Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP Hoofddorp, The Netherlands, +31 (0) 237200822, medinfo@kyowakirin.com
Pharmacotherapeutic group: Drugs for the treatment of bone diseases, other drugs affecting bone structure and mineralisation
ATC code: M05BX05
Burosumab is a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23). By inhibiting FGF23, burosumab increases tubular reabsorption of phosphate from the kidney and increases serum concentration of 1,25 dihydroxy-Vitamin D.
In paediatric study CL301 61 patients aged 1 to 12 years (56% female; 44% male, Age at first dose, mean (SD): 6.3 (3.31) years) were randomised to burosumab (n=29) or active control (n=32; oral phosphate and active vitamin D). At entry to the study all patients had to have had a minimum of 6 months treatment of oral phosphate and active vitamin D. All patients had radiographic evidence of bone disease due to XLH (Rickets severity score ≥2). Burosumab was started at a dose of 0.8 mg/kg every 2 weeks and increased to 1.2 mg/kg if there was inadequate response, as measured by fasting serum phosphate. Those patients randomised to active control group received multiple daily doses of oral phosphate and active vitamin D.
The primary efficacy endpoint was the change in severity of rickets at Week 40, as assessed by the RGI-C (Radiographic Global Impression of change) score, compared between the burosumab and active control groups.
The RGI-C is a relative rating scale that compares a patient’s rickets before and after treatment utilising a 7-point ordinal scale to evaluate change in the same abnormalities rated in the RSS (as described below). Scores range from -3 (indicating severe worsening of rickets) to +3 (indicating complete healing of rickets).
The severity of paediatric rickets was measured using the RSS, a radiographic scoring method based on the degree of metaphyseal fraying, concavity, and the proportion of the growth plate affected. In the UX023-CL301 study, the RSS was scored using a predefined scale looking at specific abnormalities in the wrists and knees.
All patients completed at least 64 weeks of randomised treatment, no patients had dose reductions and 8 (28%) of burosumab-treated patients received dose escalations to 1.2 mg/kg.
Greater healing of rickets at Week 40 was seen with burosumab treatment compared to active control and this effect was maintained at week 64, as shown in Figure 1.
Figure 1. RGI-C Global Score (Mean ± SE) – Primary Efficacy Endpoint at Week 40 and 64 (Full Analysis Set):
Key Secondary efficacy endpoint results are presented in Table 2.
Table 2. Secondary Efficacy Endpoint Results:
| Endpoint | Week | Active Control LS Mean (SE) | Burosumab LS Mean (SE) | Difference (burosumab – active control) |
|---|---|---|---|---|
| Lower Limb Deformity; assessed by RGI-C (GEE model) | 40 | +0.22 (0.080) | +0.62 (0.153) | +0.40 [95% CI: 0.07, 0.72] p=0.0162 |
| 64 | +0.29 (0.119) | +1.25 (0.170) | +0.97 [95% CI: +0.57, +1.37] p<0.0001 | |
| Height; Z-score | Baseline | -2.05 (0.87) | -2.32 (1.17) | |
| 40a | +0.03 (0.031) | +0.16 (0.052) | +0.12 [95% CI: 0.01, 0.24] p=0.0408 | |
| 64b | +0.02 (0.035) | +0.17 (0.066) | +0.14 [95% CI: 0.00, 0.29] p=0.0490 | |
| Rickets severity, RSS total Score | Baseline | 3.19 (1.141) | 3.17 (0.975) | |
| 40a | -0.72 (0.162) | -2.08 (0.104) | -1.34 [95% CI -1.74, -0.94] p<0.0001 | |
| 64b | -1.01 (0.151) | -2.23 (0.117) | -1.21 [95% CI: -1.59, -0.83] p<0.0001 | |
| Serum ALP (U/L) | Baseline | 523 (154) | 511 (125) | |
| 40a | 489 (189) | 381 (99) | -97 [95% CI: -138, -56] p<0.0001 | |
| 64b | 495 (182) | 337 (86) | -147 [95% CI: -192, -102] p<0.0001 | |
| Six Minute Walk Test (m) | Έναρξη | 450 (106) | 385 (86) | |
| 40a | +4 (14) | +47 (16) | +43 [95% CI: -0,3, 87], p=0.0514 | |
| 64b | +29 (17) | +75 (13) | +46 [95% CI: 2, 89], p=0.0399 |
a the change from Baseline to Week 40 from ANCOVA model.
b the change from Baseline to Week 64 from GEE Model.
At each study visit at which serum phosphate was assessed in both groups, changes in serum phosphate from Baseline were larger in the burosumab group compared with the active control group (p<0.0001; GEE model) (Figure 2).
