Madrigal Pharmaceuticals announced positive interim results from a phase 2 clinical trial of MGL-3196 for reducing liver fat in patients with nonalcoholic steatohepatitis, according to a press release and company presentation.
Paul A. Friedman
“The drug has the potential as monotherapy once a day to treat this disease state and the drug could also be combined with any number of other drugs in development that have different mechanisms,” Paul A. Friedman, MD, chairman and CEO of Madrigal Pharmaceuticals, told Healio Gastroenterology and Liver Disease.
MGL-3196 is an oral, once-daily, liver-direct thyroid hormone receptor beta-selective agonist. In the ongoing trial, 125 patients with biopsy-confirmed NASH received either MGL-3196 at a starting dose of 80 mg or placebo.
At baseline, all patients had 10% or more liver fat based on magnetic resonance proton-density fat fraction (PDFF) measurement. At 12 weeks, 78 patients who received MGL-3196 and 38 patients on placebo underwent MRI PDFF again.
Compared with patients who received placebo, those treated with MGL-3196 had a significantly greater reduction in liver fat from baseline (–36.3% vs. –9.6%; P < .0001) with a mean reduction of 60.3% compared with 18.4% (P < .0001).
In 44 patients treated with MGL-3196 who had higher drug levels present at follow-up MRI PDFF, the reduction in liver fat was even greater compared with placebo (–42% vs. –9.6%; P < .0001) with a mean reduction of 75% (P < .0001).
“What was attempted was to get to at least half in a low group and half in a high group for a prespecified analysis to see if having a higher exposure provided better efficacy and to see if it was as safe as the low exposure,” Friedman said. “In fact, the higher exposure was safer. There were no side effects called out and we saw better lowering of liver enzymes at the higher level.”
Secondary endpoints, adverse events
The researchers also observed statistically significant improvements in low-density lipoprotein cholesterol, triglycerides, apolipoprotein B and lipoprotein(a).
“Patients with NASH tend to be hypothyroid and they also develop hypothyroidism specifically in their liver because the cells that are responsible for reproducing inflammation and fibrosis in NASH also produce an enzyme that degrades normal thyroid hormones,” Rebecca Taub, MD, chief medical officer and executive vice president of research and development at Madrigal Pharmaceuticals, told Healio Gastroenterology and Liver Disease. “The metabolic health of the liver is restored by normal thyroid beta activity”
“This molecule reduces liver damage and inflammation,” Taub continued. “It also has the added benefit of reducing both cholesterol and triglycerides, therefore providing cardiovascular benefit in patients with NASH who die more often from cardiovascular complications than liver disease.”
MGL-3196 was well-tolerated with mostly mild adverse events and a few moderate adverse events. The researchers observed three serious adverse events considered unrelated to the drug. The nine patients who discontinued treatment were balanced between the placebo and drug-treated group. Two discontinuations were related to adverse events.
The trial will conclude at 36 weeks with follow-up MRI PDFF measurement, according to the company. – by Talitha Bennett
Disclosure: Friedman and Taub are an employees of Madrigal Pharmaceuticals.