Bone Abstracts

Objectives: The interaction between RANK and its ligand RANKL is critical for the regulation of osteoclastogenesis and bone resorption. Inhibition of this interaction helps restore the balance between bone resorption and bone formation. ALX-0141, a novel biological agent (Nanobody) that specifically targets RANKL, was studied in a phase I trial to assess the safety, tolerability, immunogenicity and PK after a single s.c. injection.

Methods: Forty-two healthy postmenopausal women (53–77 years, mean age 66 years) were included in this randomised, double-blind, placebo controlled study. Participants received a single s.c. injection of ALX-0141 (n=31) at 6 dose levels, ranging from 0.003 to 1 mg/kg, or placebo (n=11). PK, PD and safety parameters were monitored for 3 months in the lowest dose level and for more than a year in the higher dose levels.

Results: The safety analysis indicated that ALX-0141 was well tolerated. No serious adverse events related to ALX-0141 or dose-limiting toxicity occurred. The frequency of treatment emergent adverse events (TEAE) was similar in placebo-treated subjects (16 events in 7 subjects (64%)) and in subjects treated with ALX-0141 (93 events in 23 subjects (74%)). The most frequent TEAE were musculoskeletal and connective tissue disorders (n=27, reported by 14 subjects) and all TEAE were transient, of mild intensity, and did not result in any study withdrawals. After s.c. injection, ALX-0141 showed a favourable PK profile, triggering a prolonged PD response. Serum levels of the lead biomarker for bone resorption, cross-linking telopeptide of type 1 collagen (CTX-1), decreased rapidly in all ALX-0141 treated subjects and stayed suppressed (below 70% of the baseline level) up to 390 days after a single administration of 1 mg/kg ALX-0141.

Conclusion: The results from this phase I trial indicate that ALX-0141 is a potent RANKL inhibitor that is well tolerated over a wide range of doses. Collectively, this data supports the further development of ALX-0141 in bone-resorptive diseases with a reduced bone mineral density and increased fracture risk, such as in cancer-related bone diseases, osteoporosis and other disorders.

Declaration of interest: All authors are employees of Ablynx nv.