MGL-3196 is a first-in-class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR) β-selective agonist. Preclinical, toxicology, Phase 1 and Phase 2 clinical data suggest MGL-3196 has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemias, including heterozygous familial hypercholesterolemia (HeFH).
THR-β selectivity also enhances the safety profile of MGL-3196, compared to non-selective agents. MGL-3196 has shown no suppression of the central thyroid axis, no THR-α effects on heart rate or bone, and no elevation of liver enzymes. These characteristics make MGL-3196 among the most promising molecules in development in this therapeutic area.
NASH Phase 2 Clinical Trial
In Madrigal’s Phase 2 clinical trial, MGL-3196 achieved statistically significant results in the primary endpoint, the relative reduction of liver fat on magnetic resonance imaging-estimated proton density fat fraction, or MRI-PDFF, at 12-weeks. Statistically significant results were also achieved in multiple Week 36 endpoints, including key secondary endpoints, reduction and resolution of NASH:
- More patients treated with MGL-3196 compared with placebo achieved a two-point reduction in NAS (NAFLD activity score) on biopsy and resolution of NASH on biopsy.
- More patients treated with MGL-3196 compared with placebo achieved resolution of NASH on biopsy.
- MGL-3196 treated patients with > 30% 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 (i.e., fibrosis stage 0) in 50% of patients and was decreased statistically significantly relative to all placebo patients.
- MGL-3196 treated patients had sustained, highly statistically significant (p<0.0001) reductions in liver fat compared with placebo on Week 36 MRI-PDFF, and mean relative fat reduction MGL-3196 (37% compared with placebo, 8.9%).
- MGL-3196 was well-tolerated with mostly mild and a few moderate AEs, which were balanced between drug treated and placebo patients.
HeFH Phase 2 Clinical Trial
In a completed Phase 2 clinical trial, MGL-3196 demonstrated statistically significant improvement in the reduction of LDL cholesterol (LDL-C) compared to placebo – the primary endpoint of this 12-week trial in HeFH patients on maximal statin therapy:
- MGL-3196 treated patients (placebo corrected) achieved highly significant (p< 0.0001) LDL-C lowering of 18.8%, and 21% LDL-C lowering in those on an optimal dose of MGL-3196. LDL-C lowering was 28.5% in MGL-3196 treated compared to placebo in a prespecified group of patients who did not tolerate high intensity statin doses.
- Other statistically significant results achieved for MGL-3196 compared to placebo for multiple secondary endpoints included reduction of triglycerides, apolipoprotein B (ApoB), and lipoprotein(a) (Lp(a)), a highly atherogenic lipid particle commonly elevated in HeFH patients and not adequately controlled by existing therapies.
- MGL-3196 was well tolerated in this trial as compared to placebo with mostly mild and some moderate AEs balanced between drug-treated and placebo patients.
MGL-3196 Phase 3 Clinical Program
Based on evidence of broad activity and a favorable safety profile, Madrigal plans to initiate a Phase 3 clinical program in NASH and a second Phase 3 clinical program in a broader segment of patients with dyslipidemia, including potentially patients with earlier stages of fatty liver disease who, like the later stage NASH patients, are at high risk of cardiovascular disease.