“This collaboration leverages Abide’s unique and innovative therapeutic engine,” said Alan Ezekowitz, MBChB, D.Phil, President and CEO of Abide Therapeutics. “We are eager to validate unique targets that we hope will lead to the development of novel therapeutics that will benefit patients with diabetes and metabolic diseases.”

Under the terms of the agreement, Abide Therapeutics is eligible to receive an upfront payment, research funding, and potential milestone payments for up to $430 million for three products. Further details of the financial terms were not disclosed. Merck will have worldwide commercialization rights to any products that may be developed as a result of the collaboration. Abide Therapeutics is entitled to receive royalty payments on global sales from any such products.

“Diabetes and related disorders continue to represent a significant global, unmet medical need,” said Nancy Thornberry, Senior Vice President and Franchise Head, Diabetes and Metabolism, Merck Research Laboratories. “We look forward to working with Abide on the discovery and development of important new medicines.”

About Serine Hydrolases
The large family of serine hydrolases are validated but largely under explored as drug targets. These enzymes play a key regulatory role in human physiological processes, such as regulating CNS signaling, digestion, metabolism, inflammation, blood clotting, and life cycle of viruses and pathogens. Thus, the ability to target serine hydrolases has broad therapeutic applications. The proprietary Abide technology platform provides a unique highly selective small molecule collection that specifically targets the common catalytic site of serine hydrolases. The technology provides a rapid and effective method for target identification and validation.

About Abide Therapeutics

Abide Therapeutics is focused on developing innovative medicines that target serine hydrolases, one of the largest enzyme classes in nature with validated but mostly untapped therapeutic potential. Serine hydrolases play important regulatory roles in human physiology and disease. Abide has created a proprietary platform, based on technology developed at The Scripps Research Institute by Professors Ben Cravatt and Dale Boger, that specifically targets serine hydrolases with selective small molecules. The ability to target and modulate serine hydrolases has potential to develop new medicines in many therapeutic areas. Abide is located in San Diego. To learn more, visit www.abidetx.com.

“Abide Therapeutics has a unique technology platform that exploits a chemoproteomics approach to selectively target serine hydrolases and rapidly identify target lead pairs.  We are very excited to explore our discovery platform in the biological systems that Scynexis brings to bear.  Importantly, this collaboration has the potential to bring new therapies for a range of infectious diseases” said Alan Ezekowitz MBChB, D.Phil, President and CEO of Abide Therapeutics.

“SCYNEXIS is gratified that Abide Therapeutics, with its innovative technology, is joining us in the search for innovative anti-parasitic technologies to address human and animal diseases,” said Yves Ribeill, Ph.D., president and chief executive officer of SCYNEXIS.  “We look forward to partnering our technologies in this exciting search.”

By Joanne Kotz
Senior Editor

Abide Therapeutics Inc. is developing an approach to selectively block serine hydrolases, potentially expanding this class of commercially validated en zymes as targets in a range of indications. Most of the new targets will require significant preclinical characterization and validation, which Abide plans to do with partners.

Serine hydrolases cleave bonds in proteins, peptides and small molecules to regulate processes from blood clotting to nervous system signaling. There are approved small molecule inhibitors targeting six human serine hydrolases, including acetylcholinesterase (AChE) and dipeptidyl peptidase-4 (DPP-4). Marketed beta lactam antibiotics and HCV NS3/4A protease inhibitors also target serine hydrolases.

Abide believes the therapeutic potential of the remaining 250 or so human serine hydrolases and the large number of viral and bacterial enzymes has not been sufficiently explored because of difficulty in finding selective compounds.

According to President and CEO Alan Ezekowitz, companies have brought compounds they thought were highly selective for a single serine hydrolase into the clinic only to find they were not. He noted early DPP-4 inhibitors failed because poor selectivity led to toxicities.

Abide has exclusive rights to a chemical proteomic technology developed by co-founder Benjamin Cravatt, chair of the chemical physiology department at The Scripps Research Institute, to identify selective inhibitors against serine hydrolases.

The method employs a probe that permanently labels the active site of serine hydrolases in cell and tissue assays. Selective inhibitors then can be identified by screening small molecule libraries to discover compounds that block labeling of one enzyme by the probe. The method was published in the Proceedings of the National Academy of Sciences in 2010.

Abide has exclusively licensed a small molecule library containing about 1,000 compounds spanning five distinct structural classes. The library was synthesized by Cravatt and scientific co-founder Dale Boger, who is a professor in the department of chemistry at Scripps.

