Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, P43 R298, Ireland
Pharmacotherapeutic group: Drugs for treatment of bone diseases, Other drugs affecting bone structure and mineralisation
ATC code: M05BX07
Vosoritide is a modified type C natriuretic peptide (CNP). In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 (FGFR3). Binding of vosoritide to natriuretic peptide receptor-B (NPR-B) antagonises FGFR3 downstream signalling by inhibiting the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) pathway at the level of rapidly accelerating fibrosarcoma serine/threonine protein kinase (RAF-1). As a result, vosoritide, like CNP, acts as a positive regulator of endochondral bone growth as it promotes chondrocyte proliferation and differentiation.
Exposure-dependent (AUC and Cmax) increases from baseline in urinary cyclic guanosine monophosphate (cGMP, a biomarker for NPR-B activity) concentrations and serum collagen type X marker (CXM, a biomarker for endochondral ossification) were observed on treatment with vosoritide. Increase in the urinary cGMP concentrations from pre-dose baseline took place within the first four hours post-dose. Median serum CXM concentration increased over baseline by day 29 of daily administration of this medicinal product. This effect was maintained beyond 24 months of treatment. Vosoritide activity as measured by urine cGMP was near saturation while maximal increase in growth plate activity indicated by CXM was achieved at the dose of 15 μg/kg administered subcutaneously once daily.
The efficacy and safety of vosoritide in patients with achondroplasia with confirmed FGFR3 mutation were assessed in a randomised, double-blind, placebo-controlled 52-week study (ACH study 111-301). In ACH study 111-301, patients were randomised to either vosoritide (n=60) or placebo (n=61) and the dose of vosoritide was 15 μg/kg administered subcutaneously once daily. Prior to randomisation, all patients enrolled in an observational study (ACH study 111-901) for paediatric patients with achondroplasia for at least a 6-month period during which baseline standing height and other pre-treatment growth assessments were collected. Patients with limb-lengthening surgery in the prior 18 months or who planned to have limb-lengthening surgery during the study period were excluded.
The study comprised a 52-week placebo-controlled treatment phase followed by an open-label treatment extension study in which all patients received vosoritide. The primary efficacy endpoint was the change from baseline in AGV at Week 52 compared with placebo.
Patients with achondroplasia were also treated with vosoritide 15 μg/kg/day in an open label, doseescalation study and in its long-term extension study (ACH study 111-205). Data was collected from observational studies in patients to characterise the natural history of achondroplasia. Height data from untreated patients with achondroplasia in the same age range as the clinical studies was used as an historical control to assess the effect on height after up to 5 years of vosoritide treatment.
Patient demographics and baseline characteristics are shown in Table 3.
Table 3. Patient demographics and characteristics in ACH study 111-301 and ACH study 111-205:
| Parameter | ACH study 111-301 | ACH study 111-205b | |
|---|---|---|---|
| Placebo (N=61) | 15 μg/kg/day Voxzogo (N=60) | 15 μg/kg/day Voxzogo (N=10) | |
| Age at day 1 (years) | |||
| Mean (SD) | 9.06 (2.47) | 8.35 (2.43) | 8.54 (1.54) |
| Min, max | 5.1; 14.9 | 5.1; 13.1 | 6.3; 11.1 |
| Age at day 1, n (%)a | |||
| ≥5 to <8 years | 24 (39.3) | 31 (51.7) | 4 (40.0) |
| ≥8 to <11 years | 24 (39.3) | 17 (28.3) | 5 (50.0) |
| ≥11 to <15 years | 13 (21.3) | 12 (20.0) | 1 (10.0) |
| Tanner stage b, n (%)a | |||
| I | 48 (78.7) | 48 (80.0) | 10 (100.0) |
| > I | 13 (21.3) | 12 (20.0) | |
| Sex, n (%)a | |||
| Male | 33 (54.1) | 31 (51.7) | 4 (40.0) |
| Female | 28 (45.9) | 29 (48.3) | 6 (60.0) |
| Weight (kg) | |||
| Mean (SD) | 24.62 (9.07) | 22.88 (7.96) | 25.13 (5.74) |
| Min, max | 11.6; 68.9 | 13.6; 53.0 | 18.2; 36.4 |
max, maximum; min, minimum; SD, standard deviation.
a Percentages were calculated using the total number of patients in the full analysis set (N for each treatment group) as the denominator.
b Analysis from 10 out of 35 patients who only received 15 mcg/kg/day in an open label, dose-escalation study and continued into the long-term extension ACH study 111-205.
