FXR agitants: Obecholic acid leads the global market with nearly 20 varieties entering clinical development.

Text . . . Drug crazy non-alcoholic fatty liver disease (NAFLD), has become a serious impact on human health, the global incidence rate of up to 20 to 30%! Its important subset, non-alcoholic fatty hepatitis (NSAH), has seen hot drug development in recent years, but no varieties have yet been approved for the market.
In the field of many targeted drug development, FXR agonists are relatively high in pace, with the listing is only one step away, pipeline varieties, in the NASH field is very likely to expand, the probability of the birth of the explosion is very high.
FXR stands for the variety of Obecholic acid FXR astigtor, i.e. The Farniol X-subjector astigid, represents the species of Obecholic acid, which is the hottest species on the target in recent years; In addition to the above-mentioned adaptations, other adaptations are also in clinical trials, such as NASH's NDA application to the FDA, which was approved by the FDA in 2016 for the treatment of adult primary bile cirrhosis (PBC) patients with poor performance in single-drug applications such as UDCA or UDCA insatiable single-drug applications.
PS: Obecholic acid is currently the only FDA-awarded breakthrough therapy for patients with liver fibrosis NASH.
Figure 1.1 Obe bile acid and 2016-2019 global sales (data source: company annual report) domestic pharmaceutical companies for the registration of Obe bile acid declaration, mainly concentrated in two enterprises, respectively, Zhengda Tianqing company to chemical drugs 3 categories of declaration ANDA, and Suzhou Ze-Tian biopharmaceuticals to chemical drugs 2.1 category declaration IND, in addition to this has not been other enterprises to register the variety.
Form 1.1 Domestic "Obe bile acid" registration declaration situation Obe bile acid NASH adaptive disease was rejected on June 29, 2020, Obe bile acid's original research company Intercept official website announced that the variety for the treatment of NASH listing application was rejected by the FDA ... The FDA's refusal is based on the fact that "the current endpoint data do not yet provide a clear clinical benefit, and it is recommended that the development company provide follow-up validity and safety data for current clinical trials for further evaluation"... In this introduction, the above Phase III clinical trial, named REGENRATE, was launched in September 2015 and the global program recruited 2,500 patients for 72 weeks of drug use and conducted an interim analysis after 1,400 patients in the group; The patient performed a liver tissue biopsy, which was difficult to implement, so the company again communicated with the FDA and obtained permission to reduce the number of patients who met the interim analysis from 1400 to 750, while changing the standard from reaching the compound endpoint to reaching only one of the endpoints.
the results showed that 23% of patients treated with obecholic acid had improved liver fibrosis by more than 1 level, compared with nearly 12% in the control group, while 13.3% of patients had improved liver fibrosis by more than 2 levels, about three times as much as in the control group.
Obe bile acid FXR target characteristics and mechanism Obe bile acid NASH adaptor although currently rejected, but FXR target drug-based, as well as the current product pipeline characteristics, or the future can be expected.
FXR, one of the members of the nucleus superfast family, was originally named for being activated by the ultraphysiological concentration of faniol, and then the physiological level of bile acid and its metabolites were found to activate the subject, also known as the bile acid acceptor.
most important physiological function of FXR is the negative feedback effect on bile acid, which is now thought to be a signaling molecule that regulates complex liver and bowel and systemic metabolic functions.
When ligations and ligations are combined, the spatial structure of FXR changes, co-activation factors and resaldehyde derivatives are recruited, and FXRE, which is combined in the target gene initiator region in the form of a monomer or djumber, regulates the transcription of downstream target genes.
further studies have found that FXR inhibits inflammatory cell immersion, promotes liver intestinal circulation and liver cell regeneration, and delays the process of liver fibrosis/cirrhosis.
In the case of adaptive NASH, when bile acid is combined with FXR, FXR is activated and then expressed by lowering the transcription factor SREBP1c, thereby reducing liver fat production and enhancing the removal of very low-density lipoproteins in the outer tissue to promote insulin sensitivity and reduce liver glycoglobin and circulating triglyceride levels.
based on the above series of metabolic effects, FXR has been used as an important target for the treatment of non-alcoholic fatty hepatitis.
Figure 3.1 Inference of the pathogenesis of human NASH (Source: FXR drug pipeline nearly 20 varieties into the clinical development of FXR astrogen product pipeline, a total of 2 drugs have been listed worldwide, the first drug for Cell The Rapies developed bile acid, first marketed in 2013 and clinically used to treat primary bile acid synthesis defects;
Varieties entering clinical development are mainly in Clinical Phase III, namely Center Drug Research Institute's Centatin (congenital defects in the synthesis of allergenic to peroxidase/primary bile acid synthesis) and Cilofexor tromethamine (adaptation: hyperlipidemia) developed jointly by Phenex/Gilead;
, TREN-101, developed by Toro Bio, is an efficient non-bile acid FXR astigmatist, currently in Clinical Phase II, for the treatment of non-alcoholic fatty hepatitis, while another adaptive primary bile bile bile tube Inflammation is also in Clinical Phase I, and the FXR astration SIPI-7623, jointly developed by Shanghai Medical Institute and Nanjing Coffey Ping Pharmaceutical Technology Co., Ltd., is intended to be used to treat hyperlipidemia and will receive clinical approval in 2018.
addition to the above two varieties, there are currently no domestic pharmaceutical companies involved in the target drug development.
information above can be found in the table below.
Table 4.1 FXR astratives for global drug development Reference Source: 1. Pharmacological Research 134 (2018) 257-267.Pharmaproject Date4. FDA official website information 5. CDE official website information 6. CNKI data.