WASHINGTON — In patients with cirrhosis associated with non-alcoholic steatohepatitis (NASH), 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.
Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.
“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Texas.
Harrison presented the findings at The Liver Meeting 2022, the annual meeting of the American Association for the Study of Liver Diseases.
Building on Early Findings
The thyroid hormone receptor-beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and anti-fibrotic effects, Harrison said.
Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor-alpha.
In 2019, Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.
In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.
In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study, as previously reported by Medscape Medical News. Those data were presented at the International Liver Conference in London in June.
At The Liver Meeting, Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.
Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.
The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase of -20%, -18%, and -32%, respectively, in the original cohort, and -30%, -23%, and -37% in the more recent cohort.
Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.
Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.
Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.
Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of ≤ 5% and about a quarter (26%) with baseline PDFF > 5% had improvement.
Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.
The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.
Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.
Investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.
The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.
There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.
Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom vs placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Harrison concluded.
The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon, France, told Medscape Medical News. Caussy, who was not involved in the study, was a moderator of the session where Harrison presented the data.
It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Harrison’s presentation, there is a difference in cardiovascular risk factors, Caussy added.
“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Caussy said.
The study was supported by Madrigal Pharmaceuticals.
Harrison discloses the following: Scientific advisor or consultant for Akero, Altimmune, AstraZeneca, Axcella, Echosens, Galectin, Gilead, GSK, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Sagimet, Sonic Incytes, Terns, and Viking; Stock options: Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, and Northsea; Grant/research support: Akero, Altimmune, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepagene, Hepion, Hightide, Intercept, Ionis, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet, Viking, 89 Bio.
Caussy disclosed receiving consulting fees from Madrigal.
The Liver Meeting 2022: American Association for the Study of Liver Diseases (AASLD): Abstract 100. Presented November 6, 2022.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.