Edison Shedding Light on Energy Production in Diseased Cells

3/6/14Follow @Tansey_Xconomy

Back in March 2013, Dainippon Sumitomo Pharma signed a deal worth $50 million or more to Mountain View, CA-based Edison Pharmaceuticals, a developer of drugs for disorders of energy metabolism.  The big pharmaceutical company from Japan liked the results. Less than a year later, it came back for more.

The two companies have now formed a larger collaboration—worth as much as $4.2 billion to Edison—and their goal is equally large-scaled. They plan to prepare 10 new drug candidates for clinical trials within five years.

When Edison was formed as a startup in 2005, its quest was to find treatments for a group of rare, debilitating genetic diseases in children. But to do so, the company is following a scientific thread that could lead to new insights about common adult illnesses such as Alzheimer’s disease that lack such clear genetic causes. Those adult diseases of the central nervous system—a huge market—are the targets for Dainippon Sumitomo.

Edison designs drugs to correct malfunctions in the process used by cells to make the energy they need to operate. Cells do this by passing electrons from one molecule to the next in a complex network of biochemical interactions dubbed “redox reactions.”

But when things go wrong, as Edison co-founder and CEO Guy Miller, puts it simply, “Electrons don’t end up where they should be.”

The result of those misplaced, excess electrons is a type of destructive molecule you might have heard of by reading diet articles: free radicals or reactive oxygen species (ROS). Those molecules can injure cell structures and help set off a condition called oxidative stress, which is a key suspect in diseases of aging.

To guard against this damage, nutritionists may advise people to eat foods such as blueberries because they contain substances called anti-oxidants.

Miller, a critical care physician and serial entrepreneur, has been studying the cell’s energy-producing mechanisms and their malfunctions for nearly two decades. Breakdowns in that system are most likely to affect organs that burn a lot of energy, such as the heart, muscles, and brain, where “there are a lot of electrons running around,” Miller says.

The search for new treatments for brain-injured soldiers spurred the Defense Advanced Research Projects Agency (DARPA) to fund Miller’s first company, Galileo Pharmaceuticals, in 1997. Galileo produced scientific gains, though no therapies. But Miller created Edison as a spinoff from Galileo after he learned about a group of severe childhood disorders that were clearly linked to malfunctions in energy metabolism. The children had defective genes for those biological pathways.

“Instead of being hit by real artillery shells, these kids have genetic artillery shells,” Miller says.

Edison’s lead drug candidate, EPI-743, (Vincerinone) is currently in mid-stage trials in these rare genetic diseases. They include Friedreich’s ataxia, a life-threatening neuromuscular disorder that renders most patients paraplegic; and Leigh syndrome, a neurodegenerative disorder that is typically fatal to afflicted children by the age of five.

These illnesses belong to a group called “inherited respiratory chain diseases of the mitochondria.” The mitochondria are small membrane-bound organelles inside most cells, and they are specialized to crank out molecules such as ATP that serve as a chemical sources of energy for multiple functions of the cell. This is where the redox chain of electron exchanges takes place to yield that energy.

Children with Friedreich’s ataxia and Leigh syndrome have characteristic defects in the genes that direct the operations of the mitochondria. These genes are found both in the cell’s nucleus, and also within the mitochondria themselves. The loop of DNA inside each of these organelles may be a holdover from their evolutionary origins. Mitochondria are believed to have evolved from parasitic bacteria that lived inside of larger cells.

Work on EPI-743 will now be funded through a $50 million investment being made in Edison by Dainippon Sumitomo, which may later invest another $50 million, at Edison’s discretion, under terms of the new collaboration between the companies. Edison will keep full ownership of EPI-743.

The big Japanese drug company will also pay Edison $50 million in research and development support. The two companies will work together to develop 10 additional drug candidates, and Dainippon Sumitomo will fully fund the efforts required to obtain FDA clearance for clinical trials of those compounds. Edison, in turn, stands to gain revenues from milestone payments, marketing rights, and royalties under the deal.

Both companies are betting that a detailed knowledge of the specific malfunctions in energy metabolism seen in the genetic childhood diseases will yield clues about the related damage found in disorders of the adult nervous system such as Parkinson’s and Alzheimer’s disease.

As in the childhood disorders, clues to the adult neurodegenerative diseases may be found in the mitochondria, those small energy-producing bodies inside cells.

Miller compares the mitochondria to the internal combustion engine that powers a car. The engine can’t completely burn all its fuel, so its exhaust includes noxious gases such as carbon monoxide. Fortunately, cars have catalytic converters that turn the toxic gases into something more benign.

Mitochondria also release byproducts that can be toxic—our old friends the reactive oxygen species—as the tiny organelles produce energy.

“They’re inefficient even in healthy people,” Miller says.

Fortunately, mitochondria have the rough equivalent of catalytic converters. Certain molecules, such as glutathione, neutralize the noxious biochemicals. However, the neutralizing forces sometimes can’t keep up with the mitochondria’s production of harmful byproducts. That sets off a cascade of damage that leads to disease, Miller says.

A number of pharmaceutical companies are now testing drugs that might help clear out the toxic mitochondrial byproducts. EPI-743, Edison’s drug candidate for the childhood disorders stemming from defects in mitochondrial genes, is a co-factor that catalytically augments the production of glutathione, which is believed to be a neutralizing factor.

Glutathione production is also believed to be part of the activity of another Bay area Area company’s experimental drug for disorders of energy metabolism. Novato, CA-based Raptor Pharmaceuticals (NASDAQ: RPTP) recently sought the go-ahead from FDA to conduct clinical trials of its drug cysteamine bitartrate (Procysbi) in Leigh syndrome and other mitochondrial disorders.

The Raptor drug is already approved to treat nephropathic cystinosis, a rare genetic disorder that produces organ damage due to excess amounts of the amino acid cystine. But Raptor says the drug also has anti-oxidant effects, which include increasing the manufacture of glutathione.

Miller says a range of different diseases might stem from inherited inherited defects in genes for mitochondrial functions, or acquired damage to those genes. The study of any disease should involve a look at its energy metabolism, he says.

“We think whole hosts of diseases may have been inappropriately described,” Miller says. Edison estimates that illnesses can be traced to defects in about 2,200 genes that control the processes in the mitochondria.

Damage from the excess electrons released during energy production, also known as oxidative stress, has been linked to adult neurodegenerative conditions such as Parkinson’s, according to Edison. Miller says the company’s studies of mitochondrial defects in genetic childhood disorders and in adult diseases could help unravel a much-pondered scientific mystery.

“The biochemical basis of aging,” he says.

Bernadette Tansey is Xconomy's San Francisco Editor. You can reach her at btansey@xconomy.com. Follow @Tansey_Xconomy

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