Rectify Pharma is using its ABCs to treat PSC.
Three years after raising $100 million in series A funds, the Atlas Venture-backed biotech has chosen a lead drug candidate: the small molecule RTY-694, which is meant to treat the rare liver disease primary sclerosing cholangitis (PSC) by restoring and enhancing the function of two cell membrane proteins in the ABC transporter family.
The drug improved bile composition and reduced inflammation and fibrosis in a mouse model of the disease, the company announced in an Oct. 22 release.
Rectify plans to start first-in-human trials next year, President and CEO Rajesh Devraj, Ph.D., told Fierce Biotech in an interview. Afterward, the company aims to "de-risk this program in the clinic early in a phase 2a proof-of-mechanism in PSC patients," Devraj explained.
Rectify chose to focus on ABC transporters in order to build on the prior success of scientific founder and Chief Scientific Officer Jonathan Moore, Ph.D., a structural biologist who spent almost 28 years at Vertex Pharmaceuticals working on drugs for cystic fibrosis that target the ABCC7 transporter. Those efforts played a role in the creation of four approved drugs, including the blockbuster combo therapy Trikafta.
PSC is a disease of uncertain cause that leads to scarring of the bile ducts, which results in bile backing up into the liver and damaging it. Bile is a digestive fluid needed to break down fats that is made by the liver and normally stored in the gallbladder. If bile ends up trapped in the liver, it can cause liver scarring called cirrhosis as well as other symptoms like jaundice, itchiness and fever.
Advanced PSC is often treated with a liver transplant, but recurrence is common, with one study finding that 25% of transplant patients saw their disease return.
Rectify’s platform is built on a library of small molecules that the company can rapidly screen for the ability to bind to membrane proteins and restore or improve their function. The company calls these molecules positive functional modulators, or PFMs. RTY-694 won out over other PFMs to become the lead candidate because it is highly selective, can be taken orally and is projected to need a low dose, Devraj said.
RTY-694 targets two ABC transporters, ABCB4 and BSEP. BSEP shuttles bile acids from liver cells into bile, while ABCB4 transports the phospholipid phosphatidylcholine, which is critical for maintaining a healthy bile composition.
Targeted together, “they're able to change and address the core driver and the core pathophysiology of multiple hepatobiliary diseases,” Devraj said, whereas other treatments only address symptoms. Potential other liver indications include primary biliary cholangitis and low phospholipid associated cholelithiasis syndrome, he added.
“It's a pipeline-in-a-pill approach,” Devraj said, “one pill to solve a number of hepatobiliary diseases that are driven by the underlying drivers of dysregulated bile acid metabolism and increased bile acid accumulation.”
Rectify plans to present its preclinical results in two posters at the American Association for the Study of Liver Diseases meeting in November.
The company is also making headway with PFMs in its cardiorenal metabolic and neurodegenerative programs, Devraj said. “Not only have we established a platform, but we have driven what we consider a novel small molecule modality.”