RTY-694 shows promise in models of liver, bile duct diseases PFIC, PSC
Therapy is designed to boost activity of two proteins involved in bile production
In a mouse model of progressive familial intrahepatic cholestasis type 2 (PFIC2), Rectify Pharmaceuticals’ experimental oral therapy RTY-694 reduced markers of slowed bile flow and inflammation and also lowered markers of bile duct inflammation and liver scarring in a model of primary sclerosing cholangitis (PSC), the first indication for which it’s being developed.
That’s according to new data that Rectify presented this month at the European Association for the Study of the Liver (EASL) 2025 Congress in Amsterdam. The presentation, which was recognized by the EASL committee as a noteworthy contribution to the congress’s scientific program, was titled “Novel dual-acting ABCB4/MDR3 and ABCB11/BSEP positive functional modulator demonstrates anti-cholestatic and anti-cholangitis activity in two orthogonal models of hepatobiliary disease.”
“Patients living with hepatobiliary [liver and bile duct] diseases face limited treatment options, most of which fail to address the underlying mechanisms driving biliary [damage],” Rajesh Devraj, PhD, president and CEO of Rectify, said in a company press release.
“With demonstrated on-target activity and clear proof of biology, we are excited to advance rapidly toward the clinic with the goal of offering a potentially transformative option to patients suffering from serious hepatobiliary diseases, starting with PSC,” said Pol Boudes, MD, Rectify’s chief medical officer.
Boosting proteins in bile production
Bile acids and other components of bile are made in the liver, then shipped to the intestines through tubes called bile ducts. When bile flow is disrupted — a condition called cholestasis — bile can build up in the liver and spill out into the bloodstream, setting the stage for liver damage.
PFIC and PSC are both marked by cholestasis. PFIC is caused by genetic mutations that affect bile’s transport out of the liver. There are several PFIC types, each one associated with mutations in different genes. PSC is an autoimmune disease marked by chronic cholangitis, or inflammation of the bile ducts, that subsequently affects bile flow.
RTY-694 is made to boost the activity of BSEP and ABCB4, two proteins involved in bile production and located at the cell membrane. BSEP pumps bile acids out of liver cells and ABCB4 is involved in the secretion of fatty molecules called phospholipids to prevent damage to the bile ducts. Both proteins’ levels are altered in PSC and mutations in the genes that encode them are the cause of two types of PFIC, the BSEP gene for PFIC2 and the ABCB4 gene for PFIC type 3.
RTY-694 acts as a positive functional modulator (PFM) for both proteins. PFMs help restore trafficking of membrane proteins to the cell membrane and/or boost the function of such proteins at the cell membrane.
“PFMs represent a new class of oral therapeutics with the potential to restore and enhance the function of membrane proteins and modify the course of disease,” Devraj said.
Effects of RTY-694 in PFIC, PSC models
In preclinical experiments, RTY-694 significantly increased BSEP and ABCB4, and boosted the secretion of bile acids and phospholipids, respectively.
In a mouse model of PFIC2, RTY-694 significantly reduced bile acid levels in blood, while increasing those in bile. The therapy also significantly decreased blood levels of cholestasis and inflammation markers, along with the weight of the liver, which often becomes enlarged in cholestasis.
The therapy was also tested in a new mouse model of biliary diseases, that is, those affecting the bile ducts. Mice were engineered to produce low ABCB4 protein levels and were fed a special diet that promotes gallstones, or hard deposits of bile that can form in the gallbladder, where bile is stored, and become stuck in the bile ducts.
According to Rectify, these mice develop liver and bile duct damage that’s similar to what happens in people with PSC.
Preventive treatment with RTY-694 significantly increased the amount of phospholipids secreted into bile and significantly reduced the amount of bile acids in blood, the results showed. It also reduced markers of cholestasis, bile duct inflammation and scarring, and ductular reaction, which is marked by the excessive growth of bile duct cells in response to liver injury.
Increasing BSEP and ABCB4 activity with RTY-694 reduces disease markers of “ductular reaction, inflammation and fibrosis in a mouse model of biliary disease and demonstrates anti-cholestatic activity in a genetic mouse model of PFIC,” the researchers wrote.
“These encouraging translational results build on our pioneering work aimed at addressing [abnormal mechanisms] at the core of many liver and biliary diseases,” Boudes said.
The preclinical data “further strengthen the promise of [RTY-694] to improve biliary and liver health, and we remain focused on swiftly driving this candidate toward clinical evaluation to help patients with hepatobiliary diseases,” Devraj said.
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