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Silver lining as Shire rare disease programme hits a setback

Alagille syndrome candidate fails to meet phase II targets

Shire BasingstokeShire suffered a setback in its rare disease pipeline after a candidate for the genetic disease Alagille syndrome (ALGS) failed its objectives in a phase II trial.

ALGS is mainly caused by mutation or deletion of the JAG1 gene on chromosome 20, and has a prevalence of around 1 in 70,000 newborns. It is characterised by liver damage and heart problems and while life expectancy is variable up to a third of patients will eventually need a liver transplant.

Shire's SHP625 (formerly known as LUM001) - a bile acid transporter inhibitor designed to correct the liver defect in ALGS - missed all its objectives in the IMAGO study involving 20 children with the syndrome.

The primary outcome measure in IMAGO was the mean change from baseline in serum bile acid levels after 13 weeks' treatment, while secondary endpoints included pruritus (itching) and changes in liver enzyme levels, which provide a biomarker for liver damage.

SHP625 was associated with a drop of 66.1 micromoles/L in serum bile acid levels at week 13, compared to a reduction of 42.1 micromoles/L in the placebo group. The difference was not sufficient to conclude that Shire's drug was effective, although the company said there was "a positive correlation between percent changes from baseline in serum bile acid levels and pruritis."

The drug candidate had been tipped by some analysts as a blockbuster and was the most advanced asset acquired as part of Shire's $260m-plus purchase of Lumena Pharmaceuticals last year, and the disappointing results cast a shadow over the entire clinical programme for the drug.

SHP625 is being tested in three other clinical trials involving patients with primary biliary cirrhosis, progressive familial intrahepatic cholestasis and primary sclerosing cholangitis, and its disappointing impact on bile acid could also have an impact on these other programmes.  In addition, the company has two more trials in ALGS in play.

A follow-up compound called SHP626/LUM002, a drug with the same mechanism of action that is due to start phase Ib trials in non-alcoholic steatohepatitis (NASH), a condition characterised by accumulation of fat in liver cells and inflammation in the liver, later this year.

Lifitegrast priority review

The news on SHP625 was disappointing but Shire was given immediate comfort when it emerged that the FDA had granted a priority review to its dry eye treatment lifitegrast (SHP606), setting it up for a potential approval in October.

Shire has previously predicted that lifitegrast - a small molecule integrin beta(2) antagonist licensed from SARcode Bioscience in 2013 - will become a $1bn product by 2020.

Article by
Phil Taylor

10th April 2015

From: Research



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