Pharmacodynamic endpoints
NAFLD fibrosis
Treatment with survodutide did not lead to any clear dose-dependent reductions in the NASH-related Fib-4 score, APRI and NAFLD fibrosis score relative to placebo (Table Absolute change from baseline in exploratory variables at EoT0.134 ± 0.367(0.065 ± 0.350(0.035 ± 0.450(0.214 ± 0.709(0.109 ± 0.429(0.073 ± 0.468(0.111 ± 0.322(0.033 ± 0.250(0.405 ± 1.113(0.196 ± 1.059(0.105 ± 1.364(0.648 ± 2.149(0.331 ± 1.300(0.222 ± 1.417(0.337 ± 0.977(0.101 ± 0.758(29.000 ± 98.562(1.328 ± 62.680(15.637 ± 102.041(33.645 ± 149.897(13.263 ± 78.773(16.670 ± 96.480(1.553 ± 72.655(11.176 ± 44.242(–15.85 ± 27.47(–20.52 ± 41.12(–34.06 ± 42.84(–29.67 ± 46.99(–38.15 ± 40.38(–52.51 ± 55.53(–18.05 ± 33.44(–13.20 ± 31.07(–1.91 ± 7.12(–3.46 ± 5.35(–6.84 ± 8.89(–6.82 ± 7.43(–7.27 ± 9.37(–5.74 ± 7.31(–5.21 ± 7.34(–0.06 ± 10.18(0.056 ± 0.503(–0.030 ± 0.482(–0.095 ± 0.550(–0.136 ± 0.610(–0.013 ± 0.583(–0.167 ± 0.455(0.017 ± 0.622(0.193 ± 0.443(–244.4 ± 1619.0(235.9 ± 1549.2(211.3 ± 899.6(343.8 ± 1128.3(281.9 ± 1486.1(649.1 ± 2089.1(80.0 ± 1171.5(392.9 ± 1929.7(–46.93 ± 123.16(–98.36 ± 201.33(–101.57 ± 189.65(–74.47 ± 116.55(–141.93 ± 233.62(–98.36 ± 161.29(–135.20 ± 227.74(–44.68 ± 160.64(–25.93 ± 143.14(–154.17 ± 307.29(–187.07 ± 343.71(–120.06 ± 178.13(–198.79 ± 316.00(–208.24 ± 321.33(–207.16 ± 322.21(–101.55 ± 263.48(0.029 ± 0.264(–0.080 ± 0.328(–0.145 ± 0.299(–0.064 ± 0.306(–0.157 ± 0.194(–0.185 ± 0.429(–0.026 ± 0.229(–0.027 ± 0.239(–0.018 ± 0.106(–0.046 ± 0.108(–0.094 ± 0.135(–0.055 ± 0.088(–0.078 ± 0.094(–0.096 ± 0.214(–0.041 ± 0.095(–0.014 ± 0.060(0.126 ± 0.595(–0.052 ± 0.667(–0.090 ± 0.670(0.097 ± 0.604(–0.162 ± 0.659(–0.032 ± 0.586(0.004 ± 0.541(0.049 ± 0.649(Data are presented as mean ± SDCK-18, cytokeratin 18; HMW, high molecular weight; M30, caspase-cleaved cytokeratin 18; M65, full-length cytokeratin 18 (including caspase cleaved and intact)Plasma exposure to survodutide increased with escalating weekly or biweekly doses, with trough concentrations increasing in an approximately dose-proportional manner (ESM Fig. Glucagon levels decreased dose-dependently from baseline over 16 weeks’ treatment with survodutide, suggesting target engagement of GCGRs and GLP-1Rs (ESM Fig. 