ECE2020 Audio ePoster Presentations Diabetes, Obesity, Metabolism and Nutrition (285 abstracts)
Sodium taurocholate cotransporting polypeptide (NTCP) is a new and promising target for treatment of hypercholesterolemia: A proof of concept from a randomized double-blind placebo-controlled phase I trial
Zhenzhen Zhu 1 , Cuili Fan 2 , Shanwei Zhu 1 , Lizhen Wang 1 , Fei Cai 2 , Xian Gao 2 , Li Zhang 1 , Xiaolu Tang 2 , Hongli Liu 2 & Zhenman Wei 1
1No. 5 Medical Center, Chinese PLA General Hospital, Phase I unite, Peking, China; 2HEP Pharma, R&D Department, Shanghai, China
Bile acids (BAs) are synthesized by converting cholesterol in hepatocytes and recycling it via enterohepatic circulation. Most BAs are reabsorbed into hepatocytes, where they inhibit their own synthesis by activating FXR pathway. NTCP is a major transporter of BAs via absorption from portal blood into hepatocytes. Hepalatide is a 47aa synthetic peptide that specifically binds NTCP resulting in BA spillover of hepatocytes into the systemic circulation. In this way, BA synthesis is uncoupled from negative feedback and more cholesterol can be broken down, which presents a new strategy for lowering cholesterol. The current phase I trials included a single-dose escalating stage (NCT02612506) and a multiple-dose escalating stage (NCT03023787). In the single-dose trial, 45 healthy subjects were recruited into six cohorts with escalating doses of 0.525, 2.10, 4.20, 6.30, 8.40, and 10.50 mg. In each cohort, subjects were blindly randomized into the active and placebo groups at a 4:1 ratio. No SAE took place and there was no significant difference between the adverse events (AEs) in the hepalatide treatment and placebo cohorts. The concentration of BAs in plasma increased in a linear relationship with dosage.
In the multiple-dose trial, 35 healthy subjects were recruited into three cohorts with escalating daily doses of 4.20, 6.30, and 8.40 mg for 7 days. In each cohort, subjects were blindly randomized into the active and placebo groups at a 4:1 ratio. No SAE were observed and no AE was more serious than grade I as defined using NCI CTCAE (Version 4.03). Increased concentration of plasma BAs was observed, which was normalized after drug withdrawal in all hepalatide treatment cohorts. The administration of hepalatide for 7 days reduced serum total cholesterol (TC) in a dose-dependent manner, resulting in a significantly lower TC in the 8.4 mg cohort at the end of the 7-day treatment than in the placebo cohort (P = 0.0029). The LDL-c was decreased by an average of 20% in the 6.3 mg and 8.4 mg cohorts with a maximum decrease of 39% in one healthy subject. The reduction in LDL-c showed a significant difference between both the 6.3 mg and 8.4 mg cohorts and the placebo cohort.
In conclusion, administration of hepalatide increased peripheral BAs in a linear manner. Seven-day treatment with hepalatide reduced blood TC and LDL-c significantly. This is the first clinical trial to assess the concept of NTCP as a promising target for treatment of hypercholesterolemia.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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