- Author: Kathy Keatley Garvey
The drug candidate, known as EC5026, targets a novel pathway to block the underlying cause of certain types of pain. Described by EicOsis as a “novel, non-opioid and oral therapy for neuropathic and inflammatory pain,” it is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids. UC Davis recently licensed certain patents supporting the underlying technology exclusively to EicOsis.
Clinical trials are expected to begin this summer. “The clinical trials would be the world's first clinical evaluation of sEH for pain,” said William Schmidt, EicOsis vice president of clinical development, who has focused his entire professional career on developing novel pain medicines. “I am thrilled that we have a drug candidate lacking the side effects of both opioids and non-steroidal anti-inflammatory drugs that can potentially produce lead to an entirely new way to treat chronic pain.”
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said Hammock, a UC Davis a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He co-founded EicOsis in December 2011 to alleviate pain in humans and companion animals. “The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate my research to help patients with severe pain.”
National statistics show that as many as eight out of every 10 American adults suffer from chronic pain; three out of four patients consider their therapies for pain ineffective; and as many as a third of the opioid-prescribed patients misuse them.
Every day, more than 130 people in the United States die from opioid overdose, according to the National Institute of Drug Abuse. The Centers for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year. That includes the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.
“This completes the fundraising for Phase 1 of the clinical development program of this novel pain therapeutic,” said Hammock. “We are particularly pleased that the support came from Open Philanthropy with its history of both financially successful and socially important investments.”
Dushyant Pathak, UC Davis associate vice chancellor for Research and executive director of Venture Catalyst, lauded the achievement. “We are very pleased to see the achievement of this important business milestone by EicOsis,” Pathak said. “It's especially heartening to see the entrepreneurial persistence of Bruce Hammock being recognized by Open Philanthropy.”
Open Philanthropy identifies outstanding investment opportunities and makes grants based on importance, need, and tractability, according to the organization's scientific advisors Chris Somerville and Heather Youngs. They said Open Philanthropy selected the Davis project because the EicOsis drug “may reduce suffering from chronic pain conditions which are severe in both developed and developing nations.”
On its website, http://www.eicosis.com, EicOsis depicts itself as “a privately held company developing a first-in-class therapy of a once daily, oral treatment for neuropathic and inflammatory pain in humans and companion animals.”
“Our orally active compounds stabilize natural regulatory mediators in the body that reduce endoplasmic reticulum stress, which, in turn, appears to cause a variety of chronic diseases,” said EicOsis neurobiologist Karen Wagner. “The EicOsis compounds represent a new mechanism of action that both resolves inflammation and reduces pain.”
EicOsis (pronounced eye-cosis), derives its name from eicosanoid, “the major backbone of chemical mediators in the arachidonate cascade,” said Cindy McReynolds, an EicOsis project manager and a doctoral student in pharmacology and toxicology at UC Davis. “It symbolizes the epoxide group in chemistry, which is key to the anti-inflammatory chemical mediators and where the biochemical target called soluble epoxide hydrolase works.”
The National Institutes of Health (NIH) Blueprint for Neuroscience Research (Blueprint) awarded EicOsis a $4 million grant to advance compounds through Phase 1 clinical trials for diabetic neuropathic pain. A goal of the Blueprint Neurotherapeutics Network is to discover, develop and generate novel compounds that will ultimately be commercialized and benefit humankind.
In addition, EicOsis received support from the NIH's National Institute of Neurological Disorders and Stroke (NINDS), and the support of two small business programs affiliated with the National Institute of Environmental Sciences: the Small Business Innovation Research (SBIR) and the Small Business Technology Transfer (STTR).
“We are fortunate to receive all this support in the development of our oral medication for pain treatment through human Phase 1a trials, and now Open Philanthropy through human Phase 1b trials and beyond,” said Alan Buckpitt, a UC Davis retired professor of veterinary pharmacology and toxicology, and a principal investigator on the grants.
Nationally recognized for his achievements, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics.
Hammock, a member of the UC Davis faculty since 1980, received his doctorate in entomology and toxicology from UC Berkeley. He traces the history of his enzyme research to 1969 during his graduate student days in the John Casida laboratory. Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals that regulates epoxy fatty acids.
“My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”
“Basically, I began by trying to figure out how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect,” Hammock. He asked himself these questions: “Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
"It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock, marveling that “this all began by asking how caterpillars turn into butterflies.”
- Author: Kathy Keatley Garvey
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
- Author: Kathy Keatley Garvey
It chronicles how Hammock's basic research on caterpillars--how caterpillars become butterflies--led to key discoveries about chronic pain, including diabetic pain.
