We are developing sobetirome (QRX-431) for the treatment of dyslipidemia. Sobetirome selectively activates thyroid receptor beta, which is a known mechanism for lowering LDL cholesterol, trigylcerides, Lp(a) and weight.

The naturally occurring thyroid hormone, T3, has been shown to lower LDL cholesterol and Lp(a) through its effects on the thyroid beta receptor, but T3 also stimulates the thyroid alpha receptor which produces potentially harmful increases in heart rate. This lack of tissue specificity renders T3 unacceptable as a therapy to lower cholesterol because of the elevation in heart rate.

Sobetirome is selective to the thyroid receptor beta. It is also selectively taken up by the liver relative to the heart in preclinical studies. Sobetirome has been shown in preclinical studies to lower LDL cholesterol and Lp(a) and not affect heart rate, while also demonstrating a 3-4% weight reduction in 7 day studies in primates. Preclinical studies with sobetirome have also demonstrated that the compound stimulates steps of reverse cholesterol transport, or RCT.

Reverse Cholesterol Transport

RCT is an important protective mechanism involving the transport of cholesterol from the arteries, including plaques which may cause strokes, back to the liver. Sobetirome stimulates several steps in RCT including stimulation of the HDL receptor SRB1 and increasing bile acid synthesis and removal. This suggests that sobetirome might be a candidate for treatment and prevention of cardiovascular disease in humans independent of its effects on LDL and Lp(a).

Development Program

QuatRx has completed both single and multiple dose randomized, double-blind, placebo-controlled Phase I studies with sobetirome. Sobetirome was well tolerated in both studies.

Lipid-lowering effects in both single and multiple doses were seen in the Phase I studies of sobetirome. In the single dose study of 32 subjects, low-density lipoprotein (LDL) cholesterol levels decreased by up to 22% in subjects receiving up to 450 µg of sobetirome, compared to 2% in subjects who received placebo. The greatest reductions were observed 72 hours after dosing. In the multiple dose study of 24 subjects over two weeks, reductions in LDL cholesterol levels decreased up to 41% at doses up to 100 µg once a day, compared to an overall 5% reduction for placebo. Subjects, who were not enriched for LDL levels, followed a low-cholesterol diet starting one week prior to randomization and then received sobetirome or placebo.

Related Topics

Clinical Portfolio / Sobetirome / Market Opportunity

Clinical Portfolio / Sobetirome / About Dyslipidemia

Additional Reading

Selective thyroid receptor modulation by GC-1 reduced serum lipids and stimulates steps of reverse cholesterol thransport in euthyroid mice. L. Johansson et al. PNAS, 2005, 102. 10297-10302

Effects of the Thyroid Receptor Agonist GC-1 on Metabolic Rate and Cholesterol in Rats and Primates: Selective Actions Relative to 3,5,3’-Triiodo-L-Thyronine.  G. J. Grover et al.  Endocrinology, 2004, 145, 1656-1661. 

Spared bone mass in rats treated with thyroid hormone receptor TRβ-selective compound GC-1.  F. R. S. Freitas et al.  American Journal of Physiology Endocrinology and Metabolism, 2003, 285 E1135-E1141. 

Selective modulation of thyroid hormone receptor action.  J. D. Baxter et al.  Journal of Steroid Biochemistry & Molecular Biology, 2001, 76, 31-42.

The Thyroid Hormone Receptor-b-Selective Agonist GC-1 Differentially Affects Plasma Lipids and Cardiac Activity. S. U. Trost et al.  Endocrinology, 2000, 141, 3057-3064.