P5387
LDL cholesterol, apolipoprotein B, lipoprotein(a), apolipoprotein CIII and triglyceride lowering by MGL-3196, a thyroid hormone beta selective agonist, in a 12 week study in HeFH patients

Extract

Background and aims: MGL-3196 is a liver-directed, orally active, selective THR-beta agonist studied in a Phase 2 clinical trial in 116 patients with proven heterozygous familial hypercholesterolemia (HeFH). In Phase 1 studies MGL-3196 reduced LDL-cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a) and reduced ALT at 12 weeks in Phase 2 NASH patients with baseline elevated ALT. The primary endpoint was reduction in LDL-C compared with placebo and secondary endpoints included effects on additional lipids and lipoproteins.

Methods: MGL-3196–06 is a 12 week multicenter, randomized, double blind, placebo controlled trial in HeFH patients not at LDL-C target on maximally tolerated statins. Patients received MGL-3196 100 mg or placebo once daily (in a 2:1 ratio) in addition to their LDL-C lowering regimen. Based on blinded Week 2 PK, MGL-3196 patients continued on 100 mg or a dose of 60 mg from Week 4–12.

Results: Baseline characteristics: age 57.3; male 52.3%; atorvastatin 80mg, 37.1%; rosuvastatin 20/40 mg 37.1%; moderate or no statin, 25.9%; ezetimibe, 71.6%. MGL-3196 treated patients (intention-to-treat) achieved highly significant (p<0.0001) LDL-C and Lp(a) lowering compared with placebo (Table). LDL-C lowering reached 28.5% compared to placebo in the prespecified group of MGL-3196-treated patients on moderate dose/no statins. Triglyceride (TG) (25–31%) apolipoprotein CIII (Apo CIII) (24%) and ApoB (18.0–20.3%) lowering were observed (p<0.0001). MGL-3196 was well-tolerated. Seven patients did not complete the study, 5 withdrew for mild/moderate AEs (placebo, 2; MGL-3196, 3). AEs, mild to moderate, were balanced (placebo, 28; MGL-3196, 63) with five severe AEs, placebo, 3; MGL-3196, 2. Two SAEs occurred, one in a placebo and one in a drug-treated patient (unrelated).