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Endothelin receptor A (ETA) is a G protein–coupled receptor and a major therapeutic target for pulmonary arterial hypertension (PAH). We took a novel approach and developed an antagonistic monoclonal antibody, getagozumab, specifically against ETA. Getagozumab displayed a Kd value of 8.7 nM and an IC50 value of 37.9 nM in the cell-based assays. Getagozumab could significantly lower pulmonary arterial pressure in both hypoxia-induced and monocrotaline (MCT)-induced PAH monkey models and further attenuate the pulmonary arterial and right ventricular hypertrophy in MCT-induced PAH monkeys. The preclinical studies demonstrated that getagozumab is safe, long lasting, and efficacious. Getagozumab may provide a new and effective treatment for PAH patients.

Glutazumab is a humanized anti-GLP-1 receptor monoclonal antibody carrying a GLP-1 fragment. Previous in vitro and in vivo studies showed that glutazumab possessed some biased activities toward different signaling pathways of GLP-1 receptor. As a result, glutazumab exhibited significantly better safety profiles than dulaglutide (Trulicity) in our preclinical cynomolgus and phase 1a clinical studies. Although the potencies or efficacies of glutazumab and dulaglutide appeared similar to each other in all studies, the maximum tolerable dose of glutazumab determined either in preclinical cynomolgus or in phase 1 clinical studies was 3 times higher than that of dulaglutide. A randomized, placebo-controlled, double-blind, semi-sequential dose escalation phase 1b/2a study was recently initiated to further evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of glutazumab in type 2 diabetes patients. Preliminary results further indicated the well-tolerated safety profile and the glucose lowering effects of glutazumab. Disclosure S. Jing: None. C. Zhang: None. K. Fan: None. Y. Guo: None.