Oral ABI-6250 may move into Phase 2 clinical testing for PBC and PSC
Assembly Bio expects to launch a trial in early 2027, pending feedback
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Assembly Biosciences plans to develop its investigational oral treatment, ABI-6250, for people with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).
The therapy is already in development for chronic hepatitis D, a severe viral liver disease, with a Phase 2 clinical trial planned for later this year. Assembly Bio expects to launch early next year a Phase 2 trial testing ABI-6250 in people with PBC or PSC, pending regulatory feedback.
The expansion of ABI-6250’s development followed a recent pre-IND meeting with the U.S. Food and Drug Administration about the company’s clinical development plans, according to Assembly Bio.
“We are excited to expand the ABI-6250 program into PBC and PSC, where there remains significant unmet medical need despite existing PBC therapies, and in the case of PSC, no approved treatments,” Anuj Gaggar, MD, PhD, Assembly Bio’s chief medical officer, said in a company press release. “We believe ABI-6250 has the potential to address key drivers of disease … in these conditions and look forward to advancing clinical evaluation in these populations.”
PBC and PSC affect bile flow in the liver
PBC and PSC are two chronic liver diseases that cause chronic cholangitis, or long-lasting inflammation in the bile ducts. These ducts carry bile, a digestive fluid, from the liver to the small intestine. While PBC affects bile ducts inside the liver, PSC can affect ducts both inside and outside the liver.
Bile duct inflammation can slow or block bile flow, a condition known as cholestasis. This can cause bile acids to build up in the liver and bile components to leak into the bloodstream, contributing to liver damage and symptoms such as itching.
ABI-6250 is an oral small-molecule therapy designed to block a protein found at the surface of liver cells called sodium taurocholate cotransporting polypeptide (NTCP). This protein helps move bile acids, the main components of bile, back into liver cells so they can be reused. NTCP is also used by the hepatitis D virus to enter liver cells.
By blocking NTCP, ABI-6250 is designed to block hepatitis D virus entry into liver cells and reduce the movement of bile acids back into liver cells, an approach Assembly Bio believes could help address disease processes involved in PBC and PSC, including inflammation and liver damage.
The therapy targets the same NTCP pathway as Hepcludex (bulevirtide-gmod), an injectable treatment that became the first therapy approved in the U.S. for chronic hepatitis D in adults without cirrhosis or with compensated cirrhosis.
“Treatment options for cholestatic liver diseases have expanded in recent years, but important gaps remain, particularly for patients with PSC for whom no treatments currently are approved and for those with PBC who do not adequately respond to the current therapies,” said Christopher Bowlus, MD, a professor at the University of California, Davis.
“Targeting NTCP represents a mechanistically distinct approach compared to currently approved therapies, given its central role in bile acid transport,” Bowlus added. “An oral agent like ABI-6250 that modulates this pathway could offer a differentiated strategy to impact disease biology and patient symptoms.”
Early data support planned Phase 2 trial
The decision to expand ABI-6250’s development for PBC and PSC was supported by preclinical data and results from a Phase 1a trial (NCT06740474) in 40 healthy participants. The study tested single and multiple increasing doses of ABI-6250 against a placebo.
Trial data showed that ABI-6250 has a half-life of about four days, supporting once-daily dosing. The therapy also led to dose-dependent increases in blood bile acids, a sign of NTCP inhibition, when given once daily for 10 days.
According to Assembly Bio, the increases in blood bile acids matched or exceeded those reported with Hepcludex, and did so at lower doses.
Treatment-emergent adverse events were grade 1 or 2, meaning mild or moderate, and no serious adverse events were reported. Grade 1 or 2 elevations in alanine aminotransferase, or ALT, a marker of liver damage, were observed at a similar rate across all dose groups, including placebo, and Assembly Bio said similar findings were seen in early Hepcludex studies. No itching-related adverse events were reported.
According to the preliminary design of the planned Phase 2 trial in PBC and PSC, ABI-6250 will be tested against a placebo for 12 weeks, or about three months, in more than 100 patients. In people with PBC, ABI-6250 will be evaluated as either a second- or third-line treatment, while in people with PSC, it will be tested as a first-line therapy.
The study is expected to include an initial sentinel dosing phase, in which a small number of participants receive different doses first to help researchers choose doses for the larger PBC and PSC groups. The study’s key goals may include assessing changes in biochemical markers, itching, and health-related quality of life.
