LRP6

Low density lipoprotein receptor-associated protein 5/6 (LRP5/6) forms a complex with Wnt protein that triggers cytoplasmic tail phosphorylation of LRP5 or LRP6, which in turn causes Axin to bind to it and inhibit the activity of glycogen synthase kinase (GSK-3β). This process leads to increased phosphorylation of β-catenin, promotes its nuclear translocation, forms complexes with DNA-binding proteins, activates target gene promoters, and ultimately promotes differentiation, proliferation, and survival of osteoblasts. Studies have revealed that Sclerostin secreted by Osteocytes (Osteocytes) interferes with Wnt signaling and stabilizes β-catenin by competitively binding LRP5/6, thus reducing osteogenic activity and triggering osteoporosis. Therefore, blocking the interaction between sclerotin and LRP5/6 can enhance Wnt signaling, increase bone formation, and inhibit bone resorption. By specifically binding to osteosin, osteosinomumab reduces its inhibition of Wnt signaling pathway, thereby promoting osteogenesis and inhibiting osteoclast, and realizing dual mechanism therapy for osteoporosis. Currently, only one drug that targets SOST, Romozolzumab, has been approved for marketing. Romosozumab is the first humanized IgG2 monoclonal antibody targeting SOST osteosclerosis protein, but its road to market has been challenging. In 2017, the FDA rejected romosozumab's U.S. marketing application, citing concerns about an increased risk of cardiovascular events in patients. Subsequently, Amgen and UCB provided additional Phase III clinical data at the FDA request, which was not approved until April 2023. However, the EU CHMP rejected romosozumab's marketing application in June of the same year due to cardiovascular risk concerns, which also limited its projected 2024 sales to only $3.2 billion. Setrusumab is the world's second SOST monoclonal antibody for the treatment of osteogenesis imperfecta (OI). OI is a rare genetic bone disorder characterized by low bone mass and fragility fractures. Setrusumab is a fully human IgG2 monoclonal antibody that treats OI by inhibiting the function of sclerosin, a protein that inhibits the activity of osteoblasts. In June, Ultragenyx Pharmaceutical and Mereo BioPharma announced that setrusumab showed significant results in a sustained reduction in fracture rates in Orbit, the Phase 2 portion of a 2/3 clinical trial for OI patients. Blosozumab is a humanized monoclonal antibody against osteosin developed by Eli Lilly for the treatment of osteoporosis. The company is licensed to develop and commercialize Blosozumab in Greater China. Lilly completed Phase II clinical trials in the United States and Japan, showing favorable safety and efficacy. In May 2023, Transom Group announced Phase I data showing that TST002 (Blosozumab) demonstrated a good safety and tolerability profile in all dose groups, and demonstrated a clinically significant increase in lumbar bone density in terms of efficacy. SHR-1222, China's first SOST monoclonal antibody developed by Hengrui Pharmaceutical, is currently in Phase I clinical trials. Osteoporosis is a systemic bone disease characterized by loss of bone mass and destruction of bone microstructure, resulting in increased bone fragility and susceptibility to fracture. With an aging population, China has the largest number of osteoporosis patients, with about 90 million patients, accounting for 7 percent of the total population, and at least 210 million people with lower than normal bone mass. Therefore, the market potential of osteoporosis treatment drugs is huge. The market size of osteoporosis drugs in China is expected to reach 36.8 billion yuan in 2025 and further grow to 51.2 billion yuan in 2030. The sclerotinomumab represented by Romozomumab provides a new strategy for the treatment of osteoporosis, which is expected to overcome the limitations of traditional drugs and become the focus of future research and treatment.

Surrozen announced it will stop developing SZN-1326 for inflammatory bowel disease (IBD) after running into challenges finding a safe and effective dose in a Phase I trial. The news shaved off about 4% of its stock price on Thursday.The bi-specific antibody modulates Wnt signaling in target tissue by binding to particular Frizzled and LRP receptors that are highly expressed in intestinal crypts. Surrozen has said that SZN-1326 demonstrated repair of damaged intestinal epithelium and anti-inflammatory effects in preclinical models.Elevated transaminase levelsSurrozen's decision to drop the IBD programme follows the completion of a Phase I single ascending dose trial involving 37 healthy volunteers. The company said it struggled to identify an ideal dose of the drug after several participants at higher dose levels experienced asymptomatic liver enzyme increases, including four who had Grade 3 ALT and AST elevations.There were no other clinically significant lab abnormalities, and the transaminase elevations resolved spontaneously, but Surrozen had already reported that three of the four subjects had Grade 3 ALT and AST elevations back in 2022."While no safety signal was observed at lower doses, lower-dose levels would not be expected to activate Wnt signaling and produce a pharmacologic effect in the intestine," the company noted in its statement Thursday. It also pointed to broader strategic considerations, such as significant clinical development expenses and market competition in IBD.Prioritising liver disease candidateThe company said it will instead now concentrate on another investigational treatment, SZN-043 for severe liver diseases, starting with alcohol-associated hepatitis. The compound, a hepatocyte targeted R-spondin-mimetic, is designed to stimulate the regeneration of liver cells in patients with liver disease.Results from a Phase Ia trial in patients with chronic liver disease and in healthy volunteers are due this quarter. The company expects to begin enrolling patients with alcohol-associated hepatitis in a Phase Ib study this year, and says proof-of-concept data could be available in the second half.  Surrozen is also co-developing SZN-413 with Boehringer Ingelheim as a potential treatment for retinal vascular-associated diseases. The companies joined forces on the drug in 2022 under a deal worth potentially over $586.5 million.