The randomized controlled trial has been designed to gather additional data on the effects of Glybera on lipid metabolism and the mechanisms underlying the prevention of pancreatitis attacks. The trial is being performed under a Clinical Trial Application approved by Health Canada.

The new clinical trial builds on positive data obtained from two previous clinical trials in which a total of 22 LPLD patients were treated. These data indicate that a single treatment with Glybera results in a long-term, statistically significant and clinically important reduction in the incidence of acute pancreatitis in LPLD patients. The longest follow-up of individual patients is well over three years, and the cumulative follow-up of all patients is more than 45 years. The therapy was well tolerated and no drug-related severe adverse events or unexpected side-effects have been observed.

AMT will include the data from the new trial in the Marketing Authorization Application for Glybera. The submission of the dossier to the European Medicines Agency is planned for the second half of 2009.

LPLD is an orphan disease, for which no treatment exists today. The disease is caused by mutations in the LPL gene, resulting in highly decreased or absent activity of LPL protein in patients. This protein is needed in order to break down large fat-carrying particles that circulate in the blood after each meal. When such particles, called chylomicrons, accumulate in the blood, they may obstruct small blood vessels. This results in recurrent and severe acute inflammation of the pancreas, called pancreatitis, the most debilitating complication of LPLD. The disease can result in difficult-to-treat diabetes and is associated with significant morbidity and mortality.

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"Our lab has been studying CypA since the early 1990s," Berk said. "We had to determine that vessel walls were secreting something in response to ROS, then prove it was CypA, then prove CypA was required for oxidative stress and inflammation to take their toll in live animals. Our results should put an end to debates within the field and pharmaceutical companies about whether we have found a vital new role for this well known molecule. Incredibly, CypA is required both inside and outside of cells to promote angiotensin II-mediated pathogenic effects in vessel walls."

Berk and colleagues propose that ROS generated via angiotensin II trigger CypA secretion from smooth muscle cells in vessel walls. Once outside the cell, CypA docks into CypA receptor proteins on the same cells to increase ROS production in a vicious cycle. When a signaling molecule docks into its receptor, like a key turning a lock, it changes the receptor's shape such that signals get passed on. Most drugs work by interfering with receptors, and Berk's team is searching for the specific CypA receptors that, if interfered with, would shut down ROS production, CypA secretion, MMP activation and inflammatory cell recruitment in AAA. Also in the next phase, Berk expects to complete a study shortly that will confirm CypA deficiency significantly slows the progression of atherosclerosis.

Along with first author Kimio Satoh, M.D., Ph.D., and Berk, the paper was co-authored by Tetsuya Matoba, M.D., Ph.D.; Michael O'Dell, B.S.; Patrizia Nigro, Ph.D.; Zhaoqiang Cui, Ph.D.; Xi Shi, Ph.D.; Amy Mohan, B.S.; Chen Yan, Ph.D.; Jun-ichi Abe, M.D., Ph.D. and Karl Illig, M.D., all within the Aab CVRI and the University of Rochester School of Medicine and Dentistry. The work was supported by the National Heart, Lung and Blood Institute, part of the National Institutes of Health, and by the Japan Heart Foundation.

"Currently available and experimental therapies, including ACE inhibitors and antagonists of the angiotensin receptors, MCP-1 and MMPs have significant limits in terms of efficacy in AAA, and thus, CypA inhibitors have the potential to meet significant unmet need," Berk said. "Additionally, inhibition of CypA looks to have tremendous benefit in several diseases that involve blood vessels in the brain and heart. Furthermore, while drugs that inhibit CypA may overlap somewhat with other drugs targeting the same angiotensin II pathway, they also look to have additive effects that create potential for combination therapies."

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