Metabasis Announces Promising Results From Its Phase 1b Clinical Trial For MB07811, Its Novel Product Candidate For The Treatment Of Hyperlipidemia

Main Category: Cardiovascular / Cardiology
Article Date: 21 Jun 2008 - 3:00 PDT

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Metabasis Therapeutics, Inc. (Nasdaq:MBRX) announced the results of its 14-day, Phase 1b multiple-dose clinical trial in subjects with mild hypercholesterolemia, which showed that MB07811 was safe and well tolerated across the seven doses tested, ranging from 0.25 mg up to 40 mg. There were no serious adverse events, and the frequency of adverse events in MB07811-treated subjects was similar to placebo-treated subjects. No differences in heart rate, heart rhythm or blood pressure were observed between MB07811 and placebo-treated patients. Mild increases in liver enzymes were observed at the higher doses of MB07811 along with dose-related mean shifts in thyroid hormone levels. The clinical trial results also showed dose-related reductions in fasting low-density lipoprotein cholesterol (LDL-C) and fasting triglyceride (TG) levels at day 14. Significant placebo-adjusted LDL-C reductions from baseline were observed at doses of 5 mg and above and ranged from approximately 15 - 41%, while placebo-adjusted TG levels were reduced by more than 30% at doses of 2.5 mg and above.

This completed Phase 1b clinical trial was a randomized, double-blind, placebo-controlled, rising multiple-dose study that enrolled 56 subjects with a mean baseline LDL-C of 126 mg/dL and a mean baseline TG of 118 mg/dL. Subjects received either placebo or MB07811 at an oral dose of 0.25 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg or 40 mg. MB07811 is a novel, orally administered, beta-subtype-selective thyroid hormone receptor (TRβ) agonist that is designed to target the liver in order to avoid or minimize well known side effects of thyroid hormone receptor (TR) agonists.

TR agonists represent a novel and potentially important approach for reducing LDL-C (known as the "bad" cholesterol) and total cholesterol, liver and serum triglycerides and lipoprotein (a) [Lp(a)]. However, use of this approach has been limited by side effects, which include adverse cardiac effects, as well as adverse effects on the thyroid hormone axis, muscle metabolism and bone turnover. Metabasis believes that a liver-targeted TRβ-selective receptor agonist has the potential to improve the therapeutic index of TR agonists by minimizing extra-hepatic activation of thyroid receptors and the associated therapy-limiting side effects.

"The results of this clinical trial provide evidence that MB07811 is capable of significantly lowering both LDL-C and TG levels in patients with mild hypercholesterolemia without affecting heart rate, heart rhythm or blood pressure," commented Howard Foyt, M.D., Ph.D., FACP, vice president, clinical development. "The primary purpose of this Phase 1b clinical trial was to assess the safety and tolerability of MB07811 and consequently we tested doses well above doses expected to lower lipids. The changes observed in both liver enzymes and thyroid hormones at the higher doses, while not unexpected based on this class of drugs' pharmacologic mechanism, will continue to be monitored and evaluated in future clinical trials. Importantly, we believe the overall safety and tolerability results in this clinical trial support continued development of MB07811 and speak to the potential of this drug class for the treatment of hyperlipidemia."

"Although not its primary purpose, we are very encouraged with the clinically significant reductions in both LDL-C and TGs we observed in this early clinical trial," commented Dr. Paul Laikind, president and chief executive officer. "We believe that the potential ability of this new drug class to simultaneously lower LDL-C and TGs as well as other presumed cardiovascular disease risk factors such as Lp(a) may prove useful in reducing the risk of cardiovascular disease in patients with hyperlipidemia. In addition, MB07811 has been shown in preclinical studies to reduce liver fat (hepatic steatosis). Fatty liver is a common condition associated with insulin resistance and an increased risk of cirrhosis and liver failure. These results, combined with the positive results from our recently completed Phase 2a proof-of-concept clinical trial for our diabetes drug candidate, MB07803, have made for a very exciting first half of the year. In addition, our discovery group is making excellent progress toward discovering new ways to treat metabolic disease including moving towards recommendation for development of a novel glucagon antagonist for treating diabetes. Together, this preclinical and clinical progress represents a very exciting future profile for Metabasis. In addition, we are making excellent progress on our business development activities. Success in this area will help us secure the resources we need to optimize the value of our many preclinical and clinical product candidates."

About Cardiovascular Disease and Treatment with Lipid Lowering Agents

Cardiovascular disease is the leading cause of death worldwide. In the U.S., cardiovascular disease results in more deaths than cancer, chronic respiratory diseases, accidents and diabetes combined. Patients with hyperlipidemia, a clinical condition characterized by an elevation of cholesterol and/or triglycerides in the bloodstream, are at greater risk of cardiovascular disease and of experiencing a heart attack or stroke. Even though many patients take medications designed to lower serum cholesterol, such as statins, more than half of patients with hyperlipidemia remain above the targeted levels set by the National Cholesterol Education Program. Although effective for treating many patients with elevated LDL-C, statins have only modest effects on TGs. The total dyslipidemia market has worldwide annual sales around $30 billion, with statins accounting for about $25 billion of that number.

About Metabasis

Metabasis is a biopharmaceutical company using its proprietary technologies, scientific expertise and unique capabilities for targeting the liver and liver pathways. 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 drug 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 developed drug candidates indicated for the treatment of liver diseases such as hepatitis and primary liver cancer, which it now intends to license or partner. All product candidates were 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 the potential safety, efficacy and benefits of, and the potential market for, MB07811 and Metabasis' other product candidates; and the progress and prospects of Metabasis' glucagon receptor antagonist program and its business development activities. 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; and other factors discussed in the "Risk Factors" section of Metabasis' Quarterly Report on Form 10-Q for the three months ended March 31, 2008 and in Metabasis' other filings with the Securities and Exchange Commission. All forward-looking statements are qualified in their entirety by this cautionary statement. Metabasis is providing this information as of the 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.

Metabasis