Pharmacokinetics and Exposure–Response of Vosoritide in Children with Achondroplasia

Abstract

Background and Objective Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks). Methods Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. Results The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (C max ) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (C max and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. Conclusions The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed.

2021 FDA TIDES (Peptides and Oligonucleotides) Harvest

“…Vosoritide was designed to mimic CNP. Thus, it binds to natriuretic peptide receptor B (NPR-B), which subsequently stimulates intracellular cyclic guanosine monophosphate production (cGMP) and inhibits the effect of FGFR3, and promotes endochondral bone growth by stimulating chondrocyte proliferation and differentiation [20]. Interestingly, vosoritide is the first treatment of achondroplasia with a precise therapy, whereas the other treatments available focus on the management of symptoms [19].…”

The Roles of Fibroblast Growth Factor Receptor 3 (FGFR3) in the Spectrum of Skeletal Dysplasia

“…There is an increased incidence and prevalence of sporadic chondropathies especially Achondroplasia necessitating numerous clinical trials, among which is the use of C-type Natriuretic peptide analogues like Vosoritide in children with achondroplasia being explored [27][28][29].…”

A State of Natriuretic Peptide Deficiency

“…To this point, replacement therapy could be personal (meaning biomarker driven), as patients with decreased NPs may benefit from such a regimen, while patients with normal concentrations of NPs in circulation may not. Notably, current treatment options are confined to molecules with very low half-life as only synthetic versions of ANP and BNP are available for treatment of HF, whereas an analog of CNP with a half-life of ∼28 minutes is approved for treatment of children with achondroplasia ( 136 ). Development of highly selective analogs with improved pharmacokinetic profile would very likely provide basis for an optimized treatment approach that could effectively alleviate a state of NP deficiency and benefit a broad range of patients with cardiometabolic disease.…”