Rectify Pharma's Novel Dual-Targeted PFM Shows Promise for Hepatobiliary Diseases at EASL 2025
核心洞察
Rectify Pharmaceuticals (搜索) presented preclinical data at EASL 2025 showing their dual-targeted ABCB4 (搜索)/BSEP (搜索) positive functional modulator improved markers of cholestasis (搜索) and cholangitis (搜索) in hepatobiliary disease models.
The compound RTY-694 demonstrated mechanism-specific improvements in bile acid transport, reduced inflammation markers, and decreased liver fibrosis in two different mouse models of liver disease.
The research was recognized as a noteworthy contribution by EASL and supports advancing this novel therapeutic approach toward clinical trials for primary sclerosing cholangitis (搜索) (PSC (搜索)) and other hepatobiliary diseases.
Rectify Pharmaceuticals (搜索) presented promising preclinical data for their novel dual-targeted positive functional modulator (PFM) at the European Association for the Study of the Liver (EASL) 2025 Congress in Amsterdam. The oral therapeutic, designed to improve biliary and liver health, demonstrated significant improvements in cholestatic and cholangitis (搜索) markers across multiple disease models.
The presentation, delivered by Eric Bell, Ph.D., was recognized by the EASL committee as a noteworthy scientific contribution and will be featured in the "Best of EASL Congress" slide deck.
Novel Mechanism Addresses Root Causes of Hepatobiliary Disease
RTY-694, Rectify's lead compound, represents a new therapeutic approach as a dual-targeted ABCB4 (搜索)/BSEP (搜索) positive functional modulator. The drug works by increasing both ABCB4 and BSEP protein levels and enhancing the efflux of their respective substrates - phospholipids and bile acids.
"Patients living with hepatobiliary diseases face limited treatment options, most of which fail to address the underlying mechanisms driving biliary pathophysiology," said Rajesh Devraj, Ph.D., President and Chief Executive Officer of Rectify. "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."
This mechanism directly targets the pathophysiological drivers of conditions like primary sclerosing cholangitis (搜索) (PSC (搜索)), a progressive liver disease characterized by inflammation and scarring of the bile ducts.
Compelling Preclinical Evidence in Multiple Disease Models
The data presented at EASL 2025 demonstrated RTY-694's efficacy in two orthogonal models of hepatobiliary disease:
In the BsepE297G mouse model, which recapitulates Progressive Familial Intrahepatic Cholestasis (搜索) Type 2 (PFIC2 (搜索)), two weeks of therapeutic treatment with RTY-694 resulted in:
- Reduced serum bile acid levels and increased biliary bile acid levels, confirming the drug's mechanism of action
- Decreased markers of cholestasis (alkaline phosphatase, ALP) and inflammation (alanine aminotransferase, ALT)
- Reduced total liver weight, indicating improved overall liver health
In Abcb4 (搜索)+/- mice on a lithogenic diet, a novel model that mimics key features of PSC (搜索), administration of RTY-694 led to:
- Increased biliary phospholipids
- Decreased serum markers of cholestasis (serum bile acids and ALP)
- Reduced markers of ductular reaction (CK19) and cholangitis (CXCL-1 and CD11b)
- Decreased markers of liver fibrosis
These findings provide strong translational evidence supporting the potential of RTY-694 to address multiple aspects of hepatobiliary disease pathology.
Path Forward to Clinical Development
Pol Boudes, M.D., Chief Medical Officer of Rectify, emphasized the significance of these results: "These encouraging translational results build on our pioneering work aimed at addressing pathology at the core of many liver and biliary diseases. With demonstrated on-target activity and clear proof of biology, we are excited to advance rapidly towards the clinic."
The company plans to prioritize primary sclerosing cholangitis (搜索) (PSC (搜索)) as their initial clinical target. PSC represents a significant unmet medical need, with limited effective treatment options currently available. The progressive nature of the disease often leads to liver failure, with liver transplantation being the only definitive treatment.
Innovative Platform Technology
Rectify's approach leverages their proprietary platform focused on Positive Functional Modulators (PFMs), a novel class of oral small molecules designed to restore and enhance membrane protein function. This platform addresses a historically difficult challenge in drug development - modulating the activity of both wild-type and mutated membrane-bound proteins with small molecules.
The company's technology has potential applications beyond hepatobiliary diseases, with possible extensions to cardio-renal-metabolic and neurodegenerative conditions where membrane protein dysfunction plays a key role.
Rectify Pharmaceuticals (搜索) was founded and initially funded by Atlas Venture (搜索), who co-led their $100 million Series A financing round with Omega Funds (搜索), joined by Forbion (搜索) and Longwood Fund (搜索).
The full presentation from EASL 2025 will be available on the Rectify website, providing additional details on this promising therapeutic approach for researchers and clinicians interested in hepatobiliary diseases.