Assembly Biosciences Announces Expansion of ABI-6250 Clinical Development Into Cholestatic Liver Diseases

Assembly Bio Expands ABI-6250 Development into Cholestatic Liver Diseases

Assembly Biosciences is expanding the clinical development of its oral entry inhibitor, ABI-6250, into cholestatic liver diseases, specifically primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). This move builds on its ongoing development for chronic hepatitis delta virus (HDV) infection. A Phase 2 basket study for PBC and PSC is projected to commence in Q1 2027, following positive pre-IND discussions with the U.S. FDA. ABI-6250 targets the NTCP receptor, which plays a dual role in HDV entry and bile acid transport, offering a novel therapeutic approach for these conditions, particularly PSC, which currently lacks approved treatments, and PBC, where many patients do not adequately respond to existing therapies.

• Assembly Biosciences is strategically broadening the clinical scope of ABI-6250 to include primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), addressing significant unmet medical needs in these cholestatic liver diseases. This expansion leverages ABI-6250's mechanism of action, targeting the NTCP receptor, which is integral to both viral entry and bile acid transport. This positions the drug as a potential novel treatment, especially for PSC, which currently has no approved therapies, and for PBC patients who inadequately respond to existing treatments.
• ABI-6250 functions as an oral small-molecule inhibitor of the sodium taurocholate co-transporting polypeptide (NTCP), a membrane protein vital for bile acid transport into liver cells and as an entry receptor for HDV. By inhibiting NTCP, ABI-6250 blocks bile acid uptake, directly addressing a key pathological driver in cholestatic liver diseases. Preclinical data and completed Phase 1a study findings in healthy participants have demonstrated clear target engagement, including dose-dependent elevations in plasma total bile acids, supporting its potential for long-term dosing in upcoming Phase 2 trials.
• The company plans to initiate a Phase 2 clinical study for ABI-6250 in chronic HDV infection in the fourth quarter of 2026. Concurrently, a Phase 2 basket study specifically for cholestatic liver diseases, focusing on PBC and PSC, is anticipated to begin in the first quarter of 2027, subject to regulatory feedback. Assembly Bio recently held a constructive pre-IND meeting with the U.S. Food and Drug Administration, which provided helpful guidance for advancing the program in cholestatic liver diseases.

Addressing Unmet Needs in PBC and PSC Treatment

Recent research has identified several critical unmet needs in Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) treatment, highlighting specific patient populations requiring targeted therapeutic interventions. These conditions continue to present significant challenges due to limited treatment options and variable patient responses to existing therapies.

• PBC patients with inadequate UDCA response represent a key target population, as up to one-third of patients show unsatisfactory response to ursodeoxycholic acid, the standard first-line therapy, necessitating development of novel second-line treatments beyond obeticholic acid

• Asian PBC populations require validated treatment response prediction tools, with recent validation of the UDCA response score (URS) in 173 Korean patients demonstrating good performance in predicting treatment outcomes and liver-related event-free survival

• PSC patients with incomplete biochemical response to UDCA (alkaline phosphatase ≥1.5×upper limit of normal) are being targeted with combination fibrate therapy, showing 41% reduction in ALP levels and decreased pruritus in recent studies

• PSC-associated inflammatory bowel disease patients constitute a high-risk population requiring enhanced surveillance, as PSC affects up to 75% of Northern European patients with ulcerative colitis and significantly increases biliary cancer risk

• Korean ulcerative colitis patients with PSC have emerged as a critical population for cancer surveillance, with biliary cancer incidences significantly higher compared to those without PSC and distinct disease progression patterns

• Advanced PSC patients requiring liver transplantation remain an unmet need, as no effective medical therapy has been developed to delay disease progression, with liver transplantation remaining the only effective treatment for advanced disease

Beyond HDV: NTCP Inhibition for Cholestatic Liver Disease

Assembly Biosciences' decision to advance ABI-6250 into cholestatic liver diseases marks a significant strategic pivot, leveraging a well-understood mechanism for a new frontier in liver therapeutics. The sodium taurocholate cotransporting polypeptide (NTCP) receptor, the target of ABI-6250, is recognized for its dual critical functions: it is the primary entry point for hepatitis B and delta viruses into hepatocytes, and it serves as the major transporter for bile acid uptake into the liver. This dual role positions NTCP inhibitors as a compelling therapeutic avenue for conditions characterized by both viral infection and disordered bile acid metabolism.

This expansion into primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) addresses profound unmet medical needs. PSC, a progressive and severe orphan disease, currently lacks any approved pharmacological treatments. For PBC, while ursodeoxycholic acid (UDCA) is an approved therapy, many patients do not achieve an adequate biochemical response. Preclinical evidence suggests NTCP inhibition can exert hepatoprotective effects in cholestasis by reducing the intracellular burden of toxic bile salts, a mechanism distinct from UDCA, which studies indicate is not significantly transported by NTCP. This offers a new therapeutic angle for non-responders.

The success of bulevirtide, another NTCP entry inhibitor, in chronic hepatitis delta virus (HDV) infection provides a valuable precedent. Bulevirtide has demonstrated significant virologic and biochemical responses with a favorable safety profile, even in patients with decompensated cirrhosis. This clinical experience with NTCP inhibition in a severe liver disease context offers a degree of de-risking for ABI-6250's development. Strategically, this move diversifies Assembly Biosciences' pipeline, reducing reliance on a single indication and opening up substantial market opportunities, particularly for PSC where a first-in-class therapy would be transformative.

However, the path forward is not without considerations. While preclinical data in mice showed that elevated plasma bile acid levels following NTCP inhibition were well tolerated, the long-term safety implications of systemic bile acid accumulation in human patients with chronic cholestatic conditions, especially those with advanced liver disease, will require rigorous clinical evaluation. Translating the observed hepatoprotective effects from animal models to the complex pathophysiology of human PBC and PSC will also be critical. The upcoming Phase 2 basket study will be instrumental in validating ABI-6250's clinical efficacy and safety profile in these challenging indications.