One of two major assets from Shire plc's multimillion-dollar Lumena Pharmaceuticals Inc. buy, SHP625 (LUM001), is shining a little less brightly after missing both primary and secondary endpoints in a small phase II study called IMAGO, which tested its ability to lower bile acid levels and minimize itching vs. placebo for children with Alagille syndrome (ALGS), a rare genetic disorder.

The top-line data from the 13-week IMAGO study represent the first Lumena-linked clinical outcome that Shire has shared since paying Lumena shareholders $300.3 million in cash to buy the company last year for SHP625 and SHP626 (LUM002), plus up to $265 million for the successful achievement of clinical development milestones related to the programs. The company is developing SHP626 for the treatment of nonalcoholic steatohepatitis.

Both compounds are inhibitors of the apical sodium-dependent bile acid transport, which is primarily responsible for recycling bile acids from the intestine to the liver.

The company is developing SHP625, the more advanced of the programs, first for the potential relief of the extreme itching, or pruritus, associated with cholestatic liver disease as well as three other indications. In IMAGO, it sought to measure change from baseline in serum bile acid levels as compared to placebo as a primary endpoint. The secondary endpoint was relief from itching.

Mean serum bile acid levels and pruritus at the end of the study were lower in both SHP625 and placebo groups as compared to baseline.

While a post-hoc analysis uncovered a positive correlation between percent changes from baseline in serum bile acid levels and pruritus in the treatment group, the number of patients in the placebo group was too small to make an accurate assessment of the relationship.

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

Shire's R&D chief, Phil Vickers, said the company "gained important insights" from the trial and is committed to testing the drug further in ALGS, for which the company is running two larger placebo-controlled phase II studies, as well as in other indications. The company is looking at progressive familial intrahepatic cholestasis, primary biliary cirrhosis and primary sclerosing cholangitis.

"It is still early in the development program," Shire spokeswoman Stephanie Fagan told BioWorld Today. "Continued evaluation of SHP625 in clinical trials will determine our regulatory strategy."

The Lumena-sourced assets in Shire's portfolio are slated to account for at least part of the $3 billion in sales the company expects innovative medicines to contribute to its pipeline by 2020, but how big a slice of that pie they represent is unclear. Shire declined to provide further information.

Alagille syndrome is estimated to occur in one of 70,000 live births among all ethnic groups, according to Thomson Reuters Incidence & Prevalence Database, putting it among the five most common causes of chronic childhood cholestasis.

The Alagille Syndrome Alliance, a group devoted to bettering the lives of people affected by ALGS, said it applauds the efforts of Shire and other pharmaceutical companies that choose to invest their time and resources into developing therapies for the syndrome.

"Shire's ongoing efforts to understand and treat ALGS are exemplary, and I view these preliminary results as but a small hurdle in unraveling the complexities of this and other rare cholestatic liver diseases," alliance founder and CEO Cindy Hahn told BioWorld Today.

SHP625 was originally created by Pharmacia Corp. and was later licensed to Lumena via Satiogen Pharmaceuticals Inc. Thomson Reuters Cortellis Clinical Trials Intelligence lists Albireo AB's phase II candidate, a specialized formulation from a program of ileal bile acid transporter called A-4250, as the only other therapy in development to treat the syndrome.

PRIORITY REVIEW FOR DRY EYE DRUG

Despite the setback, the news wasn't all bad for Shire on Thursday. The company gained an FDA priority review designation for the small-molecule integrin inhibitor lifitegrast, an investigational treatment for dry eye disease in adults. If approved, it could be the first treatment indicated to address both signs and symptoms of the disease, Shire said.

The FDA is expected to decide whether or not to approve the drug by an Oct. 25 PDUFA date.

American D=depository receipts for Shire shares (NASDAQ:SHPG), which initially declined on Thursday, rose $7.24 to $254.32 by the market's close.