Date: 2015-04-09
Type of information: Results
phase: 2
Announcement: results
Company: Shire (UK-USA)
Product: LUM001/SHP625 (maralixibat) (4R,5R)-1-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride
Action
mechanism: protein inhibitor. SHP625/LUM001 is a 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.
Disease: Alagille syndrome
Therapeutic area: Hepatic diseases - Liver diseases - Rare diseases
Country: UK, USA
Trial
details: 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 µg/kg/day (n=6) or 280 µg/kg/day (n=8) or placebo (n=6). The primary endpoint was change in fasting serum bile acid levels from baseline to Week 13. (NCT01903460 )
Latest
news: * On April 9, 2015, Shire 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). 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. The primary endpoint was the change from baseline in serum bile acid levels as compared to placebo. 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 µmol/L and -42.1 µmol/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%).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. 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. * On May 12, 2014, Shire and Lumena Pharmaceuticals announced the acquisition of Lumena Pharmaceuticals by Shire. * On September 26, 2013, Lumena Pharmaceuticals, a company developing oral therapeutics for rare liver diseases, announced the initiation of a global clinical program to evaluate its drug candidate LUM001 in children with Alagille syndrome. The first patient has been dosed in the IMAGO Phase II study being conducted in the U.K., and enrollment of pediatric patients is expected to begin later this year in the ITCH Phase II study in the U.S. The IMAGO study is a 13 week placebo-controlled study to evaluate the safety and efficacy of LUM001 in children with ALGS. The U.K. based study will enroll children, two years of age and older, with ALGS. The ITCH study is a multi-center U.S.-based study which is expected to begin later in 2013 and will be seeking pediatric patients, two years of age and older, with ALGS. The ITCH study is being conducted in collaboration with the Childhood Liver Disease Research and Education Network (ChiLDREN), a collaborative research network supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a part of the National Institutes of Health (NIH),which has a Cooperative Research and Development Agreement (CRADA) with Lumena. Lumena and ChiLDREN are also collaborating with European investigators to evaluate LUM001 in patients with progressive familial intrahepatic cholestasis (PFIC), another rare cholestatic liver disease. Patients that complete either the IMAGO or ITCH study will be eligible for participation in a long-term extension study.
