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 (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax 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.

Clinical trials registration: NCT02055157, NCT03197766, and NCT01603095.

Conflict of interest statement

Ming Liang Chan, Yulan Qi, Kevin Larimore, Anu Cherukuri, Lori Seid, Kala Jayaram, Elena Fisheleva, Jonathan Day, Alice Huntsman Labed and Joshua Henshaw are employees of BioMarin Pharmaceutical Inc. Ravi Savarirayan and Klaus Mohnike have received consulting fees and grants from BioMarin. Melita Irving has received consulting fees from BioMarin. Carlos A. Bacino has received consulting fees, honoraria and grants from BioMarin. Julie Hoover-Fong has received consulting fees from BioMarin, Therachon and Ascendis, and grants from BioMarin. Keiichi Ozono has received consulting fees and honoraria from BioMarin. William R. Wilcox was a consultant to BioMarin and received an honoraria, and was the principal investigator for the clinical trial contract with Emory University. William A. Horton is an inventor on a patent application “Type X collagen assay and methods of use thereof”, submitted by Shriners Hospitals for Children. He has consulted for and/or received speaker honoraria from BioMarin, TherAchon (Pfizer), Ascendis, QED, Relay Therapeutics, Fortress Biotech, OPKO, and Medicell Technologies.

© 2021. The Author(s).

Figures

Fig. 1

Mean (+SD) concentration-time profiles of vosoritide in plasma observed in the phases II and III studies. a Mean (+SD) concentration-time profiles of vosoritide in plasma observed on day 1 in the phase II study, color-coded by study cohort and dose (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). Each line represents the mean plasma vosoritide concentration across patients receiving 2.5, 7.5, 15.0 or 30.0 µg/kg vosoritide on day 1. Error bars represent the standard deviation of the mean, and only the upper error bars are shown. b Mean (+SD) concentration-time profiles of vosoritide in plasma observed at 15 µg/kg in the phase III study, color-coded by visits. Each line represents the mean plasma vosoritide concentration across patients for each visit. Error bars represent the standard deviation of the mean, and only the upper error bars are shown. The LLOQ for the PK assays used in the phases II and III studies were 391 pg/mL and 137 pg/mL in neat plasma, respectively. SD standard error, LLOQ lower limit of quantitation, PK pharmacokinetic

Fig. 2

Distribution of individual mean vosoritide AUC0-∞ in plasma by serum TAb status (negative or positive) in the phase III study. The line inside the box represents the median and the box represents the limits of the middle half of the data. The range of the box, from the first quartile (Q1) to the third quartile (Q3), defines the IQR. The standard span of the data is defined within the range from Q1 − 1.5 × IQR to Q3+1.5 × IQR. Whiskers are drawn to the nearest value not beyond the range of the standard span; points beyond are drawn as individual open circles. Distribution of the individual mean vosoritide Cmax is similar and is shown in Fig. S4 of the ESM. AUC0-∞ area under the plasma concentration-time curve from time zero to infinity, TAb total anti-vosoritide antibody, IQR interquartile range, Cmax maximum observed plasma concentration, ESM electronic supplementary material

Fig. 3

Change in annualized growth velocity from baseline by individual mean AUC in the phase II and III studies. a Points represent the individual change in annualized growth velocity from baseline to day 183 of the phase II study and individual mean vosoritide AUC0-t, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high individual mean AUC0-t (4.28 × 106 pg-min/mL) relative to other patients, but a within-range change in annualized growth velocity (3.56 cm/year). This patient was included in the fit through the data, but was not included in this figure. b Points represent the individual change in annualized growth velocity from baseline to month 24 of the phase II study and individual mean vosoritide AUC0-60min, color-coded by study cohort (C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). c Points represent the individual change in annualized growth velocity from baseline from the phase III study and individual mean vosoritide AUC0-60min. Solid lines represent the fits through the data and the shaded regions represent the 95% confidence intervals. The respective analyses using the individual mean vosoritide Cmax are similar and are shown in Fig. S5 in the ESM. AUC area under the plasma concentration-time curve, AUC0-t AUC from time zero to the time of the last measurable concentration, AUC0-60min area under the plasma concentration-time curve from time zero to 60 min postdose, Cmax maximum observed plasma concentration, ESM electronic supplementary material

Fig. 4

Change in mean CXM by individual mean AUC in the phase II and III studies. (a) Points represent the individual mean CXM from day 10 to day 183 of the phase II study and individual mean vosoritide AUC0-t, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high individual mean AUC0-t (4.28 × 106 pg-min/mL) relative to other patients, but a within-range mean CXM (12,200 pg/mL). This patient was included in the fit through the data but was not included in this figure. b Points represent the individual mean CXM from day 10 to month 24 of the phase II study and individual mean vosoritide AUC0-60min, color-coded by study cohort (C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). c Points represent the individual mean CXM from week 13 to week 52 in the phase III study and individual mean vosoritide AUC0-60min. Solid lines represent the fits through the data and the shaded regions represent the 95% confidence intervals. The respective analyses using the individual mean vosoritide Cmax are similar and are shown in Fig. S6 in the ESM. AUC0-t area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, AUC0-60min area under the plasma concentration-time curve from time zero to 60 min postdose, CXM collagen type X marker, Cmax maximum observed plasma concentration, ESM electronic supplementary material

