Metabasis Therapeutics Announces the Publication of Pre-Clinical Findings on MB07811, Its Product Candidate

Metabasis Therapeutics Announces the Publication of Pre-Clinical Findings on MB07811, Its Product Candidate for the Treatment of Hyperlipidemia

SAN DIEGO--(BUSINESS WIRE)--Metabasis Therapeutics, Inc. (Nasdaq: MBRX), announced today the publication of four articles on MB07811, its product candidate for treating hyperlipidemia. The articles cover the design of MB07811 and pre-clinical findings demonstrating liver targeting, cholesterol lowering in combination with statins, and reduction of liver fat in obese mice. The articles are:

  • Serge Boyer et al., "Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs" J. Med. Chem. 51, 7075-7093 (2008).
  • James Fujitaki et al., "Preclinical pharmacokinetics of a HepDirect prodrug of a novel phosphonate-containing thyroid hormone receptor agonist" Drug Metab Dispos 36, 2393-2403 (2008).
  • Bruce Ito et al., "Thyroid hormone beta receptor activation has additive cholesterol lowering activity in combination with atorvastatin in rabbits, dogs and monkeys" Br. J. Pharmacol 156, 454-465 (2009).
  • Edward Cable et al., "Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist" Hepatology 49, 407-417 (2009).

The article in Hepatology was accompanied by an editorial by Marco Arrese, M.D. entitled "Burning Hepatic Fat: Therapeutic Potential for Liver-Specific Thyromimetics in the Treatment of Non-Alcoholic Fatty Liver Disease" published in Hepatology 49, 348-351 (2009).

The publication by Boyer et al. describes the discovery of a novel thyroid receptor-beta selective agonist and how it is used together with the Company's HepDirect liver targeting technology to limit thyroid receptor activation to the liver. Activation of the thyroid receptor-beta in the liver lowers lipids such as cholesterol and triglycerides, and lipoproteins such as LDL, apoB, and Lp(a), which, at elevated levels, are associated with increased cardiovascular risk. Activation of thyroid receptors in tissues outside of the liver is associated with dose-limiting side effects which arise primarily from direct effects on the thyroid receptor in the heart, pituitary, muscle and bone.

The publication by Fujitaki et al. describes preclinical evidence for liver targeting based on studies completed in rats, dogs and monkeys. In each species, MB07811 undergoes metabolism in the liver by an enzyme that exists predominantly in the liver, cytochrome P450 3A. This metabolism leads to the formation of the active thyroid receptor agonist, MB07344, whose drug distribution and elimination characteristics contribute to the high liver specificity associated with the pharmacologic activity of MB07811.

The publication by Ito et al. details studies demonstrating that the combination of MB07811 and atorvastatin, a commonly used statin for the treatment of hyperlipidemia, decreases cholesterol in rabbits, dogs and monkeys beyond that achieved by either agent alone. Although statins are first-line therapy for lowering elevated cholesterol, there are a large number of patients who do not achieve adequate cholesterol lowering on statins alone and require add-on therapies to achieve recommended target levels. Additionally, a significant number of patients are statin intolerant. Patients with a combination of high cholesterol and high triglyceride levels could also potentially benefit from the triglyceride-lowering action of a thyroid receptor agonist since statins are often ineffective in lowering triglycerides to target levels.

Last, the publication by Cable et al. describes the ability of MB07811 to reduce liver fat and serum triglycerides in obese rats and mice. Reduction in liver fat occurred via increased fatty acid oxidation and without evidence of liver damage. Reduction in liver fat may benefit patients with metabolic diseases such as type 2 diabetes as well as patients with fatty liver diseases who are at increased risk of liver failure and of developing primary liver cancer. Patients with hyperlipidemia often have type 2 diabetes and fatty liver disease as well as elevated serum triglycerides. Elevated serum triglycerides represent an independent risk factor for cardiovascular disease.

MB07811 has successfully completed a rising single-dose Phase 1a clinical trial in healthy subjects and a rising multiple-dose 14-day Phase 1b clinical trial in subjects with mild elevations in LDL cholesterol. MB07811 was well-tolerated in both clinical trials. In the Phase 1b clinical trial, effective doses of MB07811 were associated with substantial placebo-corrected decreases in LDL (15-41%), triglycerides (> 30%), apoB (9-40%), and Lp(a) (28-56%). No apparent cardiac effects were observed, including no differences in heart rate, heart rhythm or blood pressure between subjects treated with MB07811 and placebo. Mild increases in liver enzymes were observed at the higher doses of MB07811 along with dose-related mean shifts in thyroid hormone levels.

"We are pleased to have our preclinical findings on MB07811 published in prestigious journals," said Dr. Mark Erion, president, chief executive officer and chief scientific officer of Metabasis." "These publications cover a substantial amount of research conducted at Metabasis in the development of this novel strategy for unlocking the lipid-lowering potential of thyroid receptor agonists. The recently announced clinical results from our 14-day multidose trial are consistent with the pre-clinical findings and support our intent to develop this class of compounds for hyperlipidemia. We plan to initiate a Phase 2 clinical trial in subjects with high LDL levels in the first half of 2009. We believe that MB07811, if approved, could be one of the first in an entirely new class of anti-hyperlipidemic agents which may help patients to reach target cholesterol and triglyceride levels either as first-line therapy or in combination with statins."

About Metabasis (

Metabasis is a biopharmaceutical company using its proprietary technologies, scientific expertise and unique capabilities for targeting the liver and liver pathways to develop novel therapies to treat metabolic and other diseases. The Company has established a broad pipeline of product candidates and advanced research programs targeting large markets with significant unmet needs. Metabasis' core area of focus is on the discovery and development of product candidates to treat metabolic diseases such as hyperlipidemia and diabetes, among others. Although not a core focus of the Company, Metabasis has also discovered and is developing product candidates indicated for the treatment of liver diseases such as hepatitis and primary liver cancer, which it now intends to license or sell. All product candidates have been developed internally using proprietary technologies.

Forward-Looking Statements:

Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to Metabasis' product pipeline, capabilities and long term goals. Such forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause Metabasis' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. These factors include, but are not limited to, risks and uncertainties related to the progress and timing of clinical trials for Metabasis' product candidates; the fact that positive results from preclinical studies and early clinical trials does not necessarily mean later clinical trials will succeed; difficulties or delays in development, testing, obtaining regulatory approval, producing and marketing Metabasis' product candidates; serious adverse side effects or inadequate efficacy of, or serious adverse events related to, Metabasis' product candidates or proprietary technologies; the risk that Metabasis will not be able to build more value or retain rights for direct commercialization of its product candidates; Metabasis' dependence on its licensees and collaborators for the clinical development and registration of, as well as information relating to, certain of its product candidates; potential conflicts with collaborators that could delay or prevent the development or commercialization of Metabasis' product candidates; the scope and validity of intellectual property protection for Metabasis' product candidates, proprietary technologies and their uses; competition from other pharmaceutical or biotechnology companies; Metabasis' ability to obtain additional financing to support its operations; ability to generate financing through partnerships; maintaining compliance with Nasdaq Global Market continued listing requirements; and other factors discussed in the "Risk Factors" section of Metabasis' Quarterly Report on Form 10-Q for the quarter ended September 30, 2008. All forward-looking statements are qualified in their entirety by this cautionary statement. Metabasis is providing this information as of this date of this release and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.