SUN-212 - BMN 333 Achieves High Sustained Released Vosoritide Exposure with Favorable Safety: Phase 1 Results That Support Phase 2/3 Trials in Achondroplasia

Background: Achondroplasia is a skeletal dysplasia caused by excess fibroblast growth factor 3 (FGFR3) signaling. Vosoritide, an approved once-daily subcutaneous injection, is a C-type natriuretic peptide analog that counteracts excess FGFR3 signaling via natriuretic peptide receptor B (NPR-B) to stimulate endochondral bone growth and treat achondroplasia. BMN 333 is an investigational, fully biodegradable drug designed to extend exposure to vosoritide, its active moiety, and reduce dosing frequency. In preclinical studies, BMN 333 (350 µg/kg once weekly) demonstrated sustained vosoritide release with a >100x lower maximum concentration (Cmax) than directly administered vosoritide (300 µg/kg daily), mitigated hemodynamic effects, and promoted dose-dependent long-bone growth without adverse effects. These data supported a first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of BMN 333.

Methods: In this phase 1, randomized, double-blind, placebo-controlled study, healthy adult volunteers received a single subcutaneous injection of BMN 333 or placebo at 15, 50, 100, 200, 350, or 500 µg/kg (7:3 BMN 333:placebo). Safety and tolerability of BMN 333 were evaluated as the primary objective of the study. PK and PD were assessed by half-life (t1/2) and Cmax of BMN 333 and released vosoritide and plasma cyclic guanosine monophosphate (cGMP; a measure of NPR-B activity).

Results: A total of 60 participants enrolled and received BMN 333 (n = 42) or placebo (n = 18). Incidence of adverse events (AEs) was similar for BMN 333 (35.7%) and placebo (33.3%); most were mild (grade 1; 9/42 [21.4%] and 2/18 [11.1%], respectively) or moderate (grade 2; 5/42 [11.9%] and 3/18 [16.7%], respectively). BMN 333 was well tolerated, with no treatment-related serious AEs or dose-limiting toxicities observed. Overall, no consistent changes in vital signs, laboratory evaluations, or electrocardiogram parameters were observed between BMN 333 and placebo. BMN 333 demonstrated linear PK, with dose-proportional increases in systemic exposure (as measured by Cmax). Sustained, continuous, systemic exposure (as measured by t1/2) to released vosoritide was observed, with PD target engagement (measured by cGMP) seen for at least 7 days after receiving BMN 333.

Conclusions: BMN 333 was well tolerated in adults, with no dose-limiting toxicities identified. Low Cmax and extended vosoritide exposure support the potential to safely improve growth with a weekly dosing schedule, which will be studied in phase 2/3 trials of BMN 333 in children with achondroplasia.

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