In ACH study 111-301, improvements in AGV and height Z-score from baseline were observed in patients treated with Voxzogo 15 µg/kg/day compared with placebo. Efficacy results are shown in Table 4.
Table 4. Results from placebo-controlled clinical trial:
| Placebo (N=61) | Voxzogo 15 µg/kg daily (N=60c) | Voxzogo vs. placebo | |||||
|---|---|---|---|---|---|---|---|
| Baseline | Week 52 | Change | Baseline | Week 52 | Change | LS Mean difference in changes (95% CI) | |
| Annualised growth velocity (cm/year) | |||||||
| Mean ± SD | 4.06 ± 1.20 | 3.94 ± 1.07 | -0.12 ± 1.74 | 4.26 ± 1.53 | 5.61 ± 1.05 | 1.35 ± 1.71 | 1.57a (1.22; 1.93) (p = <0.0001)b |
| Height Z-score | |||||||
| Mean ± SD | -5.14 ± 1.07 | -5.14 ± 1.09 | 0.00 ± 0.28 | -5.13 ± 1.11 | -4.89 ± 1.09 | 0.24 ± 0.32 | 0.28a (0.17; 0.39) (p = <0.0001)b |
AGV, annualised growth velocity; 95% CI, 95% confidence interval; LS, least-square; SD, standard deviation.
a Difference is 15 µg/kg Voxzogo minus placebo.
b Two-sided p-value. c Two patients in the Voxzogo group discontinued from the study before Week 52. The values for these 2 patients were imputed for this analysis.
LS mean estimated from the ANCOVA (analysis of covariance) model adjusted for baseline differences between the two arms, analysis of covariance.
The benefit of improvement in AGV in favour of Voxzogo was consistent across all predefined subgroups analysed including sex, age group, Tanner stage, baseline height Z-score, and baseline AGV. In the subgroup of males Tanner stage > I, the point estimate of treatment effect was in favour of vosoritide however there were only 8 subjects in this subgroup (3 and 5 subjects in vosoritide and placebo arms, respectively).
The observed increase in growth occurred proportionally in both the spine and the lower limbs. There was no difference in bone mineral density after treatment with Voxzogo compared to placebo. During treatment with this medicinal product, the mean increase in bone age was comparable to the mean increase in chronological age, indicating no acceleration of bone maturation.
Figure 1 shows the effect of Voxzogo over the two-year period in the Voxzogo treatment group, as well as the effect in the placebo control group after receiving daily subcutaneous injections of Voxzogo for 52 weeks in the open label extension study. Improvements in AGV were maintained during continued Voxzogo therapy, with no evidence of tachyphylaxis.
Figure 1. Mean (±SD) 12-Month Interval AGV Over Time:
The figure includes all subjects enrolled in the pivotal trial who had a height assessment at week 52 in the extension study. Solid lines represent treatment with vosoritide 15 ug/kg; dashed lines represent placebo. Baseline is defined as the last assessment before the first dose of active study drug (i.e. vosoritide) or Placebo in 111-301. 12-Month AGV at post-baseline visits is derived over the previous 12 months. For example, 12-Month Interval AGV at Week 52 111-302 = [(Height at Week 52 111-302 Visit- Height at Week 52 111-301 Visit)/(Date of Week 52 111-302 Visit – Date of Week 52 111-301 Visit)] x 365.25.
In the long-term extension study (ACH study 111-205), 10 patients were treated with Voxzogo 15 µg/kg/day dose continuously for up to 5 years. The mean (SD) improvement in AGV compared to baseline at 60 months was 1.34 (1.31) cm/year.
The gain in height after 5 years of treatment with 15 µg/kg/day of Voxzogo was compared with an age and sex matched historical control. The 5-year cross-sectional comparative analysis adjusted for baseline height differences, demonstrated, there was a statistically significant mean (95% CI) difference in height in favour of Voxzogo (9.08 [5.77, 12.38] cm; p=0.0002) compared with untreated patients with achondroplasia.
Use in the age group 2 to <5 is supported by evidence from studies in children aged 5 to 18 and children aged less than 5 years of age. The safety and efficacy profiles were similar between children aged 5 years and above and children aged 2 to <5 years. An ongoing study (ACH study 111-206) is assessing the safety and efficacy of vosoritide in patients aged between 0 to <5 years and has enrolled 62 patients by a 30 June 2020 data cut-off. Interim data from ACH study 111-206 showed a positive effect on growth in 4 patients aged ≥2 to <5 years treated with vosoritide 15 µg/kg/day for 2 years. No data are available for children under the age of 2 years.