It includes information on Hammock's collaborator, John Imig, professor of pharmacology and toxicology at the Medical College of Wisconsin, who recently received a $2.3 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases "to investigate the development of a drug to treat type 2 diabetes and metabolic syndrome."
"But what we didn't tell you is that this translational grant is all thanks to some caterpillars in California and decades of research," wrote communication specialist Karri Stock. "It's a tale of pure curiosity with a great lesson for budding scientists and the public alike: You can't always predict where basic science discoveries will lead."
She related how, more than 40 years ago, a young entomologist in California named Bruce Hammock found a key enzyme (epoxide hydrolase or EH) in the metamorphosis of caterpillars into butterflies. "The enzyme degrades a caterpillar's juvenile hormone, allowing it to move from the larval stage into an adult insect. Early in his career, Dr. Hammock found that if he exploited this EH and prevented larvae from becoming adults, he had on his hands an effective genetically engineered insecticide."
Then came the basic science and fundamental questions that Hammock asked. "Does the enzyme occur in plants? Does it occur in mammals?"
"And it turns out that it does, particularly as soluble epoxide hydrolase (sEH) in mammals, including mice and humans, and its distribution suggested it was involved in regulatory biology," Stock wrote. She went on to detail the collaboration of Hammock and Imig. Read the entire MCW story here.
Hammock's work has drawn national and international attention. Groundbreaking neuropathic pain research emanating from the Hammock lab made Discover magazine's Top 100 Science Stories of 2015 ranking among the Top 15 in the medicine/genetics category.
The UC Davis research was singled out for its “Endoplasmic Reticulum Stress in the Peripheral Nervous System is a Significant Driver of Neuropathic Pain,” published in July 2015 in the Proceedings of the National Academy of Sciences. (See UC Davis news story).
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
- Author: Kathy Keatley Garvey
Hammock, a distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, just received a copy of the magazine listing the research as No. 76. The space exploration of Pluto made No. 1. The top stories encompassed space exploration, medicine, technology, paleontology and the environment.
The UC Davis research was singled out for “Endoplasmic Reticulum Stress in the Peripheral Nervous System is a Significant Driver of Neuropathic Pain,” published in July 2015 in the Proceedings of the National Academy of Sciences. (See UC Davis news story)
Lead researchers Bora Inceoglu of the Hammock lab UC Davis Department of Entomology and Nematology/UC Davis Comprehensive Cancer Center, and Ahmed Bettaieb, then of the Fawaz Haj lab, Department of Nutrition, pinpointed the key mechanism that causes neuropathic pain--a complex, chronic and difficult-to-treat pain caused by nerve injuries from trauma or from such diseases as diabetes, shingles, multiple sclerosis and stroke.
They found that a biological process, termed endoplasmic reticulum stress or ER stress, is the significant driver of neuropathic pain. The research is expected to ignite the discovery of a new generation of therapeutics, paving the way for more efficient and effective ways to alleviate neuropathic pain.
Discover magazine headlined its story on the UC Davis research: “A Key Piece of the Pain Puzzle Is Solved.” Writer Heather Stringer quoted Hammock as saying: “Medications have historically focused on turning down the nerve response to pain, but now we've found one way to block the stress signal that generates the pain.
“Neuropathic pain, however, affords its sufferers no such luxuries,” Stringer pointed out. “It's chronic and unrelenting, and its cause is unknown, making treatment difficult. It turns out that neuropathic pain is triggered when the body experiences endoplasmic reticulum (ER) stress, a condition in which the production and transport of protein exceeds the cells' capacities, say researchers from the University of California, Davis. Because diabetics are at high risk of having neuropathic pain, the team studied diabetic rats that had neuropathic symptoms: hypersensitivity to touch and lack of heat sensation. And the rats' nerve cells showed clear signs of ER stress.”
“When the researchers treated the rats with a compound that blocks ER stress, the pain symptoms disappeared. Conversely, healthy rats developed neuropathy when they received chemicals that induce the stress response.”
Hammock, a member of the National Academy of Sciences and a fellow of the National Academy of Inventors, discovered a human enzyme termed sEH which regulates a new class of natural chemical mediators. He and his lab then developed inhibitors of the sEH enzyme which degrades natural mediators reducing hypertension, inflammation and pain.
The UC Davis research was earlier recommended for F1000 (Faculty 1000), a continually updated collection of more than 145,000 recommendations of top articles in biology and medicine.
The research is the work of a six-member research team: Inceoglu, Bettaieb, Haj, and Hammock, as well as K.S. Lee and Carlos Trindade da Silva, both of the Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center.
