CRYSVITA.

Table 6. Adverse Reactions Reported in More Than 10% of Pediatric Patients Receiving CRYSVITA in Trials 1 and 2

Adverse ReactionTrial 1 (N=52)
n (%)
Trial 2 (N=13)
n (%)
Overall (N=65)
n (%)
Headache38 (73)1 (8)39 (60)
Injection site reaction1 reaction reaction1 reaction135 (67)3 (23)38 (59)
Vomiting25 (48)6 (46)31 (48)
Pyrexia23 (44)8 (62)31 (48)
Pain in extremity24 (46)3 (23)27 (42)
Vitamin D decreased219 (37)2 (15)21 (32)
Rash314 (27)1 (8)15 (23)
Toothache12 (23)2 (15)14 (22)
Myalgia9 (17)1 (8)10 (15)
Tooth abscess8 (15)3 (23)11 (17)
Dizziness48 (15)0 (0)8 (12)

n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA
1 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 urticarial
2 Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased
3 Rash includes: rash, rash pruritic, rash maculo-papular, and rash pustular
4 Dizziness includes: dizziness, and dizziness exertional

CRYSVITA Prescribing Information

Table 7. Adverse Reactions Occurring in more than 5% of CRYSVITA-Treated Adult Patients and in at Least 2 Patients More Than with Placebo in Trial 3

Adverse ReactionCRYSVITA
(N=68)
n (%)
Placebo
(N=66)
n (%)
Back pain10 (15)6 (9)
Headache19 (13)6 (9)
Tooth infection29 (13)6 (9)
Restless legs syndrome8 (12)5 (8)
Vitamin D decreased38 (12)3 (5)
Dizziness7 (10)4 (6)
Constipation6 (9)0 (0)
Blood phosphorus increased44 (6)0 (0)

n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or placebo
1 Headache includes: headache, and head discomfort
2 Tooth infection includes: tooth abscess, and tooth infection
3 Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased
4 Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia

CRYSVITA Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The risk of side effects was similar in males and females.
  • Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in side effects among races could not be determined.
  • Age: The risk of side effects was similar in patients above and below 50 years of age

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The tables below summarize the most common adverse reactions by sex, race and age that occurred in the trials.

Table 8. Safety Analysis of Adverse Reactions in CRYSVITA Treated Pediatric Patients by Sex and Race (Trials 1 and 2)

Adverse ReactionSexRace
Male
N=33
Female
N=32
White
N=58
Non-White*
N=7
Injection site reaction, n (%)21 (64)16 (50)34 (59)3 (43)
Vomiting, n (%)15(45)16 (50)24 (41)7 (100)
Headache, n (%)20 (61)19 (59)33 (57)6 (86)
Pyrexia, n (%)17 (52)14 (44)28 (48)3 (43)

Clinical Trial Data

Table 9. Safety Analysis of Adverse Reactions in CRYSVITA and Placebo Treated Adult Patients by Sex, Race and Age (Trial 3)

Adverse ReactionCRYSVITAPlacebo
Sex
 Male
n/N (%)
 Female
n/N (%)
 Male
n/N (%)
Female
n/N (%)
Back Pain4/24 (17)6/44 (14)3/23 (13)3/43 (7)
Headache3/24 (13)6/44 (14)1/23 (4)5/43 (12)
Tooth Infection2/24 (8)7/44 (16)2/23 (9)4/43 (9)
Race
 White
n/N (%)
Non-White*
n/N (%)
White
n/N (%)
Non-White*
n/N (%)
Back Pain6/55 (11)4/13 (31)4/53 (8)2/13 (15)
Headache8/55 (15)1/13 (8)5/53 (9)1/13 (8)
Tooth Infection9/55 (16)05/53 (9)1/13 (8)
Age Group
 50 years
n/N (%)
>50 years
n/N (%)
50 years
n/N (%)
>50 years
n/N (%)
Back Pain8/52 (15)2/16 (13)4/54 (7)2/12 (17)
Headache5/52 (10)4/16 (25)4/54 (7)1/12 (8)
Tooth Infection7/52 (13)2/16 (13)6/54 (11)0

*All other races combined because of predominant White patients’ participation

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved CRYSVITA based primarily on evidence from 3 clinical trials of 199 patients with X-linked hypophosphatemia.

Trial 1 (NCT02163577) was conducted in children at 9 sites in the following countries: France, Netherlands, United Kingdom, and the United States.

Trial 2 (NCT02750618) was conducted in children at 3 sites in the United States.

Trial 3 (NCT02526160) was conducted in adults at 25 sites in Europe, Japan, South Korea, and the United States.

Figure 1 summarizes how many males and females were enrolled in the clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many males and females were in the clinical trials. In total, 80 males (40%) and 119 (60%) females participated in the clinical trials.

