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BridgeBio launches CoA Therapeutics to treat a rare neurodegenerative disease

The startup is developing allosteric activators to increase levels of the vital metabolic molecule coenzyme A in pantothenate kinase-associated neurodegeneration

by Ryan Cross
June 13, 2018 | APPEARED IN VOLUME 96, ISSUE 25

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Credit: Mi Kyung Yun and Stephen W. White
A structure of the inactive form of PANK3—the enzyme that CoA Therapeutics aims to activate—bound to aceteyl-CoA, which inhibits the enzyme.

BridgeBio Pharma is expanding its roster of laser-focused subsidiaries this week. This morning, it launched CoA Therapeutics to develop small-molecule drugs that boost levels of an important biochemical called coenzyme A (CoA) in genetic diseases where it is in short supply.

And earlier this week, BridgeBio launched a company called Origin Biosciences, which licensed a compound from Alexion Pharmaceuticals to treat an ultra-rare metabolic disease caused by a specific kind of molybdenum cofactor deficiency.

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Credit: BridgeBio Pharma
Virani

Founded in 2015, BridgeBio now has 19 subsidiary companies, each focused on a single drug development program or a group of programs for closely related diseases. “We’ve been moving so fast that it has been difficult to keep tabs on how many programs morph into subsidiaries,” says Shafique Virani, CEO of CoA Therapeutics. Although details for most of the companies are not disclosed, BridgeBio has so far stuck to launching firms focused on genetically defined cancer targets or rare genetic diseases.

One such disease, pantothenate kinase-associated neurodegeneration (PKAN), is the focus of CoA Therapeutics. Children born with PKAN develop involuntary muscle contractions and have difficultly speaking and swallowing. They are usually diagnosed before the age of 10 and often die as young adults, due to a shortage of CoA.

“The amount of CoA in the cell has been largely ignored over the years,” says Suzanne Jackowski, a cell and molecular biologist at St. Jude Children’s Research Hospital in Memphis who has studied CoA metabolism since 1980. CoA plays a central role in scores of metabolic processes, and for decades many scientists focused on what happened after CoA was used. “People pretty much thought there was plenty of CoA,” she adds.

Then in the early 2000s, scientists discovered that mutations in a gene called PANK2, which produces the enzyme pantothenate kinase 2, were linked to PKAN disease. In short, the PANK2 enzyme is the first stop in a pathway that metabolizes vitamin B5 (or pantothenate) into CoA. Without properly functioning PANK2 enzymes, the brain faces shortages of CoA, which ultimately leads to the neurodegeneration associated with PKAN.

People with PKAN, and dysfunctional PANK2, still have a pair of similar enzymes called PANK1 and PANK3 that work just fine. The problem is that the latter is turned off most of the time. “It is like a back-up system,” Jackowski says, making it a prime target to turn on with a drug.

A few years ago Jackowski and three of her St. Jude colleagues began looking for ways to prevent PANK3 from defaulting to its inactive state. The team devised a series of allosteric activators, which bind one half of the PANK3 “and reach across the interface to tickle the other half,” keeping it in an active state, Jackowski says.

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The group also created a mouse model that mirrored aspects of PKAN and demonstrated the ability of the activator compounds to readily cross the blood-brain barrier and correct the behaviors associated with the disease. “That’s where we got interested,” Virani says.

CoA Therapeutics has licensed and further refined the St. Jude team’s compounds, which are allosteric activators of both PANK1 and PANK3. Virani says the company plans to run a healthy volunteer study of the drug early next year, followed by testing in people with PKAN by the end of 2019. BridgeBio isn’t disclosing financial details at this time.

PKAN is an ultra-rare condition whose prevalence is difficult to estimate. The regularly cited statistic is that PKAN affects three in one million people, but Virani estimates that his company’s compound could help 1,000 patients worldwide.

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