Figure 2. Serum Phosphate Concentration and Change from Baseline (mg/dL) (Mean ± SE) by Treatment Group (PD Analysis Set):
Note: Dashed line in figure indicates the lower limit of the serum phosphate reference range, 3.2 mg/dL (1.03 mmol/L)
In paediatric Study UX023-CL201, 52 paediatric patients aged 5 to 12 years (mean 8.5 years; SD 1.87) with XLH were treated for 64 weeks. Nearly all patients had radiographic evidence of rickets at baseline and had received prior oral phosphate and vitamin D analogues for a mean (SD) duration of 7 (2.4) years. This conventional therapy was discontinued 2-4 weeks prior to burosumab initiation. The burosumab dose was adjusted to target a fasting serum phosphate concentration of 3.50 to 5.02 mg/dL (1.13 to 1.62 mmol/L). Twenty six of 52 patients received burosumab every 4 weeks (Q4W). Twenty six of 52 patients received burosumab every two weeks (Q2W) at an average dose (min, max) of 0.73 (0.3, 1.5), 0.98 (0.4, 2.0) and 1.04 (0.4, 2.0) mg/kg at weeks 16, 40 and 60 respectively, and up to a maximum dose of 2.0 mg/kg.
Burosumab increased serum phosphate concentration and increased TmP/GFR. In the group that received burosumab every 2 weeks, mean (SD) serum phosphate concentration increased from 2.38 (0.405) mg/dL (0.77 (0.131) mmol/L) at baseline), to 3.3 (0.396) mg/dL (1.07 (0.128) mmol/L) at Week 40 and was maintained to Week 64 at 3.35 (0.445) mg/dL (1.08 (0.144) mmol/L).
Mean (SD) serum total alkaline phosphatase activity was 459 (105) U/L at baseline and decreased to 369 (76) U/L at Week 64 (-19.6%, p<0.0001).
Bone-derived serum alkaline phosphatase content was 165 (52) μg/L [mean (SD)] at Baseline and 115 (31) μg/L at Week 64 (mean change: -28.5%).
The severity of paediatric rickets in Study UX023-CL201 was measured using the RSS, as described above. In Study UX023-CL201, the RSS was scored using a predefined scale looking at specific abnormalities in the wrists and knees.As a complement to the RSS assessment, the RGI-C rating scale was used. Results are summarised in Table 3.
Table 3. Rickets Response in Children 5-12 years receiving Burosumab in Study UX023-CL201:
| Endpoint | Duration of Burosumab (week) | Effect Size | |
|---|---|---|---|
| Q2W (N=26) | Q4W (N=26) | ||
| RSS Total Score | |||
| Baseline Mean (SD) | 40 | 1.92 (1.2) -1.06 (0.1) (p<0.0001) | 1.67 (1.0) -0.73 (0.1) (p<0.0001) |
| LS Mean change (SE) from baseline in total scorea (reduced RSS score indicates improvement in rickets severity) | 64 | -1.00 (0.1) (p<0.0001) | -0.84 (0.1) (p<0.0001) |
| RGI-C Global Score | |||
| LS Mean score (SE)a (positive indicates healing) | 40 | +1.66 (0.1) (p<0.0001) | +1.47 (0.1) (p<0.0001) |
| 64 | +1.56 (0.1) (p<0.0001) | +1.58 (0.1) (p<0.0001) | |
a The estimates of LS means and p-values are from the generalized estimation equation model accounting for baseline RSS, visits and regimen and its interaction.
In paediatric Study UX023-CL205, burosumab was evaluated in 13 XLH patients, aged 1 to 4 years (mean 2.9 years; SD 1.1) for 40 weeks. All patients had radiographic evidence of rickets at baseline and twelve patients had received oral phosphate and vitamin D analogues for a mean (SD) duration of 16.7 (14.4) months. This conventional therapy was discontinued 2-6 weeks prior burosumab initiation. Patients received burosumab at a dose of 0.8 mg/kg every two weeks.
In Study UX023-CL205, mean (SD) fasting serum phosphate concentration increased from 2.51 (0.284) mg/dL (0.81 (0.092) mmol/L) at baseline to 3.47 (0.485) mg/dL (1.12 (0.158) mmol/L) at Week 40.
Mean (SD) serum total alkaline phosphatase activity was 549 (193.8) U/L at baseline and decreased to 335 (87.6) U/L at Week 40 (mean change: -36.3%).
After 40 weeks of treatment with burosumab, mean total RSS improved from 2.92 (1.367) at baseline to 1.19 (0.522), corresponding to a change from baseline in LS mean (SE) change of -1.73 (0.132) (p<0.0001).
After 40 weeks of treatment with burosumab, the LS mean (SE) RGI-C Global score was +2.33 (0.08) in all 13 patients (p<0.0001) demonstrating healing of rickets. All 13 patients were considered RGI-C responders as defined by RGI-C global score ≥+2.0.
