NPC1L1

UCLA researchers have described a previously unknown step in the complex process by which dietary cholesterol is processed in the intestines before being released into the bloodstream -- potentially revealing a new pathway to target in cholesterol treatment. UCLA researchers have described a previously unknown step in the complex process by which dietary cholesterol is processed in the intestines before being released into the bloodstream -- potentially revealing a new pathway to target in cholesterol treatment. Although an existing drug and statins impact part of the process, an experimental drug being studied in UCLA research labs appears to specifically target the newfound pathway, possibly adding a new approach to the cholesterol management toolbox. "Our results show that certain proteins in the Aster family play a critical role in moving cholesterol through the absorption and uptake process," said Dr. Peter Tontonoz, a UCLA professor and researcher in Pathology and Laboratory Medicine and Biological Chemistry, senior author of an article in Science. "The Aster pathway appears to be a potentially attractive target for limiting intestinal cholesterol absorption and reducing levels of plasma cholesterol." Cholesterol from food is absorbed by cells that line the inner surface of the intestines -- enterocytes -- where it is processed into droplets that eventually reach the bloodstream. But this journey involves a multistep process. Free cholesterol is drawn into the cell's plasma membrane -- the external boundary of the cell -- by a protein called NPC1L1. It then must move to another membranous network in the cell called the endoplasmic reticulum. This is where an enzyme called ACAT2 prepares the cholesterol for packaging and transport, in a process called esterification. Scientists have not known how cholesterol finds its way into the endoplasmic reticulum to be acted upon by ACAT2. In this study, the researchers investigated the Aster protein family, which is known to bind cholesterol and help it move from one membrane to another. "How cholesterol that enters the cell through NPC1L1 reaches the endoplasmic reticulum for esterification and regulation of cholesterol synthesis has been a longstanding mystery," Tontonoz said. "We solve that mystery by showing that two members of the Aster protein family -- Aster-B and -C -- provide the link between NPC1L1 and ACAT2. By attaching to the plasma membrane, these proteins facilitate cholesterol transport to the endoplasmic reticulum." It was previously understood that NPC1L1 was a key player, but this study breaks the process into distinct steps. When NPC1L1 pulls cholesterol from the intestine into the enterocyte, it triggers the recruitment of the Aster proteins. "We show that NPC1L1 and Asters play sequential, nonredundant roles in the delivery of dietary cholesterol from the intestinal lumen to the enterocyte ER (endoplasmic reticulum)," the authors write. Additionally, the researchers found that the Aster proteins may provide a new treatment target for the control of cholesterol levels. When the actions of Aster-B and -C are blocked, cellular cholesterol stores are reduced, and the processing of cholesterol is impaired. An existing drug, ezetimibe, targets NPC1L1, inhibits the activity of ACAT2, and reduces cholesterol absorption. It sometimes is used in combination with statins to reduce blood cholesterol. But ezetimibe doesn't bind sufficiently to Asters to prevent all cholesterol transport. The research team, however, has identified an experimental drug -- a small molecule called AI-3d -- that potently inhibits Aster-A, -B, and -C. In a series of studies in both mice and human cells, the researchers found that the drug inhibits cholesterol absorption by directly targeting the effects of the Asters.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Catabasis Pharmaceuticals, Inc. (NASDAQ: CATB), a clinical-stage drug development company built on a pathway pharmacology technology platform, today announced that the first patient has been dosed in a Phase 2a trial of CAT-2054 for the treatment of hypercholesterolemia. CAT-2054 is an oral small molecule that modulates the SREBP pathway. SREBP is a master regulator of lipid metabolism that impacts LDL, triglycerides and glucose with the potential to impact liver fat and hepatocellular carcinoma. “Compared with currently approved cholesterol drugs, CAT-2054 represents a novel pharmacologic approach to treating dyslipidemia” The CAT-2054 Phase 2a trial is a 4-week randomized, double-blind, placebo-controlled trial in patients with hypercholesterolemia. Catabasis plans to enroll approximately 150 patients that will receive one of four doses of CAT-2054 or placebo, both in addition to a stable dose of a high intensity statin, atorvastatin 40 mg per day. The primary efficacy endpoint for this trial will be percent reduction in LDL cholesterol. Catabasis will also explore the activity of CAT-2054 on other metabolic parameters such as triglycerides and glucose. “Compared with currently approved cholesterol drugs, CAT-2054 represents a novel pharmacologic approach to treating dyslipidemia,” said Harold Bays, M.D., Medical Director / President of the Louisville Metabolic and Atherosclerosis Research Center Inc. “Based on the encouraging Phase 1 study results, and the continued unmet need in treating patients with abnormal lipid levels, we look forward to participating as a research site in evaluating this agent.” “CAT-2054, via its modulation of SREBP activity, has the potential to impact LDL cholesterol, triglycerides and glucose metabolism,” said Joanne Donovan, M.D., Ph.D., Chief Medical Officer of Catabasis Pharmaceuticals. “The initiation of the Phase 2a trial is an important milestone in the development of CAT-2054 and signifies that we are one step closer to potentially providing a novel oral treatment option to patients with hypercholesterolemia.” More information about the CAT-2054 Phase 2a trial can be found on ClinicalTrials.gov under trial identifier NCT02608697. About CAT-2054CAT-2054 is an investigational oral drug initially being developed for the treatment of hypercholesterolemia in patients for whom existing therapies are insufficient. By modulating the SREBP pathway, CAT-2054 may inhibit production of important cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase and NPC1L1. If approved, CAT-2054 may have the potential to be the first therapy to simultaneously modulate cholesterol synthesis, clearance and absorption. Catabasis is currently conducting a Phase 2a trial of CAT-2054 in addition to high intensity statin therapy in patients with hypercholesterolemia. Catabasis has previously reported positive top-line Phase 1 data. About CatabasisCatabasis Pharmaceuticals is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics using its proprietary Safely Metabolized And Rationally Targeted, or SMART, linker technology platform. The Company's SMART linker technology platform is based on the concept of treating diseases by simultaneously modulating multiple targets in one or more related disease pathways. The Company engineers bi-functional product candidates that are conjugates of two molecules, or bioactives, each with known pharmacological activity, joined by one of its proprietary SMART linkers. The SMART linker conjugates are designed for enhanced efficacy and improved safety and tolerability. The Company’s focus is on treatments for rare diseases. The Company is also developing other product candidates for the treatment of serious lipid disorders. For more information on the Company's technology and pipeline of drug candidates, please visit . Forward Looking StatementsAny statements in this press release about future expectations, plans and prospects for the Company, including statements about future clinical trial plans, the potential therapeutic effectiveness of CAT-2054 and other statements containing the words “believes,” “anticipates,” “plans,” “expects,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of the Company’s product candidates, including CAT-2054; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials of or to market CAT-2054; availability of funding sufficient for the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial potential of CAT-2054; and general economic and market conditions and other factors discussed in the “Risk Factors” section of the Company’s Quarterly Report on Form 10-Q for the three months ended September 30, 2015, which is on file with the Securities and Exchange Commission, and in other filings that the Company may make with the Securities and Exchange Commission in the future. In addition, the forward-looking statements included in this press release represent the Company’s views as of the date of this press release. The Company anticipates that subsequent events and developments will cause the Company’s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this release. Contacts Catabasis Pharmaceuticals, Inc.Andrea Matthews, 617-349-1971amatthews@catabasis.com