Ester Neurosciences Challenges Conventional Wisdom

Ester Neurosciences is developing a unique, disease-modifying approach to combat neurological disorders that result from disrupted acetlycholinesterase (AChE) neuromodulation.

“Cholinergic mechanisms represent a basic pathophysiological pathway underlying neurodeterioration that is characteristic of several disorders such as Alzheimer’s disease, Parkinson’s disease, post traumatic stress, myasthenia gravis and others.

Current therapeutic approaches remain largely palliative leaving an immense and rapidly growing unmet clinical need”, said Dr. Oded Ben-Joseph, Ester’s President.

Ester’s novel therapeutic approaches rely on the discovery of a novel stress response protein, a normally rare AChE variant (AChE-R), which undergoes dramatic upregulation under conditions of acute stress, head injury and exposure to AChE blockers, with consequent long-term detrimental effects. These previously unrecognized effects stem from the protein’s structural and morphogenic properties, which are unrelated to its catalytic activities. Chronic over-production of AChE-R seems to lead to morphological deterioration followed by impairment of cognitive and neuromotor functioning, as well as muscle fatigue, phenomena that characterize patients with neurodegenerative diseases.

“We have therefore adopted a genome-based, upstream strategy to control AChE at the pre-expression level, i.e. before messenger RNA is translated into protein. This new paradigm provides a novel disease-modifying approach for the treatment of a wide range of neurological diseases because it simultaneously preserves transmitter acetylcholine (ACh) levels while controlling the unwanted long-term damages triggered by AChE accumulation, thereby slowing or arresting the progression of these diseases”, said Ben-Joseph.

EN101, Ester’s lead compound for the treatment of peripheral diseases such as myasthenia gravis (MG), constitutes a pre-expression, antisense approach to the regulation of AChE. MG is a progressive and debilitating disease caused by a defect in neuromuscular transmission due to autoantibodies that severely reduce the number of functional ACh receptors. The current treatment for MG involves the administration of Mestinon, a conventional AChE blocker, attempting to preserve neurotransmitter ACh levels. About 40,000 individuals are known to be affected by MG in the United States, while the true number of cases may be as high as 100,000 as a result of under diagnosis.

Following the demonstration of safety and efficacy of orally administered EN101 in rodent and primate models, the company is now entering Phase Ib clinical trials in he UK. This trial is likely to demonstrate EN101’s safety and efficacy in MG patients in a timely fashion and allow the Company to file for an Orphan drug status toward FDA approval.

“We believe that EN101 will provide a superior treatment for MG patients, which currently receive the short-acting Mestinon, due to its high specificity, low dosing, clean side-effect profile and long action. In addition, Mestinon triggers the overproduction of the destructive AChE-R variant, a situation likely to exacerbate the disease” Ben-Joseph maintains.

Ester’s family of antisense compounds may extend well beyond MG to other neuromuscular diseases as well as play a role as a co-therapy for muscular dystrophy and multiple sclerosis, where the preservation of neurotransmitter ACh may be beneficial in reducing fatigue and muscle weakness that accompany the diseases.

In order to enhance the drug development process, Ester researchers have also developed a cell-based assay to rapidly screen a large number of small molecules for drug candidates with potential disease-arrest properties i.e. synthetic chemical moieties, which will be capable of pre-expression inhibition of AChE while easily permeating the blood-brain-barrier.

“We are entering a partnership with a major high throughput screening (HTS) company, which will provide us not only with an extensive library of potential compounds relevant to the central nervous system, but also with capabilities for combinatorial chemistry and lead optimization toward clinical development” said Ben-Joseph.

The company believes that its pipeline generation program will provide a large number of potential drug leads and form the basis for multiple corporate deals.

“One of our core strengths is that we posses a powerful and highly versatile proprietary technology platform relevant to multiple indications in high value growth markets, coupled to a broad patent estate” Ben-Joseph said. The company holds the rights for numerous intellectual assets including 10 granted patents and nearly 30 pending.

Ester was established in 1997 by Medica Venture Partners, a leading American-Israeli healthcare fund. The company is currently seeking between $3 and $4 million to fund its application for orphan drug status for MG in the US, to complete development of HTS and start generating leads and to develop additional indications.

The company’s scientific leadership in AChE neurobiology has its roots in the laboratory of Prof. Hermona Soreq, a Hebrew University Researcher who is the company’s Chief Scientific Advisor. She was awarded The Israel Ministry of Health Prize for Excellence in Biomedical Research in 2000.

Dr. Ben-Joseph, President, holds a PhD degree in biochemistry from the University of Cambridge, and completed his post-doctoral training at the University of Michigan. Prior to joining Ester a year and a half ago, he was Assistant Professor in the Departments of Radiology and Neuroscience at the University of Michigan and a Visiting Scientist at Parke-Davis Pharmaceuticals. Dr. Ben-Joseph also holds an MBA degree from the University of Bradford. Professor Eli Hazum, CEO, was Head of Receptor Research and Metabolic Diseases at Glaxo Inc, VP of Research and Development at Peptor and Professor at the Wiseman Institute of Science. Dr. Ehud Geller, Chairman, is a General Partner at Medica, the former President and CEO of Interpharm Laboratories, and former President of the Pharmaceutical Division of Teva and Executive VP of the Teva Group.

Further details about the Ester Neurosciecnes Ltd can be viewed at their Pharmalicensing profile here.

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