A4250 is a highly potent and selective inhibitor of the ileal bile acid transporter (IBAT, sometimes also referred to as the apical sodium dependent bile acid transporter (ASBT)) that acts locally in the gut resulting in a reduced risk of systemic side effects and undesirable drug-drug interactions. We are developing A4250 as a treatment initially for PFIC and plan to consider additional development in other pediatric cholestatic liver diseases and disorders in the future.  A4250 has been granted orphan drug designation for PFIC in the United States and the European Union.

When the flow of bile from the liver stops or is disrupted, known as cholestasis, bile acids accumulate in the liver. Elevated bile acid levels in the liver and serum are primary characteristic of cholestatic liver diseases and have been linked to the severe pruritus in these patients. The IBAT is primarily responsible for mediating the uptake of bile acids from the small intestine to the liver as part of a process known as enterohepatic circulation. Typically, approximately 95% of bile acids are recirculated via the IBAT to the liver. Accordingly, a product capable of inhibiting the IBAT would lead to less bile acids returning to the liver and represent a promising approach for treating cholestatic liver diseases.

In addition to the effects on liver and serum bile acids, IBAT inhibition has also been shown in the clinic to decrease LDL cholesterol and increase GLP1 secretion (which is linked to decreased insulin resistance) and, in preclinical models, to decrease pro-inflammatory markers (such as tumor necrosis factor alpha, or Tnf-α), and profibrotic markers (such as collagen, type 1, alpha 1 and 2) in the liver. High cholesterol, insulin resistance, increased liver inflammation and fibrosis are all key hallmarks of NASH, making IBAT inhibition likewise a promising approach for treating NASH.

A4250 is currently being evaluated in a Phase 2 clinical trial in children with chronic cholestasis.

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