Survodutide safe to use in cirrhosis patients

Treatment with survodutide, which has previously shown its efficacy in reducing body weight and glycaemia in people with obesity or type 2 diabetes, is well tolerated by patients with compensated or decompensated cirrhosis, reports a study.

In addition, survodutide requires no pharmacokinetic-related dose adjustment and has the potential to improve liver-related noninvasive tests.

“Survodutide has demonstrated efficacy for metabolic dysfunction-associated steatohepatitis (MASH) with earlier stages of fibrosis, and this trial provides safety and efficacy insights into its use in individuals with the most advanced disease stage, including decompensated cirrhosis,” the researchers said. [N Eng J Med 2024;391:311-319]

Patients with Child-Pugh class A, B, or C cirrhosis and healthy individuals with or without overweight or obesity, matched for age, sex, and weight, were enrolled in this multinational, nonrandomized, open-label, phase I clinical trial. The area under the plasma concentration-time curve from 0 to infinity (AUC0-N) and maximal plasma concentration (Cmax) served as the primary endpoints.

Participants with overweight or obesity with or without cirrhosis (Child-Pugh class A or B) were administered once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks. Drug-related treatment-emergent adverse events (AEs) were assessed.

The single-dose cohorts consisted of 41 individuals, and the mean AUC0-N and Cmax did not differ significantly between cirrhosis patients and healthy individuals (90 percent confidence interval for adjusted geometric mean ratios spanned 1). [J Hepatol 2024;81:837-846]

Safety

Drug-related AEs occurred in 14/17 (82.4 percent) participants without cirrhosis, 14/16 (87.5 percent) patients with Child-Pugh A cirrhosis, and 7/8 (87.5 percent) patients with Child-Pugh B cirrhosis. Serious AEs occurred in 0, five (31.3 percent), and three (37.5 percent) participants, respectively.

“None were fatal or drug-related except hepatic encephalopathy, which occurred in one participant,” the researchers said. “This event was minimal hepatic encephalopathy and did not cause discontinuation of survodutide or prevent the participant from completing the trial.”

Furthermore, AEs leading to treatment discontinuation happened in eight (47.1 percent), three (18.8 percent), and two (25.0 percent) participants without cirrhosis or with Child-Pugh A or B cirrhosis, respectively. Most of these AEs were gastrointestinal disorders such as vomiting or nausea. None of the affected individuals developed acute kidney injury.

In addition, reductions were seen in liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers after 28 weeks of survodutide treatment.

“Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related noninvasive tests, supporting its investigation for MASH-related cirrhosis,” the researchers said.

The pharmacokinetics of survodutide in cirrhosis patients in the current study supported that of phase I trials in healthy volunteers and those with overweight or obesity. [Diabetes Obes Metab 2023;25:1973-1984; Diabetes Obes Metab 2023;25:1011-1023]

“These pharmacokinetic properties support once-weekly dosing with no need for dose adjustment in people with hepatic impairment,” the researchers said.