Bone Abstracts

Introduction: The interaction between RANK/RANKL is critical for the regulation of osteoclastogenesis and bone resorption. Inhibition of this interaction helps restore the balance between bone resorption and 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 single injection.

Methods: Forty-two healthy postmenopausal women (53–77 years, mean 66 years) were included in this study, which was approved by the local Ethical Committee. Participants received a single s.c. injection of ALX-0141 (n=31) at six dose levels, ranging from 0.003 to 1 mg/kg, or placebo (n=11). PK, PD and safety parameters were monitored for 3 months at 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. ALX-0141 showed a favourable PK profile, triggering a prolonged PD response. Serum levels of the lead biomarker for bone resorption CTX-1 decreased rapidly and stayed suppressed for up to 390 days after a single administration of 1 mg/kg.

Conclusions: 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. This data supports the further development in bone-resorptive diseases with reduced BMD and increased fracture risk, such as in cancer-related bone diseases, osteoporosis and other disorders.