CLINICAL PHARMACOLOGY
Mechanism Of Action
X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which
suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin
D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate
reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.
Pharmacodynamics
Following SC administration in XLH patients, higher burosumab-twza concentrations were associated
with greater increase of serum phosphorus levels. The increase in serum phosphorus was reversible
and returned to baseline with elimination of systemic burosumab-twza.
Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate
(TmP/GFR) showed dose-dependent increases from baseline [see Clinical Studies].
Elevation in serum total FGF23 was observed after initiation of burosumab-twza treatment, however,
the clinical implication is unknown.
Pharmacokinetics
The following pharmacokinetic parameters were observed in patients with XLH administered the
approved recommended starting dosage based on a 70 kg patient, unless otherwise specified.
Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of
0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg
patient).
The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in
adult patients.
Absorption
The burosumab-twza mean Tmax values ranged from 8 to 11 days.
Distribution
The apparent volume of distribution of burosumab-twza is 8 L.
Elimination
The apparent clearance is 0.290 L/day. The half-life of burosumab-twza is approximately 19 days.
Metabolism
The exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is
expected to be degraded into small peptides and amino acids via catabolic pathways.
Specific Populations
No clinical significant difference in burosumab-twza pharmacokinetics was observed based on age.
The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknown.
Pediatric Patients
The steady-state trough concentration was 15.8 (± 9.4) mcg/mL in patients aged 5-12 years,
and 11.2 (± 4.6) mcg/mL in patients aged 1-4 years.
Body Weight
Clearance and volume of distribution of burosumab-twza increases with body weight.
Drug Interaction Studies
No drug interaction studies have been conducted with CRYSVITA.
Animal Toxicology And/Or Pharmacology
In rabbits and cynomolgus monkeys, inhibition of FGF23 signaling by burosumab-twza increased
serum phosphate and 1,25 dihydroxy vitamin D. Ectopic mineralization in multiple tissues and organs
was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels
in the non-XLH animals. In a study in wild type (WT) and hypophosphatemic Hyp mice, a murine
model of XLH, ectopic mineralization was markedly less in Hyp mice.
In adult cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or
mineral density and cortical thickness at 37- to 65-fold human exposure at the dose of 1 mg/kg every
4 weeks. Adverse effects on bone including reductions in bone mineral density, bone mineralization
and bone strength were observed in adult male monkeys at 37- to 47-fold human exposure at the
dose of 1 mg/kg every 4 weeks.
In juvenile cynomolgus monkeys, burosumab-twza increased bone turnover, mineral content and/or
mineral density and/or cortical thickness at 0.5- to 5-fold clinical pediatric exposure.
Bone mineralization was decreased in a male monkey at 5-fold pediatric exposure but there was no
effect on bone strength. Burosumab-twza did not affect bone development in juvenile monkeys at
doses up to 5-fold pediatric exposure.
Clinical Studies
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 (3.1) 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 (0.24) mg/dL at baseline
to 3.3 (0.43) mg/dL at Week 40 and to 3.3 (0.42) mg/dL at Week 64. In the active control group, mean
(SD) serum phosphorus concentrations increased from 2.3 (0.26) mg/dL at baseline to 2.5 (0.34) mg/dL at
Week 40 and to 2.5 (0.39) 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 (0.37) mg/dL at baseline
to 3.4 (0.67) mg/dL and 3.3 (0.65) mg/dL at Week 40 and Week 64, respectively. In the active control
group, mean (SD) TmP/GFR decreased from 2.0 (0.33) mg/dL at Baseline to 1.8 (0.35) mg/dL at Week
40, and remained below baseline at Week 64 at 1.9 (0.49) 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 (0.98) in the CRYSVITA group and 3.2 (1.14) in
the active control group. After 40 weeks of treatment with CRYSVITA, mean total RSS decreased
from 3.2 to 1.1 (0.72) and from 3.2 to 2.5 (1.09) in the active control group. LS mean (SE) RGI-C
Global score was +1.9 (0.11) in the CRYSVITA group and +0.8 (0.11) in the active control group at
Week 40 (see Table 7). 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 7.