The European Medicines Agency has deferred the obligation to submit the results of studies with CRYSVITA in one or more subsets of the paediatric population in treatment of X-linked hypophosphataemia. See 4.2 for information on paediatric use.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Burosumab absorption from subcutaneous injection sites to blood circulation is nearly complete. Following subcutaneous administration, the time to reach maximum serum concentrations (Tmax) of burosumab is approximately 5-10 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is dose proportional over the dose range of 0.1-2.0 mg/kg.
In XLH patients, the observed volume of distribution of burosumab approximates the volume of plasma, suggesting limited extravascular distribution.
Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Due to its molecular size, burosumab is not expected to be directly excreted. The clearance of burosumab is dependent on body weight and estimated to be 0.290 L/day and 0.136 L/day in a typical adult (70 kg) and paediatric (30 kg) XLH patient, respectively, with corresponding disposition half-life (t1/2) in the serum of approximately 19 days.
Burosumab displays time-invariant pharmacokinetics that is linear to dose over the subcutaneous dose range of 0.1 to 2.0 mg/kg.
With the subcutaneous route of administration, a direct PK-PD relationship between serum burosumab concentrations and increases in serum phosphate concentration is observed and well described by an Emax/EC50 model. Serum burosumab and phosphate concentrations, as well as TmP/GFR, increased and decreased in parallel and reached maximum levels at approximately the same time point after each dose, supporting a direct PK-PD relationship. The AUC for the change from baseline in serum phosphate, TmP/GFR and 1,25(OH)2D increased linearly with increasing burosumab AUC.
No significant difference has been observed in paediatric patient pharmacokinetics or pharmacodynamics as compared with PK/PD in the adult population. Burosumab clearance and volume of distribution are body weight dependent.
Adverse reactions in non-clinical studies with normal animals were observed at exposures which resulted in serum phosphate concentration greater than normal limits. These effects were consistent with an exaggerated response to the inhibition of normal FGF23 levels resulting in a supraphysiologic increase in serum phosphate beyond the upper limit of normal.
Studies in rabbits and adult and juvenile cynomolgus monkeys demonstrated dose-dependent elevations of serum phosphate and 1,25 (OH)2D confirming the pharmacologic actions of burosumab in these species. Ectopic mineralisation of multiple tissues and organs (e.g. kidney, heart, lung, and aorta), and associated secondary consequences (e.g. nephrocalcinosis) in some cases, due to hyperphosphataemia, was observed in normal animals at doses of burosumab that resulted in serum phosphate concentrations in animals greater than approximately 2.58 mmol/L. In a murine model of XLH, a significant reduction in the incidence of ectopic mineralisation was observed at equivalent levels of serum phosphate, suggesting that the risk of mineralisation is less in the presence of excess FGF23.
Bone effects seen in adult and juvenile monkeys included changes in bone metabolism markers, increases in thickness and density of cortical bone, increased density of total bone and thickening of long bone. These changes were a consequence of higher than normal serum phosphate levels, which accelerated bone turnover and also led to periosteal hyperostosis and a decrease in bone strength in adult animals, but not in juvenile animals at the doses tested. Burosumab did not promote abnormal bone development, as no changes in femur length or bone strength were noted in juvenile animals. Bone changes were consistent with the pharmacology of burosumab and the role of phosphate in bone mineralization, metabolism and turnover.
In repeat-dose toxicology studies of up to 40 weeks duration in cynomolgus monkeys, mineralisation of the rete testis/seminiferous tubules was observed in male monkeys; however, no changes were observed in semen analysis. No adverse effects on female reproductive organs were observed in these studies.
In the reproductive and developmental toxicology study performed in pregnant cynomolgus monkeys, moderate mineralisation of the placenta was seen in pregnant animals given 30 mg/kg of burosumab and occurred in animals with peak serum phosphate concentration greater than approximately 2.58 mmol/L. Shortening of the gestation period and associated increased incidence of premature births were observed in pregnant monkeys at doses of ≥0.3 mg/kg which corresponded to burosumab exposures that are ≥0.875- to 1.39-fold anticipated clinical levels. Burosumab was detected in serum from fetuses indicating that burosumab was transported across the placenta to the fetus. There was no evidence of teratogenic effects. Ectopic mineralisation was not observed in foetuses or offspring and burosumab did not affect pre- and postnatal growth including survivability of the offspring.
In preclinical studies, ectopic mineralisation has been observed in normal animals, most frequently in the kidney, given burosumab at doses that resulted in serum phosphate concentrations greater than 2.58 mmol/L (see section 5.3). Neither new or clinically meaningful worsening of nephrocalcinosis nor ectopic mineralisation have been observed in clinical trials of patients with XLH treated with burosumab to achieve normal serum phosphate levels.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
