Metabasis Therapeutics Inc. had a rough summer: Slammed with failure of its metabolic disease lead compound the same day that Schering-Plough Corp. returned the rights to its lead hepatitis drug, the company still is trading near its 52-week low.
Still, there appears to be plenty of fight left in the company. This week, Metabasis researchers reported preclinical studies on the cholesterol-lowering compound MB07811 in the Sept. 18, 2007, issue of the Proceedings of the National Academy of Sciences. The company also presented preclinical data on glucose-lowering compounds at the annual meeting of the European Association for the Study of Diabetes in Amsterdam.
MB07811 targets thyroid receptors, which have to date frustrated all efforts to unlock their considerable therapeutic potential. Activating the receptors both lowers lipid levels in the liver and can lead to weight loss. But in 40 years of trying, no one has managed to make a compound that would induce those desirable effects without too many undesirable ones.
Metabasis' executive vice president of research and development and chief scientific officer, Mark Erion, told BioWorld Today that side effects of thyroid receptor activation include increases in heart rate as well as bone loss, muscle wasting and effects on blood glucose levels.
One past approach that was scientifically sound in principle, but nevertheless not successful on its own, was to specifically target the TR-beta receptor subtype. Like all receptors, there are several subtypes of thyroid receptors. The beta subtype is found in the liver, while the heart mainly has alpha subtypes.
Unfortunately, however, TR-beta also is the main receptor of the pituitary gland, so targeting that subtype helped with some of the side effects, but not all of them. But a strategy of targeting anatomically as well as to a receptor subtype might be more successful. "If we could just activate receptors in the liver . . . we should be able to get the lipid-lowering effect without all these side effects," Erion explained.
The researchers achieved that tissue specificity through making a so-called prodrug: a compound that does not itself have the desired therapeutic effect, but is metabolized by the liver into a compound that does. Metabasis used its HepDirect technology, which the company also used to develop pradefovir for hepatitis B and MB07133 for liver cancer, to develop MB07811 from its MB07344.
Even with such a prodrug, though, the battle isn't over yet. "Some of that drug, once produced in the liver, will leak out," Erion explained. And when it does, that once again could lead to the activation of other TR-beta receptors.
To prevent that possibility, the scientists modified the compound so it doesn't readily penetrate into other cells. They took advantage of the fact that thyroid hormone usually is transported into cells by a carboxylic acid transporter, but the liver has an additional transporter, the organic anion transporter. By turning MB07811 into a phosphonic acid, the scientists enabled it to be taken up by the liver's organic acid transporter, but not by the carboxylic acid transporter that usually delivers thyroid receptor agonists into cells.
In the PNAS paper, the researchers compared MB07811 to two other control thyroid receptor agonists, T3 and KB141. T3 is the hormone that normally activates all subtypes of thyroid receptor in all tissues; KB-141 is targeted to the beta receptor subtype, but is not specific to the liver.
The scientists found that MB07811 was converted into the active drug both in vitro and when administered to rats. The drug lowered cholesterol levels in rats, and induced genes that are related to cholesterol metabolism as well as low-density lipoprotein clearance. While both control compounds also induced gene expression in other organs including the heart, muscle and pituitary gland, no such changes were seen with MB07811.
MB07811 is currently in clinical trials. The company is testing the drug in healthy volunteers with elevated cholesterol, and will look at cholesterol levels, though the study primarily is to evaluate safety. Metabasis also is doing preclinical studies with related compounds. Erion said the company "hasn't made firm decisions" on commercialization strategies, "but ultimately we will partner a drug in the area of hyperlipidemia."