CONSHOHOCKEN, Pa., May 31, 2018 — Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) today announced positive top-line, 36-week results from a Phase 2 clinical trial in patients with biopsy-proven non-alcoholic steatohepatitis (NASH). In this trial, MGL-3196, a first-in-class, oral, once-daily, liver directed, thyroid hormone receptor (THR) β-selective agonist, demonstrated statistical significance in the primary endpoint (p<0.0001), relative reduction of liver fat on magnetic resonance imaging estimated proton density fat fraction (MRI-PDFF) at 12 Weeks in December 2017, and, reported here, statistically significant results in multiple Week 36 endpoints including key secondary endpoints, reduction and resolution of NASH.
• MGL-3196 treated patients with ≥ 30% fat reduction on MRI-PDFF at Week 12 demonstrated a higher percentage of NAS reduction and NASH resolution • In patients with NASH Resolution, 35% of MGL-3196 treated and no placebo patients had baseline NAS ≥5
• In MGL-3196 patients with NASH resolution, fibrosis also resolved in 50% of patients and was decreased statistically significantly relative to all placebo patients.
Other Week 36 endpoints and safety:
• Sustained, highly statistically significant (p<0.0001) reduction in liver fat compared with placebo on Week 36 MRI-PDFF; mean relative fat reduction MGL-3196 37%; placebo, 8.9%
• Sustained, statistically significant reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, ApoB and lipoprotein(a)
• Statistically significant reductions in liver enzymes, of greater magnitude with longer duration of MGL-3196 treatment. Statistically significantly more MGL-3196 treated than placebo patients had normalization of ALT
• Statistically significant reductions in fibrosis biomarkers in treated compared with placebo patients • On liver biopsy, fibrosis was reduced by at least 1 point in 23% of placebo and 29% of MGL-3196 treated patients
• Very good all subject tolerability: mostly mild and a few moderate AEs which were balanced between drug treated and placebo patients
• An increase in incidence of a transient mild diarrhea at beginning of study, often a single episode, in MGL-3196-treated compared with placebo “NASH is a common liver disease in the United States, with a growing prevalence, for which no FDA approved treatment is yet available,” said Dr. Stephen Harrison, M.D., Principal Investigator of the study as well as Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University.
“Compared with Week 12, at Week 36 MGL-3196 showed sustained effects to reduce liver fat on MRI-PDFF, and more reduction in liver enzymes than placebo. MGL-3196 demonstrates improvement relative to placebo on measurements of NASH on liver biopsy, including resolution of NASH. Importantly, this study is the first to demonstrate a correlation between efficacy in a non-invasive imaging test, MRI-PDFF at 12 weeks, and improvement in NASH on liver biopsy at 36 weeks”
“The degree of NASH resolution, an approvable FDA endpoint, in patients who received MGL-3196 for 9 months we believe suggests a high likelihood of success in a larger trial with a somewhat longer treatment period in a Phase 3 study designed similarly to this Phase 2 study, pending regulatory agreement with such a design. Further, considering what we have learned regarding drug exposure and dosing, we believe there is potential to resolve NASH in as little as 9 months in 30-40% of patients receiving only MGL-3196, a well-tolerated once a day oral therapy,” stated Paul Friedman, M.D., Chief Executive Officer of Madrigal.
Becky Taub, M.D., CMO and Executive VP, Research & Development of Madrigal stated, “We are excited by the results of this study that demonstrate that MGL-3196 has the potential to show a clear benefit in patients with NASH, including both reduction and resolution of NASH and improvement in multiple atherogenic lipids. Cardiovascular disease is the primary reason for death in patients with NASH. We look forward to advancing MGL-3196 in a Phase 3 clinical trial in patients with NASH.”