Romosozumab: A Breakthrough in Osteoporosis Treatment

Low density lipoprotein receptor-associated protein 5/6 (LRP5/6) forms a complex with Wnt protein, initiating the phosphorylation of LRP5 or LRP6's cytoplasmic tail. This event causes Axin to bind and inhibit glycogen synthase kinase (GSK-3β) activity. Consequently, β-catenin undergoes increased phosphorylation, promoting its translocation to the nucleus, where it forms complexes with DNA-binding proteins, activating target gene promoters. This sequence ultimately supports the differentiation, proliferation, and survival of osteoblasts.

Research indicates that Sclerostin, secreted by osteocytes, disrupts Wnt signaling by competitively binding to LRP5/6, thus stabilizing β-catenin and reducing osteogenic activity, which can trigger osteoporosis. Blocking the interaction between sclerostin and LRP5/6 can enhance Wnt signaling, increasing bone formation and inhibiting bone resorption. Osteosinomumab, by binding specifically to sclerostin, reduces its inhibition of the Wnt signaling pathway, thereby promoting osteogenesis and inhibiting osteoclast activity, providing a dual mechanism therapy for osteoporosis.

Among the drugs targeting SOST, Romosozumab stands out as the first humanized IgG2 monoclonal antibody aimed at SOST sclerosis protein. However, its path to approval was challenging. The FDA initially rejected its U.S. marketing application in 2017 due to concerns about an increased risk of cardiovascular events in patients. After Amgen and UCB submitted additional Phase III clinical data, the FDA approved it in April 2023. Nevertheless, the EU CHMP also rejected its marketing application in June of the same year due to similar concerns, which limited its projected 2024 sales to $3.2 billion.

Setrusumab is the second SOST monoclonal antibody globally, developed for osteogenesis imperfecta (OI), a rare genetic disorder characterized by low bone mass and brittle bones. Setrusumab, a fully human IgG2 monoclonal antibody, targets the inhibition of sclerosin to enhance osteoblast activity. In June, Ultragenyx Pharmaceutical and Mereo BioPharma announced promising results from the Phase 2 portion of a Phase 2/3 clinical trial, showing a sustained reduction in fracture rates in OI patients.

Blosozumab, another humanized monoclonal antibody against sclerostin, was developed by Eli Lilly for osteoporosis treatment. The company holds a license to develop and commercialize Blosozumab in Greater China. Phase II clinical trials in the United States and Japan demonstrated favorable safety and efficacy. In May 2023, Transom Group announced Phase I data showcasing TST002 (Blosozumab) had a good safety and tolerability profile across all dose groups, and exhibited a clinically significant increase in lumbar bone density.

China's first SOST monoclonal antibody, SHR-1222, developed by Hengrui Pharmaceutical, is currently in Phase I clinical trials.

Osteoporosis is a systemic bone disease marked by reduced bone mass and deterioration of bone microstructure, leading to increased bone fragility and fracture risk. With an aging population, China has the highest number of osteoporosis patients, totaling about 90 million, or around 7% of the population, and at least 210 million people with below-normal bone mass. The market for osteoporosis treatments is vast, with the market size expected to reach 36.8 billion yuan in 2025 and grow to 51.2 billion yuan by 2030.

Romosozumab and other sclerostin-targeting drugs represent a new therapeutic strategy for osteoporosis, potentially overcoming the limitations of traditional treatments and becoming a focal point for future research and therapy.