Key Drugs in the ActRII Pathway - Targeting MSTN/GDF8 and BMPs

By conducting in - depth searches in relevant databases, the development of drugs targeting MSTN/GDF8 and bone morphogenetic proteins (BMPs) has been revealed. Understanding these drugs' roles and potential in muscle - related diseases and obesity treatment is essential for exploring new therapeutic strategies and improving patient outcomes.

For drugs targeting MSTN/GDF8, Apitegromab (SRK - 015) is a fully human monoclonal antibody developed by Scholar Rock. It specifically targets pro/latent myostatin, inhibiting its activation through tolloid enzyme - mediated cleavage without binding to mature myostatin or other myogenic factors. It has shown significant efficacy in the treatment of spinal muscular atrophy (SMA) and is now being investigated for obesity indications. Another drug, Talditercept alfa, a fusion protein targeting myostatin, has had a complex development history. Initially developed by BMS and later licensed to Roche, it was halted by Roche due to lack of efficacy and safety concerns. Now, Biohaven Pharmaceuticals is taking over its development for SMA and obesity indications. When considering drugs targeting MSTN, it is crucial to differentiate between pro/latent myostatin and mature myostatin. Targeting latent myostatin, which is downstream in the pathway, may offer higher selectivity (inactive on GDF11 and Activin), potentially resulting in lower efficacy but improved safety. Conversely, targeting mature myostatin, upstream in the pathway, may offer higher efficacy but lower selectivity and safety.

Regarding drugs targeting BMPs, although BMP9 interacts with ActRII receptors and affects bone formation, the clinical development of MGX - 292 targeting BMP9 has been terminated in the preclinical stage. Other subtypes such as BMP2, BMP6, and BMP4 show minimal relevance to obesity - related indications. Therefore, currently, drugs targeting BMPs are not suitable for obesity treatment.

In conclusion, drugs targeting MSTN/GDF8 show potential in treating muscle - related diseases and obesity, but more head - to - head clinical trials are needed to determine the optimal target. Drugs targeting BMPs, on the other hand, face challenges in the context of obesity treatment. Future research should focus on optimizing the development of MSTN/GDF8 - targeting drugs and exploring new applications or modifications of BMP - targeting drugs.

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