ESPE Abstracts (2018) 89 FC15.6

Vosoritide for Children with Achondroplasia:a 30 Month Update from an Ongoing Phase 2 Clinical Trial

Melita Irvinga,b, Julie Hoover-Fongc, Carlos Bacinod, Joel Charrowe, Valerie Cormier-Dairef,g,h, Patti Dicksoni, Paul Harmatzj, Alice Huntsman Labedk, Kala Jayaramk, George Jehak, Jonathan Dayk, Kevin Larimorek, John Phillipsl & Ravi Savarirayanm,n,o


aGuy’s and St. Thomas’ NHS Foundation Trust, London, UK; bEvelina Children’s Hospital, London, UK; cJohns Hopkins University School of Medicine, Baltimore, Maryland, USA; dBaylor College of Medicine, Houston, Texas, USA; eAnn and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA; fInstitut Imagine, Paris, France; gUniversité Paris Descartes, Paris, France; hHôpital Necker - Enfants Malades, Paris, France; iLos Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA; jUCSF Benioff Children’s Hospital Oakland, Oakland, California, USA; kBioMarin Pharmaceutical Inc, Novato, California, USA; lVanderbilt University Medical Center, Nashville, Tennessee, USA; mMurdoch Children’s Research Institute, Parkville, Victoria, Australia; nRoyal Children’s Hospital Victoria, Parkville, Australia; oUniversity of Melbourne, Victoria, Australia


Objectives: Achondroplasia (ACH), caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), leads to inhibition of endochondral bone growth. Vosoritide is a biological analogue of C-type natriuretic peptide (CNP), a potent stimulator of endochondral bone growth. A Phase 2, open-label, sequential cohort, dose-escalation study was conducted to evaluate the safety, tolerability, and efficacy of vosoritide for 24 months in children with ACH aged 5–14 years. An extension study assesses long-term safety and efficacy for up to 5 years.

Methods: All subjects completed ≥6 months of growth measurements in an observational study prior to enrollment to establish their baseline annualized growth velocity (AGV) before treatment. 35 children (mean age 7.6±1.68 years; range: 5–11) were enrolled into 4 separate dose cohorts: 2.5 μg/kg (Cohort 1, n=8), 7.5 μg/kg (Cohort 2, n=8), 15 μg/kg (Cohort 3, n=10) and 30 μg/kg (Cohort 4, n=9) given daily by subcutaneous route. Vosoritide was maintained at these doses for the initial 6-month period for each cohort. Patients were dose-escalated to higher doses in Cohort 1 (to 7.5 and 15 μg/kg) and Cohort 2 (to 15 μg/kg). Patients in Cohort 3 and Cohort 4 remained on their initial doses (15 and 30 μg/kg, respectively). At 30 months, 24/35 patients had completed the open-label study; 22 enrolled in the extension study.

Results: Vosoritide was generally well-tolerated at all doses tested up to 30 months. The majority of adverse events (AEs) were mild; no serious AEs were reported as study drug-related. The most common AEs were injection site reactions, which were all mild and transient. The mean (SD) baseline AGV for Cohort 3 was 4.04 cm/year (2.275). After 30 months at 15 μg/kg, the mean (S.D.) increase in AGV over baseline was +1.58 (1.873) cm/year. The mean (S.D.) height Z-score at baseline was −4.61 (1.136) and increased by +0.88 (0.369). There was slight improvement in upper-to-lower body segment ratio of −0.08 (0.054) from baseline of 1.91 (0.229). An increase in urine cGMP, a biomarker of vosoritide pharmacological activity, was sustained at 30 months.

Conclusions: Vosoritide was generally well-tolerated for up to 30 months administration. There was no evidence of tachyphylaxis with growth velocity and biomarker activity being sustained over 30 months. These data support the continued development of vosoritide for the treatment of children with ACH.