Background & Aims Survodutide is a glucagon/glucagon-like peptide-1 receptor dual
agonist in development for treatment of metabolic dysfunction-associated steatohepatitis
(MASH). We investigated survodutide in people with cirrhosis. Methods This multinational,
non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous
(s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis
and healthy individuals with or without overweight/obesity matched for age, sex, and
weight; the primary endpoints were the area under the plasma concentration-time curve
from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently,
people with overweight/obesity with or without cirrhosis and Child-Pugh class A or
B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then
maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse
events, with MASH/cirrhosis-related endpoints explored. Results In the single-dose
cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared
with healthy individuals (90% confidence intervals for adjusted geometric mean ratios
spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and
≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively,
of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness,
liver volume, body weight, and other hepatic and metabolic disease markers were generally
reduced after 28 weeks of survodutide treatment. Conclusions Survodutide is generally
tolerable in people with compensated or decompensated cirrhosis, does not require
pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive
tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number;
ClinicalTrials.gov identifier: NCT05296733. Impact and implications Survodutide is
a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for
treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes
cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile
of survodutide in people with compensated or decompensated cirrhosis, and revealed
associated reductions in liver fat content, markers of liver fibrosis and body weight.
These findings have potential relevance for people with MASH—including those with
decompensated cirrhosis, who are usually excluded from clinical trials of investigational
drugs. Based on this study, further investigation of survodutide for MASH-related
cirrhosis is warranted.