The European Medicines Agency has deferred the obligation to submit the results of studies with Voxzogo in one or more subsets of the paediatric population in achondroplasia (see section 4.2 for information on paediatric use).
Vosoritide is a modified recombinant human CNP. The 39 amino acid peptide analogue includes the 37 C terminal amino acids of the human CNP53 sequence plus the addition of 2 amino acids (Pro Gly) to convey resistant to neutral endopeptidase (NEP) degradation, resulting in prolonged half-life in comparison to endogenous CNP.
The pharmacokinetics of vosoritide were evaluated in a total of 58 patients aged 5 to 18 years with achondroplasia who received subcutaneous injections of vosoritide 15 µg/kg once daily for 52 weeks. The pharmacokinetics of vosoritide in 18 patients aged 2 to <5 years old were comparable with older children.
Vosoritide was absorbed with a median Tmax of 15 minutes. The mean (± SD) peak concentration (Cmax) and area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) observed after 52 weeks of treatment was 5 800 (±3 680), and 290 000 (± 235 000) pgmin/mL respectively. The bioavailability of vosoritide was not assessed in clinical studies.
The mean (± SD) apparent volume of distribution after 52 weeks of treatment was 2 910 (± 1 660) mL/kg.
The metabolism of vosoritide is expected to occur via catabolic pathways and be degraded into small peptide fragments and amino acids.
The mean (± SD) apparent clearance after 52 weeks of treatment was 79.4 (53.0) mL/min/kg. The mean (± SD) half-life was 27.9 (9.9) minutes.
The inter-subject variability (coefficient of variation) in apparent clearance was 33.6 %.
The increase in plasma exposure (AUC and Cmax) with dose was greater than dose proportional across the dose range of 2.5 (0.17 times the recommended dose) to 30.0 μg/kg/day (twice the approved dose).
No clinically significant differences in the vosoritide pharmacokinetics was observed based on age (0.9 to 16 years), sex, race or ethnicity.
Body weight is the only significant covariate for vosoritide clearance or volume of distribution. The apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (9 to 74.5 kg). The proposed posology (see section 4.2) takes account of this deviation and recommends the use of doses above (in patients between 10 and 16 kg body weight), or below (in those above a body weight of 44 kg) the 15 µg/kg “standard dose” in order to enable a similar level of exposure across all weight-ranges.
The safety and efficacy of vosoritide in patients with renal or hepatic impairment has not been evaluated. Based on the elimination mechanism, renal or hepatic impairment is not expected to alter the pharmacokinetics of vosoritide.
In vitro cytochrome P450 (CYP) inhibition and induction studies indicated that vosoritide did not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, nor induce CYP 1A2, 2B6, or 3A4/5 at clinically relevant concentrations. In vitro interaction studies also indicated that the potential for interaction with the drug-transporters OAT1, OAT3, OCT 1, OCT 2, OATP1B1, OATP1B3, MATE 1, KATE2-K, BCRP, P-gp, and BSEP is low at clinically relevant concentrations.
Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels, and with possible relevance to clinical use.
Transient decreases in blood pressure and increases in heart rate were observed in healthy monkeys across multiple studies in doses of 28 to 300 μg/kg in a dose-related manner. Peak effects were typically observed within the first hour post dose and were generally asymptomatic. In some monkeys receiving higher doses of vosoritide, brief bouts of sternal/lateral recumbency or hypoactivity, were observed. These effects could be related to decreased blood pressure.
Adverse effects on body posture, bone shape, mobility, and bone strength were observed in normal animals in repeat-dose toxicity studies in rats and monkeys. In monkeys, the NOAEL for vosoritide is 25 μg/kg (mean Cmax value of 1 170 pg/mL; approximately equivalent to the recommended human dose in a 20 kg human) when administered daily via subcutaneous injection for 44 weeks.
Carcinogenicity and genotoxicity studies have not been performed with vosoritide. Based on the mechanism of action, vosoritide is not expected to be tumorigenic.
In a fertility and reproductive study in male and female rats at dose levels up to 540 μg/kg/day, vosoritide had no effect on mating performance, fertility, or litter characteristics.
Vosoritide was not associated with effects on reproductive performance, in utero or developmental parameters measured in rats and rabbits to investigate fertility, or embryo-foetal development in preand post-natal development studies.
Vosoritide was detected in the breast milk in rats.
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