FDA Review

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trials. In total, 166 White (83%), 6 Black or African American (3%), 21 Asian (11%), and 6 Other patients (3%) participated in the clinical trial.

FDA Review

Table 1. Demographics of Trials by Race

RaceNumber of PatientsPercentage
White16683%
Black or African American63%
Asian2111%
Other63%

FDA Review

Figure 3 summarizes the percentage of patients by age group enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie charts summarizing how many individuals of certain age groups were enrolled in the clinical trials. In total, 65 patients (33%) were less than 18 years old, 106 patients (53%) were 18 - 50 years old, and 28 patients (14%) were greater than 50 years old.

FDA Review

Who participated in the trials?

The table below summarizes patients who participated in the combined 3 trials.

Table 10. Baseline Demographics (Trials 1, 2, and 3)

 Trial 1
N=52
Trial 2
N=13
Trial 3
N=134
Total
N=199
Sex – n(%)
Male24 (46)9 (69)47 (35)80 (40)
Female28 (54)4 (31)87 (65)119 (60)
Race – n(%)
White46 (88)12 (92)108 (81)166 (83)
Black or African American2 (4)1 (8)3 (2)6 (3)
Asian0021 (16)21 (11)
Other4 (8)02 (1)6 (3)
Age (years)
Mean (SD)8.5 (1.9)2.9 (1.2)40.0 (12.2)17.1 (5.1)
Age Group– n(%)
Age <>52 (100)13 (100)065 (33)
Age > 18 to 5000106 (79)106 (53)
Age > 50  28 (21)28 (14)
Ethnicity – n (%)
Hispanic2 (4)2 (15)12 (9)16 (8)
Non-Hispanic50 (96)11 (85)122 (91)61 (92)
Country – n (%)
U.S.36 (69)13 (100)69 (52)118 (59)
U.K.10 (19)011 (8)21 (11)
Netherlands4 (8)004 (2)
France2 (4)030 (22)32 (16)
Europe006 (5)6 (3)
Japan0011 (8)11 (6)
South Korea007 (5)7 (4)

Adapted from FDA Review

How were the trials designed?

The benefit and side effects of CRYSVITA were evaluated in three clinical trials of patients with X-linked hypophosphatemia. Each trial was designed differently.

Trial 1: Children aged 5 – 12 years were randomly assigned to receive various doses of CRYSVITA every 2 weeks or every 4 weeks for 64 weeks. Dose adjustments were made to maintain a target range of serum phosphorus. Patients were evaluated for improvement of rickets using Rickets Severity Score (RSS) where 0 means no rickets and 10 means worst possible rickets. The grade on the scale was assigned by looking at the bone abnormalities of the knee and wrist on an X-ray image.

Trial 2: Children aged 1 – 4 years received CRYSVITA every 2 weeks for 40 weeks. Dose adjustments were made to maintain a target range of serum phosphorus. Patients were evaluated for improvement of rickets using Rickets Severity Score (RSS) and serum phosphate (phosphate levels in the blood).

Trial 3: Adult patients were randomly assigned to receive CRYSVITA or placebo every 4 weeks for 24 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. Patients were evaluated for improvement in serum phosphorus (phosphate levels in the blood) at week 24.

How were the trials designed?

The efficacy and safety of CRYSVITA were evaluated in three clinical trials.

Trial 1 evaluated CRYSVITA, in children (5 to 12 years of age), with X-linked hypophosphatemia. This trial was a randomized, open-label trial. Treatment with CRYSVITA administered every 2 weeks was compared to administration every 4 weeks, with dose adjustments to achieve a target range of serum phosphorus. After a 16-week dose titration phase, patients continued their assigned treatment until week 64. The efficacy was assessed using 10-point Thacher Rickets Severity Score (RSS), the primary endpoint. The RSS score is assigned based on images of the wrist and knee from a single time point, with higher scores indicating greater rickets severity.

Trial 2 evaluated CRYSVITA in children (1 to 4 years of age) with X-linked hypophosphatemia. This trial was an open-label trial. Treatment with CRYSVITA was administered every 2 weeks with dose adjustments made to maintain a target range of serum phosphorus. Patients continued their assigned treatment until week 40. The primary efficacy endpoint was the change from baseline over time in serum phosphorus level.

Trial 3 evaluated adults with X-linked hypophosphatemia. This trial was a randomized, double-blind, placebo-controlled trial. An initial 24-week placebo-controlled treatment phase was followed by a 24-week open-label phase. During the open-label phase, patients initially randomized to placebo switched to open-label CRYSVITA. All patients continued treatment through week 48. The primary efficacy endpoint was mean serum phosphorus level at the midpoints of the 4-week dosing intervals (i.e. 2 weeks post-dose) between baseline and week 24.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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