New primary sclerosing cholangitis treatment to target ACLY enzyme
Esperion: The enzyme plays a 'central role in metabolic regulation'
With ESP-1336 as their lead candidate, Esperion Therapeutics is developing new treatments for primary sclerosing cholangitis (PSC) by targeting an enzyme called ACLY.
“We are leveraging our deep expertise in ACLY biology … to address the urgent needs of patients living with PSC,” which is “a rare and progressive liver disease with no approved therapies proven to slow or halt its progression,” Sheldon Koenig, CEO of Esperion, said in a company press release.
In a separate press release announcing its latests financial results and business updates, Koenig said: “We were especially pleased to share our exciting news regarding pipeline expansion at our recent R&D Day, where we unveiled our promising research supporting lead development candidates, including ESP-1336, for the treatment of primary sclerosing cholangitis.”
“ACLY is a promising target in hepatic [liver] disease, given its central role in metabolic regulation,” said David E. Cohen MD, PhD, chief of the gastroenterology, hepatology, and endoscopy division at Brigham and Women’s Hospital in Boston.
According to Esperion, there are about 76,000 people in the U.S. and Europe with PSC, an autoimmune disease marked by chronic cholangitis, or inflammation of bile ducts, the series of tubes that carry the digestive fluid bile from the liver to the intestines. Chronic cholangitis in PSC can set the stage for liver damage and scarring (fibrosis), which can lead to liver failure or cancer. There are no approved therapies proven to cure PSC or halt its progression.
ACLY (adenosine triphosphate citrate lyase) is the main enzyme responsible for producing acetyl-coenzyme A, a molecule involved in the noncanonical tricarboxylic acid pathway, which cells use to generate energy.
Role of ACLY enzyme in PSC progression
The pathway becomes dysregulated in multiple diseases and is usually accompanied by an increase in ACLY, Christos Mantzoros, MD, PhD, a professor of medicine at Harvard Medical School, said during Esperion’s R&R Day webcast. For example, higher ACLY levels have been detected in cells of people with fatty liver disease, a condition marked by excess fat in the liver. Increased levels of the enzyme are also known to be associated with mechanisms of PSC progression, including slowed bile flow (cholestasis) and tissue injury, inflammation, and fibrosis. Specifically, high ACLY is linked to abnormal production of bile and fatty molecules like cholesterol that cause cholestasis and injury of bile ducts and liver, production of pro-inflammatory molecules, and the activation of hepatic stellate cells, which are liver cells with a central role in liver fibrosis.
“By modulating acetyl-coenzyme A levels in multiple hepatobiliary cell types, these inhibitors may disrupt key disease-driving pathways in PSC, offering a potentially transformative approach to treatment,” Cohen said.
“Even though we don’t know, intrinsically, what is the exact cause of PSC, we know that all of these processes contribute. And if we can address them, even without addressing the root cause of this primary disease that we don’t know the cause of, we really think we can make some progress,” Cohen said in the webcast. “I think this is a very exciting opportunity.”
Esperion is working to identify lead, orally available allosteric suppressors, or inhibitors, of ACLY that have the potential to be tested in the clinics. Allosteric inhibitors are molecules that reduce the activity of an enzyme by binding to a region that doesn’t correspond to the enzyme’s active site, where it binds to the molecule it acts upon.
ESP-1336 has been shown to reduce liver injury, inflammation, and fibrosis in multiple PSC-relevant preclinical models.
“Our lead candidates, including ESP-1336, are promising, potential first-in-class allosteric ACLY inhibitors, well characterized with significant preclinical data, and represent a natural extension of our metabolic franchise,” Koenig said. “Our next-generation ACLY inhibitor discovery program was purpose-built to improve potency, selectivity, and guide indication and patient population selection through data-driven innovation.”
Esperion plans to meet with the U.S. Food and Drug Administration (FDA) this year to discuss plans for an investigational new drug application, which is a formal request to begin clinical testing in humans. If all goes well, the company wants to begin Phase 1 clinical testing next year, with the hope of bringing a new therapy to market sometime around 2030.
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