Shire plc announced that the 13-week phase 2 IMAGO trial of its investigational compound SHP625 (LUM001) did not meet the primary or secondary endpoints in the study of 20 pediatric patients with Alagille syndrome (ALGS), a rare, life-threatening genetic disorder that presents with chronic cholestasis (accumulation of bile acids in the liver) and severe pruritus (itching). The primary endpoint was the change from baseline in serum bile acid levels as compared to placebo. The secondary endpoint of pruritus was assessed using the novel ItchRO instrument.

Mean serum bile acid levels and pruritus at the end of the study were lower in both SHP625 and placebo treated groups as compared to baseline. However, in a post-hoc analysis, a positive correlation between percent changes from baseline in serum bile acid levels and pruritis was observed in the SHP625 treated group. The number of patients in the placebo treated group was too small to make an accurate assessment of this relationship.

There were no treatment emergent serious adverse events in this study. As expected, the most common adverse events were diarrhea and abdominal pain, which were more frequent with SHP625 than with placebo.

We have gained important insights from these first results from one of several phase 2 studies in the SHP625 development program, said Philip J. Vickers, Ph.D., head of research and development, Shire. We remain committed to continuing the ongoing studies of SHP625 in ALGS and other indications.

In addition to IMAGO, two larger placebo-controlled phase 2 studies in ALGS are in progress, one of which has pruritus as the primary endpoint. SHP625 is also being studied in progressive familial intrahepatic cholestasis, primary biliary cirrhosis and primary sclerosing cholangitis.

IMAGO is a phase 2 multicenter, randomized, placebo-controlled study of children with ALGS, 1-18 years of age, conducted in the United Kingdom. Subjects (n=20) were randomized to receive oral, once-daily SHP625, 140 g/kg/day (n=6) or 280 g/kg/day (n=8) or placebo (n=6). The primary endpoint was change in fasting serum bile acid levels from baseline to Week 13. Serum bile acid level reductions from baseline were -66.1 mol/L and -42.1 mol/L (p=0.69) in the SHP625 and in the placebo treated groups, respectively. For the secondary endpoint of pruritus, the change from baseline for the ItchRO(Obs) scores was -0.61 and -0.59 (p=0.95) in the SHP625 and the placebo treated groups, respectively. Additional secondary endpoints included change in liver enzymes. The most common adverse events with SHP625 vs placebo were diarrhea (64.3% vs 33.3%) and abdominal pain (42.9% vs 16.7%).

SHP625 is being studied in several rare cholestatic liver diseases for both pediatric and adult populations. Preclinical models demonstrate that SHP625 is a potent, selective minimally absorbed inhibitor of the apical sodium-dependent bile acid transporter. It blocks bile acid reabsorption in the terminal ileum and increases fecal bile acid excretion, thereby reducing recirculation of bile acids to the liver.

Alagille syndrome (ALGS) is a rare, life-threatening genetic disorder occurring in approximately one in 30,000 live births that affects the liver, heart, kidney and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood. A person with Alagille syndrome has fewer than the normal number of bile ducts inside the liver. This causes bile to build up in the liver, a condition called cholestasis, and leads to liver damage. In addition, a buildup of bile acids in the blood also can cause pruritus, or itching, which can be severe. There are no approved medical therapies for ALGS, but some treatments can address its symptoms. Ten to 30 per cent of people with ALGS will require a liver transplant.