The company has initial hits against 40 of the human enzymes. Its most advanced program targets monoacylglycerol lipase (MAGL), which regulates levels of the endocannabinoid 2-arachidonoylglycerol in the brain. The first selective inhibitor of MAGL, which Cravatt’s laboratory identified, induced analgesia in mouse models of pain (see SciBX: Science-Business eXchange, Jan. 15, 2009).

Last October, Cravatt’s team also showed that MAGL inhibitors reduced neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease (PD) (see SciBX: Science-Business eXchange, Nov. 17, 2011).

According to Ezekowitz, unpublished animal studies suggest the molecules also may have a therapeutic benefit in multiple sclerosis (MS) and Alzheimer’s disease (AD).

The company has selected a lead MAGL inhibitor and expects to file an IND for neuropathic pain in about 15 months.

Abide also has a lead dual inhibitor of MAGL and fatty acid amide hydrolase (FAAH) that requires further optimization. FAAH is a pain target that acts in the same endocannabinoid pathway as MAGL. Ezekowitz said the dual inhibitors may provide increased efficacy over selective FAAH inhibitors by simultaneously block ing two steps in the pathway.

“We aren’t short of targets. The trick will be validating targets and defining path ways with small groups of patients for rapid clinical POC,” Ezekowitz told BioCentury.

To this end, Ezekowitz said the company will focus on chemistry and set up collaborations with companies that have biological screening capabilities in therapeutic areas of interest.

Abide hopes to announce agreements with two biotechs in the near future, one focusing on antibiotics and the other on antivirals. Ezekowitz also hopes to establish two more screening collaborations by the end of this quarter, and is in discussions with an undisclosed pharma for metabolic and endocrine indications.

Abide also is looking for partners to jointly complete preclinical development and design initial human POC studies for the MAGL and MAGL/FAAH programs. However, Ezekowitz said Abide could take one molecule as far as Phase 1b on its own.

In November, Abide raised $2.2 million in seed funding from Cardinal Partners. The company has a commitment for further funds from Cardinal that Ezekowitz believes will be sufficient to bring the lead MAGL inhibitor to IND. The company is looking to bring other investors in for a series A financing late this year.

At least three FAAH inhibitors are in or have completed Phase I testing for pain, but Ezekowitz said he knows of no companies systematically targeting serine hydrolases.

Nature Publishing Group Senior Editor Joanne Katz primarily writes for SciBX: Science-Business eXchange, the translational science journal jointly published by BioCentury and NPG.

COMPANIES AND INSTITUTIONS MENTIONED
Abide Therapeutics Inc., La Jolla, Calif.
The Scripps Research Institute, La Jolla, Calif.

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Abide Therapeutics Inc.
La Jolla, Calif.
Technology: Chemical proteomics to discover small molecule inhibitors of serine hydrolases
Disease focus: Neurology, endocrine/metabolic, infectious
Clinical status: Preclinical
Founded: 2011 by Dale Boger, Benjamin Cravatt, Alan Ezekowitz, Todd Jones and Keith Lenden
University collaborators: The Scripps Research Institute
Corporate partners: None
Number of employees: 3
Funds raised: $2.2 million
Investors: Cardinal Partners
CEO: Alan Ezekowitz
Patents: 10 issued covering MAGL, FAAH, arylacetamide deacetylase-like I (AADACLI; KIAAI363) and inhibitors of the targets

Newco Abide Therapeutics is exercising an option to license the monoacylglycerol lipase (MAGL) inhibitors.

MAGL is a serine hydrolase enzyme that degrades 2-arachidonoylglycerol (2-AG), a ligand of pain-relieving cannabinoid receptors in the brain. In 2008, a team led by Benjamin Cravatt
identified a brain-permeable small molecule inhibitor of MAGL that causes 2-AG levels to increase in the brain, inducing analgesia in mice.²

Cravatt is chair of the Department of Chemical Physiology at The Scripps Research Institute.

At the time, Cravatt and collaborators observed that in addition to boosting 2-AG levels, MAGL inhibitors also triggered a decrease in brain levels of arachidonic acid, the precursor molecule to inflammatory prostaglandins.^2,3 Phospholipase enzymes had previously been considered the principle regulators of arachidonic acid levels, and these observations suggested a link between MAGL activity and prostaglandin-mediated neuroinflammation.

Based on this, a team led by Cravatt and Daniel Nomura, an assistant professor in the Department of Nutritional Science and Toxicology at the University of California, Berkeley, has now looked more closely at the impact of blocking MAGL on brain inflammation.