Table 7: 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 (0.98) |
3.2 (1.14) |
LS Mean change from baseline in total scorea (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 Scoreb |
LS Mean scorea (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) |
a) 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.
b) RGI-C at Week 40 is the primary endpoint of Study 1 |
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 [SE]: +1.25 [0.17] versus +0.29 [0.12]; 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 (125) at
baseline to 337 (86) U/L in the CRYSVITA group (mean change: -33%) and from 523 (154) at
baseline to 495 (182) 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 (1.17) at baseline to -2.11 (1.11) at Week 64 (LS mean change (SE) of +0.17 (0.07)).
In the active control group, mean (SD) height Z score increased from -2.05 (0.87) at baseline
to -2.03 (0.83) at Week 64 (LS mean (SE) change of +0.02 (0.04)). 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 (2.4)
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 (14.4) 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 (0.40) at baseline to
3.3 (0.40) and 3.4 (0.45) 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 (0.49) at baseline to 3.3
(0.60) and 3.4 (0.53) mg/dL at Week 40 and Week 64.
In Study 3, 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.
Radiographic Evaluation Of Rickets
In Study 2, baseline mean (SD) RSS total score was 1.9 (1.17) 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 8). 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 8.
In Study 3, baseline mean (SD) total RSS was 2.9 (1.37) 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 (0.08) (see Table 8). All 13 patients achieved a RGI-C global score ≥ +2.0.
Table 8: 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 2a
(N=26) |
Study 3b
(N=13) |
RSS Total Score |
|
|
Baseline Mean (SD) |
1.9 (1.17) |
2.9 (1.37) |
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) |
|
a) 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.
b) 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. |
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 (0.14) at Week 40.
Serum Alkaline Phosphatase Activity
For Study 2, mean (SD) serum total alkaline phosphatase activity was 462 (110) U/L at baseline and
decreased to 354 (73) 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 (194) U/L at baseline and
decreased to 335 (88) 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 (1.03) at baseline to -1.54 (1.13) in the patients who received CRYSVITA every two weeks (LS
mean change of +0.19 (95% CI: 0.09 to 0.29).
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 (0.31) 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 (0.32) and 2.0 (0.30) mg/dL in the
placebo and CRYSVITA groups respectively. During the initial 24-week double-blind, placebocontrolled
period, mean (SD) serum phosphorus across the midpoints of dose intervals (2 weeks post
dose) was 2.1 (0.30) and 3.2 (0.53) mg/dL in the placebo and CRYSVITA groups, and mean (SD)
serum phosphorus across the ends of dose intervals was 2.0 (0.30) and 2.7 (0.45) 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 9).
Table 9: 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) |
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 |
|
< 0.0001 |
The 95% CIs are calculated using the Wilson score method.
a P-value is from Cochran-Mantel-Haenszel (CMH) testing for association between achieving the primary endpoint and treatment group, adjusting for randomization stratifications. |
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 4a,b
 |
a. Placebo subjects cross over to receive open-label CRYSVITA treatment at Week 24
b. 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 (0.37) and 1.68 (0.40) mg/dL in the placebo and
CRYSVITA groups respectively. At Week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was
1.69 (0.37) and 2.73 (0.75) mg/dL in the placebo and CRYSVITA groups. At Week 24 (end of a dose
interval), mean (SD) TmP/GFR was 1.73 (0.42) and 2.21 (0.48) 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 10. During the double-blind, placebocontrolled
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 10).
Table 10: 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 [active fractures (n = 8, 57%), active pseudofractures (n =
33, 65%)]. 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 patientreported
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% (12.4) at baseline to 11% (6.5), a change of -57%. Osteoid thickness (O.Th) declined in eleven
patients from a mean (SD) of 17 (4.1) micrometers to 12 (3.1) micrometers, a change of -33%.
Mineralization lag time (MLt) declined in 6 patients from a mean (SD) of 594 (675) days to 156 (77)
days, a mean change of -74%.