Fig. 5

Distribution of the change from predose to maximum postdose urine cGMP/Cr levels observed in the phase III study. The line inside the box represents the median and the box represents the limits of the middle half of the data. The range of the box, from the first quartile (Q1) to the third quartile (Q3), defines the IQR. The standard span of the data is defined within the range from Q1 − 1.5 × IQR to Q3 + 1.5 × IQR. Whiskers are drawn to the nearest value not beyond the range of the standard span; points beyond are drawn as individual open circles. cGMP cyclic guanosine monophosphate, cGMP/Cr cGMP normalized to creatinine, IQR interquartile range

Fig. 6

Distribution of the change in CXM from baseline from week 13 to week 52 of the phase III study. The line inside the box represents the median and the box represents the limits of the middle half of the data. The range of the box, from the first quartile (Q1) to the third quartile (Q3), defines the IQR. The standard span of the data is defined within the range from Q1 − 1.5 × IQR to Q3 + 1.5 × IQR. Whiskers are drawn to the nearest value not beyond the range of the standard span; points beyond are drawn as individual open circles. CXM collagen type X marker, IQR interquartile range

Fig. 7

Visit-matched maximum increase in urine cGMP/Cr by individual AUC in the phase II and III studies. a Points represent the individual patient urine cGMP/Cr data and individual plasma vosoritide AUC0-t at each visit during the initial 6 months of the phase II study, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high AUC0-t (1.63 × 107 pg-min/mL) relative to other patients, but a within-range maximum change from pre-dose cGMP/Cr (8190 pmol/mg Cr). This patient was included in the fit through the data but was not included in this figure. b Points represent the individual patient urine cGMP/Cr data and individual plasma vosoritide AUC0-60min at each visit during the phase III study. Solid lines represent Emax model fits through the data and the shaded regions represent the 95% confidence intervals. The respective analyses using the individual plasma vosoritide Cmax are similar and are shown in Fig. S7 in the ESM. cGMP cyclic guanosine monophosphate, cGMP/Cr cGMP normalized to creatinine, AUC0-t area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, AUC0-60min area under the plasma concentration-time curve from time zero to 60 min postdose, Emax maximum possible effect, ESM electronic supplementary material

Fig. 8

Visit-matched vosoritide Cmax in plasma and maximum increase in heart rate in the phase II and III studies. a Points represent the individual patient maximum increase in HR and individual plasma vosoritide Cmax at each visit during the initial 6 months of the phase II study, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high Cmax (8.39 × 105 pg/mL) relative to other patients, but a within-range maximum increase in HR (39 bpm). This patient was included in the fit through the data but was not included in this figure. b Points represent the individual patient maximum increase in HR and individual plasma vosoritide Cmax at each visit during the phase III study. Solid lines represent the linear fits through the data and the shaded regions represent the 95% confidence interval. The respective analyses using the individual plasma vosoritide AUC is similar and is shown in Fig. S8 in the ESM. Cmax maximum observed plasma concentration, HR heart rate, bpm beats per min, AUC area under the plasma concentration-time curve, ESM electronic supplementary material

Fig. 9

Visit-matched vosoritide Cmax in plasma and maximum decrease in systolic and diastolic blood pressures in the phase II and III studies. a Points represent the individual patient maximum decrease in SBP and individual plasma vosoritide Cmax at each visit during the initial 6 months of the phase II study, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high Cmax (8.39 × 105 pg/mL) relative to other patients, but a within-range maximum decrease in SBP (−7 mmHg). This patient was included in the fit through the data but was not included in this figure. b Points represent the individual patient maximum decrease in SBP and individual plasma vosoritide Cmax at each visit during the phase III study. c Points represent the individual patient maximum decrease in DBP and individual plasma vosoritide Cmax at each visit during the initial 6 months of the phase II study, color-coded by study cohort (C1: Cohort 1, 2.5 µg/kg; C2: Cohort 2, 7.5 µg/kg; C3: Cohort 3, 15 µg/kg; C4: Cohort 4, 30 µg/kg). One patient had a high Cmax (8.39 × 105 pg/mL) relative to other patients, but a within-range maximum decrease in DBP (−2 mmHg). This patient was included in the fit through the data but was not included in this figure. d Points represent the individual patient maximum decrease in DBP and individual plasma vosoritide Cmax at each visit during the phase III study. Solid lines represent the linear fits through the data and the shaded regions represent the 95% confidence interval. The respective analyses using the individual patient AUC are similar and are shown in Fig. S9 in the ESM. Cmax maximum observed plasma concentration, SBP systolic blood pressure, DBP diastolic blood pressure, mmHg millimeter of mercury, ESM electronic supplementary material