Encore Pharmaceuticals, Inc. (EPI) is a drug discovery and development company with advanced proprietary products for the treatment and prevention of cancer and neurologic and cardiovascular diseases. EPI's principal drug innovations have come from discoveries made by researchers at Loma Linda University Medical Center (LLUMC). EPI was founded in 1997 and concluded a technology transfer license agreement with LLUMC in January 1999. The discovery operation continues to be located in the LLUMC environment where operations in 1999 were expanded to include clinical development of EPI's lead drug candidate E-7869 (now known as MPC-7869) for treatment of prostate and colon cancer. The company's research efforts have also led to the discovery of a g-tocopherol (member of the Vitamin E family) metabolite designated as E-8110 (also known as LLU-a) and bioanalogs which have natriuretic (sodium excretion) activity. These compounds are being examined for their anti-hypertensive, anti-oxidant and anti-cancer properties. Patent applications for EPI drug discoveries have been filed and are in review worldwide. Issued patents and allowed applications for E-7869 (MPC-7869) are listed on the Intellectual Properties page.
The Company's lead product, E-7869 (MPC-7869, R-flurbiprofen), is the pure (single-enantiomer) form of the non-steroidal antiinflammatory drug flurbiprofen, a 50/50 mixture of R- and S-enantiomers of flurbiprofen (marketed under the brand name ANSAID®). Flurbiprofen, like its more well known, but less potent, non-steroidal anti-inflammatory ("NSAID") "cousin", ibuprofen, has been marketed worldwide for over 20 years. It was first introduced in Europe in 1976 and in the US in 1987. Until recently, the widely accepted mechanism for all the anti-inflammatory, anti-cancer, and anti-Alzheimer's activity of this class of drugs was the cyclo-oxygenase inhibiting activity of the S-enantiomer. Unfortunately, the S-enantiomer is also responsible for the mild to sometimes severe gastrointestinal ("GI") side effects associated with NSAIDs. It is this undesirable side effect profile which can delay the clinical development of NSAIDs for cancer, precancerous conditions, and Alzheimer's disease. Company scientists following a different mechanistic line of investigation have recently discovered that the pure, R-form of flurbiprofen surprisingly has anti-cancer (and possibly anti-Alzheimer's) properties with no detectable cyclooxygenase inhibiting activity or harmful GI side effects. E-7869 (MPC-7869) therefore, holds the promise of an effective, safe drug for the treatment and prevention of cancers and Alzheimer's disease. (See Project A in "Project Overviews".)
A. R-Enantiomers of NSAIDs as Anti-Cancer Agents
The working hypothesis for one experimental and clinical research project of Encore Pharmaceuticals, Inc., (EPI) is: enantiomerically purer forms of currently used pharmaceutical agents have previously unrecognized pharmacological activities which can be developed more efficiently than traditional new chemical entities. Pursuing this hypothesis with nonsteroidal anti-inflammatory drugs (NSAIDs) has led EPI researchers to discover that some R-enantiomers of arylpropionic acids have previously unrecognized and desirable anticancer activities.
R-flurbiprofen (E-7869, MPC-7869) is the first example of a non-cyclooxygenase-enzyme-inhibiting arylpropionic acid molecule with potential for cancer treatment and prevention without the liability of gastrointestinal adverse effects. E-7869 (MPC-7869) has shown antitumor effects in mouse models of prostate (TRAMP) and colon (Min) cancer. This discovery was efficiently progressed into clinical development through innovative pre-clinical/clinical study designs. These study designs accomplished a bio-bridge to animal toxicology and human-use data from the FDA-approved enantiomeric mixture. This approach is expected to reduce time to commercialization by 3-7 years as compared to traditional new chemical/biological entities.
Objectives of the year 2000 Clinical Development Program with E-7869 (MPC-7869) are to conduct and report on initial Phase I and Phase IIa studies in normal subjects and prostate cancer patients. A completed and reported IND Phase-I safety, tolerance and pharmacokinetics clinical trial demonstrated 1) excellent tolerability as single oral doses up to 2000 mg; 2) definitive single-dose pharmacokinetics data between 200 and 2000 mg; and 3) E-7869 (MPC-7869) to be refractory to enzymatic bioinversion to its S-enantiomer (highly associated with gastrointestinal adverse effects). The clinical portion of two Phase IIa multiple-dose/multiple-dose-level, safety/tolerability, pharmacodynamic/pharmacokinetics trials in prostate cancer patients and a formulation comparison trial in normal subjects were completed in October, 2000.