Related Links:
- Discover Magazine 100 Top Stories of 2015
- Discover Magazine: Key Piece of the Pain Puzzle Is Solved
- PNAS article
- UC Davis News Story: Groundbreaking Research on Neuropathic Pain
- Faculty 1000 Honor
- Author: Kathy Keatley Garvey
The grant, “Development of an Oral Analgesic for Neuropathic Pain," is funded by the Blueprint for Neuroscience Research. National Institutes of Health (NIH).
The clinical trials, scheduled to begin in 2017, will target diabetic neuropathic pain, occurring in an estimated half of the world's 347 million diabetics, and 29 million Americans.
The compound “is an inhibitor of the soluble epoxide hydrolase (sEH) enzyme,” said Hammock, whose fundamental research on the developmental biology of insects led to the discovery. “It is a key regulatory enzyme involved in the metabolism of fatty acids and treats pain by stabilizing natural analgesic and anti-inflammatory mediators.”
“We are really honored to have been the first company to enter directly into the clinical development phase of the NIH Blueprint Neurotherapeutics Network award program,” said William Schmidt, EicOsis vice president of clinical development. “Since this was a highly competitive grant, this demonstrates the enthusiasm that the NIH has for developing non-opioid therapeutic options for treating severe pain. With the support and direct collaboration of outside experts in the NIH network, we look forward to advancing this novel type of analgesic drug into human clinical trials.”
Current therapies for diabetic neuropathy pain are ineffective in more than three of four patients. “The EicOsis technology may solve a great need in pain treatment in providing a powerful analgesic which avoids the side effects of opioids (narcotics) and nonsteroidal anti-inflammatory drugs (NSAIDs),” said physician Scott Fishman, professor and chief of the Division of Pain Medicine, UC Davis Health System, who is not affiliated with the company. “The EicOsis compound holds great promise for controlling neuropathic pain in general and particularly for this difficult and common medical problem.”
Hammock said EC5026 and close analogs have already shown to be effective “against naturally-occurring moderate-to-severe pain in dogs, cats, and horses.”
The $4 million grant will provide both financial support and shared resources for advancing the EicOsis compound through early clinical trials. The Blueprint for Neuroscience Research is a cooperative effort among the 15 NIH Institutes, centers and offices that support neuroscience research and accelerates discoveries through pooled resources and expertise.
"The Blueprint has funded early drug development efforts in the past, but EicOsis is the first group in the nation to be funded in their advanced development phase," said EicOsis project manager Cindy McReynolds, program manager of the Hammock lab in the UC Davis Department of Entomology and Nematology.
EicOsis (pronounced eye-cosis), is described on its website, http://www.eicosis.com/, as a privately held Davis-based company developing a first-in-class therapy of a once daily, oral treatment for neuropathic and inflammatory pain in humans and companion animals. Hammock developed the technology for the lead compound. UC Davis licensed the compound exclusively to EicOsis. The company maintains a strong patent position with both method-of-use and composition-of-matter patents.
Research was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number UH2NS094258.
Much of the research was supported through the UC Davis Department of Entomology by the NIH, National Institute of Environmental Health Sciences (NIEHS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the American Asthma Society.
Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
A member of the UC Davis faculty since 1980, Hammock received his bachelor of science degree magna cum laude from Louisiana State University in entomology and chemistry, and his doctorate from UC Berkeley in entomology and toxicology, working in xenobiotic metabolism. (For biographies on the other EicOsis officers, see website on EicOsis personnel.)
For more information, access the website at http://www.eicosis.com or contact project managere Cindy McReynolds at cbmcreynolds@eicosis.com or 530-341-4194.
Related Links:
Key mechanism that causes neuropathic pain found (July 7, 2015)
A biological process called endoplasmic reticulum stress appears to play a key role in causing neuropathic pain, according to a new study. The discovery could eventually lead to new therapeutics for controlling chronic pain associated with trauma, diabetes, shingles, multiple sclerosis or other conditions that cause nerve damage.
UC Davis to test experimental drug for laminitis in horses (VIDEO) (Nov. 14, 2012)
Veterinarians at the UC Davis School of Veterinary Medicine have announced plans to conduct the first clinical trial of an experimental drug that has shown promise in treating horses stricken with laminitis, an excruciatingly painful and often life-threatening foot-related disease.
Discovery could help combat chronic pain in diabetics (June 26, 2015)
Researchers at UC Davis have discovered a class of natural compounds found within the body that may someday lead to pain relief for millions of diabetics and others suffering from chronic pain.
Pest Control Research Leads To Pain Control Discovery (Sept. 1, 2006)
A newly discovered enzyme inhibitor, identified by researchers originally looking for biological pest controls, may lead to pain relief for sufferers of arthritis and other inflammatory diseases, say UC Davis researchers. The finding, hailed by a noted inflammatory disease expert "as the most important discovery in inflammation in more than a decade," may also reduce side effects associated with the painkiller, Vioxx.
