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.
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 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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