Specific aims of the multidisciplinary research and clinical support efforts of EPI Research are: 1) use relevant animal models to define optimal E-7869 (MPC-7869) dose regimens 2) conduct structure/activity studies; 3) develop/apply chiral-specific analytical methods to biological fluids; and 4) continue to pursue in vitro and in vivo mechanism of action studies in collaboration with expert investigators in the field.
B. Synthesis and Biological Characterization of Natriuretic / Anti-Oxidant Molecules
In 1988, investigators in the Laboratory of Chemical Endocrinology at Loma Linda University began the isolation of the putative natriuretic hormone predicted from experimental work in dogs by H. deWardner in the early 60's. This project, now under the direction of EPI, has lead to the isolation and identification of a variety of bioactive molecules. The molecule of greatest current interest is LLU-a [S-2,7,8-trimethyl-6-(b-carboxyethyl)-6-hydroxychroman] a sodium specific natriuretic agent. It is synthesized in the liver (rat and human) by b-oxidation of the phytyl side chain of g-tocopherol. It is the most potent inhibitor yet evaluated in patch clamping of the 70 pS K+ channel on cells found in the apical membrane of the thick ascending limb (TAL) of the kidney. These site-of-action versus site-of-synthesis characteristics mark LLU-a as possibly a new hormone. Judicious, rational bio-analog synthesis is being pursued to 1) maximize the ideal pharmacological properties of LLU-a, and 2) convert one or more of these highly active bioanalogs to high affinity, radiolabeled, photoaffinity substrates. These compounds will then be employed to identify the "natriuretic receptor(s)" in renal TAL cells. Cloning of this natriuretic receptor and developing an assay based on receptor-ligand interactions may ultimately lead to an understanding of extracellular fluid homeostasis.
Concurrently, researchers at EPI have developed a very sensitive GC-MS assay for LLU-a in human urine, blood and tissues. Results to date have shown the urine concentration of LLU-a in hypervolemic individuals, particularly congestive heart failure and hypertensive patients, is much greater than in normal healthy individuals. Ultimately, this work will lead to the synthesis and clinical development of new potassium-sparing natriuretic anti-hypertensive agents.
In addition, unlike the hydrophobic members of the vitamin E group from which it is derived, LLU-a provides a water-soluble anti-oxidant, which might be useful for reducing the oxidative stress associated with a variety of diseases including cancer.
Anti-hypertensive and anti-oxidant properties of LLU-a and its parent, g-tocopherol, are being evaluated.
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The Company's clinical development programs are designed to allow early definition of clinical activity and confirmation of safety with relatively modest resource requirements. Working with clinical centers of excellence and CRO's, The Company can efficiently design and conduct parallel and synergistic studies for several therapeutic areas. This is done without establishing a large (and expensive) in-house clinical development infrastructure for each indication.
The in-house R&D operations include research collaborations with academic and industrial organizations to probe the mode of action of the drug candidates. In these collaborations The Company has licensed the E-7869 (MPC-7869) program to Myriad Genetics, Inc. but has retained rights to all other programs. Preclinical efficacy screening continues in-house using various model systems including, genetically altered animal models of human cancer.
The current focus of drug discovery operations is in cardiovascular diseases. Current research in this area is concentrated on the structure activity relationship of non-peptide natriuretic hormone analogues.
|EPR-7869-0001||Normal Subjects||Phase I / Safety, Tolerance, PK||
|EPR-7869-0003||Prostate Cancer Patients||Phase IIa / Safety, Tolerance, PK-PD||
|EPR-7869-0004||Prostate Cancer Patients||Phase IIa / Extended Dosing||
|EPR-7869-0005||Normal Subjects||Phase I / Bioequivalence||
*Clinical program completed but study report not yet prepared.
J. Wechter, Ph.D.
Chief Executive Officer and Chief Scientific Officer
E. Loughman, Ph.D.
Chief Operating Officer
Executive Vice President, Drug Development and Medical Affairs
Board of Directors
J. Wechter, Ph.D.
E. Loughman, Ph.D.
L. Bratzler, Ph.D.
CEO, Coley Pharmaceutical Group
CEO, Paradise Valley Hospital
Sears Capital Management
A. Weisbach, Ph.D.
President Emeritus, Parke Davis Research
President Emeritus, Loma Linda Medical Center
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