Survodutide has an “acceptable safety profile” in patients with metabolic dysfunction-associated steatohepatitis with compensated and decompensated cirrhosis, with no dose reduction needed based on pharmacokinetics, according to data.
“There is a large unmet need for treatment of MASH cirrhosis both in compensated and decompensated patients,” Eric J. Lawitz, MD, FAASLD, AGAF, FAPCR, CPI, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at University of Texas Health San Antonio, told Healio. “We undertook this trial to look at three important topics: pharmacokinetics of survodutide in varying degrees of hepatic dysfunction, the safety of survodutide in compensated and decompensated cirrhosis and the early efficacy signals.”
We found there is no dose reduction needed for survodutide based on pharmacokinetics, and survodutide has an acceptable safety profile in both compensated and decompensated cirrhotic [patients] in this trial
Eric Lawitz, MD, FAASLD, AGAF, FAPCR, CPI
At EASL Congress, Lawitz presented a two-part, nonrandomized phase 1 trial assessing the pharmacokinetics and safety of survodutide in patients with MASH with compensated cirrhosis and decompensated cirrhosis.
“These are the first safety and efficacy data for a dual agonist in people with decompensated cirrhosis,” he said.
Pharmacokinetics ‘not affected’ by cirrhosis
In the first part of the trial, 41 adult patients with varying degrees of hepatic impairment (Child-Pugh A, n = 8; B, n = 8; C, n = 9) received a single dose of subcutaneous survodutide 0.3 mg and were compared with a healthy matched population (n = 16). Patients were followed for 16 days with end-of-study visits at days 28 and 35. The primary endpoint was pharmacokinetics.
According to results, area under the plasma concentration-time curve from 0 to infinity and maximal plasma concentration were similar between patients with hepatic impairment and the healthy matched group.
“The pharmacokinetics of survodutide were not affected by cirrhosis,” Lawitz told Healio.
Further, after a single dose of survodutide, adverse events “were common, although a minority of them were deemed investigational product-related,” he told attendees, with most gastrointestinal-related. There were no serious adverse events or hepatic injury reported.
Survodutide ‘generally tolerable’
In the second part of the trial, which was an open-label, multidose design, 41 patients with compensated cirrhosis (n = 16) or decompensated cirrhosis (n = 8) received survodutide for 28 weeks and were compared with patients without cirrhosis (n = 17). In a dose-escalating regimen, patients on day 1 received subcutaneous survodutide 0.3 mg, with up to 6 mg by week 24. Dose maintenance occurred from weeks 24 to 28.
Efficacy analyses were performed with MRI-proton density fat fraction (MRI-PDFF) and Enhanced Liver Fibrosis (ELF) test, and liver stiffness was measured by magnetic resonance elastography (MRE). The primary endpoint was drug-related adverse events.
According to Lawitz, “adverse events were universal across the population” and primarily survodutide-related, GI in nature and mild to moderate in severity. Eight serious adverse events were reported.
In addition, adverse events that led to discontinuation were “more common” in those without cirrhosis compared with patients with compensated or decompensated cirrhosis (eight events vs. three events and two events, respectively).
“Survodutide was generally tolerable,” Lawitz told Healio.
Results also showed that after 28 weeks, at least a 30% reduction in MRI-PDFF was achieved in 52.9% of patients without cirrhosis, 62.5% with compensated cirrhosis and 37.5% with decompensated cirrhosis.
“Both cohorts of cirrhotic [patients] had at least a 1 kPa decline in MRE after 28 weeks of therapy,” Lawitz told attendees, noting a 1.12 kPa decline in patients with compensated cirrhosis and 1.02 kPa decline in those with decompensated cirrhosis.
“There was nominal change in the noncirrhotic group but … they had baseline normal liver stiffness at presentation,” he added.
There also was an “increasing decline with degree of hepatic dysfunction” in ELF score, with a 0.37 and 0.52 decline in those with compensated and decompensated cirrhosis, respectively, vs. “nominal changes” in those with no cirrhosis. Improvements in other fibrosis-related tests and metabolic risk factors were reported as well.
“We found there is no dose reduction needed for survodutide based on pharmacokinetics, and survodutide has an acceptable safety profile in both compensated and decompensated cirrhotic [patients] in this trial,” Lawitz told Healio. “We saw both liquid and radiologic NITs suggesting positive effects on the patient’s liver status. This trial opens the door to further trials in the cirrhotic high unmet medical need population.”
SOURCE: https://www.healio.com/news/gastroenterology/20240619/survodutide-may-have-positive-effects-on-patients-liver-status-in-mash-cirrhosis
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