Bristol Myers Squibb's Ipilimumab BLA Accepted for Review in China

Recently, according to information from the official website of the Center for Drug Evaluation (CDE), the marketing application for another blockbuster monoclonal antibody drug, ipilimumab, by Bristol-Myers Squibb (BMS), has been officially accepted.

It is understood that ipilimumab is an anti-CTLA-4 monoclonal antibody drug developed by Bristol-Myers Squibb (marketed under the brand name Yervoy). It effectively blocks a molecule known as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, also known as CD152). CTLA-4 is a leukocyte differentiation antigen and a transmembrane receptor on T cells (thymus-dependent lymphocytes). It shares the B7 molecule ligand with the CD28 molecule; that is, both CTLA-4 and CD28 can bind to B7 molecules. However, the binding of CTLA-4 to B7 molecules induces T cell anergy, making CTLA-4 a negative regulatory protein during T cell activation. Under normal circumstances, T cell activation relies on dual signaling: the first signal (formation of antigen-antibody complexes) and the second signal (B7-mediated activation signal). The binding of CTLA-4 to B7 generates an inhibitory signal that suppresses T cell activation. Since T cell-mediated anti-tumor immune responses play a crucial role in combating tumors, CTLA-4 affects the human immune system by weakening its ability to kill cancer cells. The blocking effect of ipilimumab on CTLA-4 involves binding to CTLA-4, thereby hindering its interaction with ligands. This leads to increased T cell activation and proliferation, ultimately achieving an anti-tumor effect.

In March 2011, the U.S. FDA approved ipilimumab for the treatment of advanced melanoma, making it the first CTLA-4 monoclonal antibody approved by the FDA worldwide for this indication. In July 2017, the FDA approved a new indication for ipilimumab: the treatment of unresectable or metastatic melanoma in patients aged 12 years and older. To date, in addition to melanoma, Yervoy has been approved for three other indications: renal cell carcinoma and MSI-H or dMMR tumors. Sales of Yervoy reached $1.33 billion in 2018.

Ipilimumab has not yet been approved in China, but multiple clinical studies are currently underway. According to publicly available information, more than ten clinical trials involving ipilimumab have been completed or are ongoing, covering various indications such as melanoma, small cell lung cancer, and non-small cell lung cancer.

It is also worth noting that Bristol-Myers Squibb’s nivolumab injection (brand name: Opdivo) has simultaneously applied for its third indication in China. Previously, it was approved in June 2018 for the treatment of non-small cell lung cancer, and in October this year for the treatment of head and neck squamous cell carcinoma, making it the first and currently only PD-1 inhibitor approved in China for the treatment of head and neck squamous cell carcinoma.

In China, Opdivo is currently undergoing multiple Phase 3 clinical trials across several indications, including urothelial carcinoma, EGFR mutation-positive advanced non-small cell lung cancer, gastric or gastroesophageal junction (GC/GEJ) cancer, and hepatocellular carcinoma.