In mice stimulated with lipopolysaccharide (LPS) to induce neuroinflammation, Magl deficiency or a MAGL inhibitor prevented increases in inflammatory prostaglandins and cytokines and blocked microglial activation compared with Magl expression or vehicle (see Figure 1, “Connecting cannabinoid and prostaglandin pathways”).

Moreover, blocking Magl reduced LPS-stimulated increases in brain prostaglandin levels at least three-fold, whereas blocking cPla2-␣ (phospholipase A2 group IVA cytosolic calcium-dependent; Pla2g4a), which is a known regulator of prostaglandin production in neuroinflammation, only resulted in an approximately 20% decrease in LPS-induced prostaglandins.

In a mouse model of neurotoxin-induced Parkinson’s disease (PD), the MAGL inhibitor reduced neuroinflammation and dopaminergic neurodegeneration compared with vehicle.

Finally, the team asked whether MAGL also controlled inflammation
in peripheral tissues. In LPS-treated mice, Magl regulated prostaglandin
levels in the liver and lung, whereas cPla2-␣ controlled levels in the
gut and spleen. Neither Magl nor cPla -␣ regulated prostaglandin
2
production in the heart and kidney.

Results were published in Science.

“It’s been thought since the early 1900s that phospholipases dominate
the production of arachidonic acid,” said Nomura. It now appears there are tissue-specific mechanisms that control production, he added.

Casting a MAGL net

The work “opens up another angle to approach inflammation in the brain,” said Johan Luthman, leader of the Early Development Neuroscience and Ophthalmology Franchise at Merck & Co. Inc. “Targeting MAGL might provide a combined pain and anti-inflammatory mechanism that could be interesting not only for PD but also for many other neurological diseases.”

Figure 1. Connecting cannabinoid and prostaglandin pathways. A team led by researchers from The Scripps Research Institute and the University of California, Berkeley have shown that mono- metabolite in the brain, also regulates neuroinflammation. Thus, blocking MAGL could provide a therapeutic benefit in neurodegen- Previous work from Scripps had shown that in mice, a small molecule inhibitor of MAGL (a) increased the levels of 2-arachidonoylglycerol (2-AG) in the brain, which added through the cannabinoid receptors to decrease pain (b). The team has now shown that in a mouse model of neuroinflammation, inhibiting MAGL lowers the production of arachidonic acid to decrease levels of inflammatory prostaglandins and blunt inflammation in the brain (c). In a mouse model of neurotoxin-induced Parkinson’s disease (PD) a MAGL inhibitor reduced neuroinflammation and dopaminer neurodegeneration compared with vehicle.

The weakness of the paper is the use of an acute, neurotoxin-based PD model, said Luthman. He noted that results from this model have not translated well into the clinic and suggested the authors should test MAGL inhibitors in newer PD models, such as the so-called MitoPark mouse, which better recapitulates the chronic neurodegeneration of the human disease.

Whether neuroinflammation is a cause or a symptom in PD and other chronic neurodegenerative diseases is still unclear, added Luthman. “The general idea is that neuroinflammation is a contributor and not causative, although this can be debated.”

Thus, Luthman said it is more likely that a MAGL inhibitor would improve symptoms but not affect the underlying disease process.

Luthman told SciBX that MAGL inhibitors also could be interesting to test in multiple sclerosis (MS), in which “the ongoing brain and spinal cord inflammation not only leads to physical disability but also commonly to sensory problems and pain.” Compared with current anti- inflammatory approaches, “the interesting angle is that this is a more brain-specific pathway,” he said.

The California team now is looking at the effects of MAGL inhibitors in genetic models of PD, as well as in MS and Alzheimer’s disease (AD) models, said Nomura.

He added that the team also would like to explore the therapeutic potential of blocking MAGL in acute neurological diseases. “An interesting avenue may be stroke or brain injury, where you could simultaneously enhance cannabinoid and decrease prostaglandin signaling in an acute treatment regimen.”

Given MAGL’s involvement in liver and lung inflammation, Nomura said inhibitors might also have a therapeutic benefit in fibrosis of those tissues.

Scripps holds patents on the MAGL inhibitor used in the Science paper. Abide Therapeutics, which was cofounded in 2011 by Cravatt to develop serine hydrolase inhibitors, is exercising its exclusive option to license patents covering MAGL inhibitors, according to CEO Alan Ezekowitz. “The MAGL program
is the most advanced program, and the company intends to explore MAGL inhibitors in the treatment of pain, neuroinflammation and potentially neurodegenerative diseases like Parkinson’s disease,” said Ezekowitz.