Henlius Received IND Approval For Its Ipilimumab Biosimilar HLX13 From NMPA

Shanghai Henlius Biotech, Inc. (2696.HK) announced that the investigational new drug (IND) application of its ipilimumab biosimilar HLX13 (a recombinant anti-CTLA-4 fully human monoclonal antibody injection) has been approved by the National Medical Products Administration (NMPA) for treatment of unresectable or metastatic melanoma, advanced renal cell carcinoma (RCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer and adjuvant treatment of melanoma.

Developed for patients around the globe with high similarity to originatoripilimumab
HLX13 is a biosimilar of ipilimumab targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The development of HLX13 is strictly in accordance with Chinese Biosimilar Guidelines. So far, originator ipilimumab has been approved and launched in the U.S. and Europe. Approved indications for ipilimumab onotherapy include adjuvant treatment of melanoma and treatment of advanced melanoma. Combination therapy of ipilimumab and PD-1 inhibitor are approved for the treatment of advanced RCC, MSI-H/dMMR metastatic colorectal cancer and advanced hepatocellular carcinoma. According to an estimation from Datamonitor, the peak sales of ipilimumab will be more than USD 2.6 billion.

Strictly following the principles of comparability, stepwise development, consistency and similarity assessment, Henlius has conducted a series of head-to-head pre-clinical studies to compare the pharmacology, pharmacokinetics and toxicokinetics profiles, immunogenicity and toxicity profile of HLX13 and originator ipilimumab. Results from these studies showed that there is a high similarity or no significant difference between HLX13 and originator ipilimumab in terms of in vivo and in vitro pharmacology, pharmacokinetics, toxicokinetics, immunogenicity and toxicity characteristics. Henlius is committed to provide quality biologics to benefit patients around the globe and will actively explore opportunities to bring HLX13 mono or combination therapies to the global market.

Blocking inhibitory effects on T cell activation to release the brake of anti-tumour immune response
Anti-CTLA-4 monoclonal antibody (mAb) is an immune checkpoint inhibitor that can block the inhibitory effects of CTLA-4 on the co-stimulation signal necessary to T cell activation. It is known that two signals are required to activate T cells and the co-stimulation signal generated by binding between CD28 on T cells and B7 molecules on antigen-presenting cells is one of the required signals. CTLA-4, which is also expressed on T cells, has a higher affinity to B7 molecules compared with CD28, and thus can competitively bind to B7 molecule to inhibit the CD28/B7 co-stimulation signal. In addition, signals of CTLA-4 pathway can also terminate T cell activation^[1]. HLX13 can specifically bind to CTLA-4 to block these inhibitory effects and as a result can help T cell activation in anti-tumour immune response.

Great clinical application potential for dual immune checkpoint inhibitor combination therapy
With the broad application of immune checkpoint inhibitors in clinical practice, the potential of the combination therapy of anti-CTLA-4 mAb and anti-PD-1 mAb is becoming more and more attractive. Based on their mechanisms of action (MoA), there is probably a synergistic effect between these two immune checkpoint inhibitors. During the early phase of immune response, anti-CTLA-4 mAb can help maintain T cell activation, while in effector phase anti-PD-1 mAb can inhibit immune escape of tumour cells and restore killing of tumour cells by cytotoxic T cells.

MoA and clinical data suggest treatment with this dual immune checkpoint inhibitor combination therapy have significant clinical benefit for cancer patients with relatively hightumour mutation burden (TMB) or neoantigen burden, e.g. patients with intermediate- to high-risk renal cell carcinoma, MSI-H/dMMR metastatic colorectal cancer，advanced hepatocellular carcinoma or advanced melanoma. Effective treatment options for these patient populations are usually limited and their prognosis is relatively bad. Immune combination therapies for these patients are in urgent need.

Expanding Henlius future immune combination and bispecific antibody options
The product pipeline of Henlius has a broad coverage of immune-oncology targets, anti-angiogenesis targets and tumour-specific targets. Clinical development of the company’s anti-PD-1 mAb HLX10 is progressing smoothly and its monotherapy and multiple combination therapies have entered pivotal phases. In the future, there is a great potential of HLX13 to be combined with HLX10 to form a dual immune checkpoint inhibitor combination therapy. Apart from the indications approved for clinical trials of HLX13 monotherapy, this immune checkpoint inhibitor combination therapy also has the potential to be evaluated in non-small cell lung cancer, hepatocellular carcinoma, small cell lung cancer, urothelial carcinoma and other solid tumors.

Henlius has established an integrated bispecific antibody R&D and engineering platform and has accumulated extended data and insights on immune-oncology targets like PD-(L)1, OX40, LAG3, TIGIT etc... Clinical progress of HLX13 will lay the foundation for Henlius future endeavors in the development of bispecific antibodies with CTLA-4 target. Leveraging the company’s well-established innovation platform, Henlius will continue discovering and developing quality and affordable innovative therapies to benefit patients around the globe.