Intercept’s big Nash day draws near

If 2019 is the year of non-alcoholic steatohepatitis then Intercept Pharmaceuticals is the liver disease’s standard bearer. Pivotal data with the company’s FXR agonist Ocaliva, due this quarter, could not only make or break Intercept; they could also fuel or dent enthusiasm for the many other Nash players.

The Regenerate trial of Ocaliva in Nash has a reasonable chance of success, given that the drug only has to hit one of two co-primary endpoints. But the bar is higher for success on the market: if Ocaliva does only score on one endpoint, its commercial chances would look shaky. Moreover, its safety – which has been a problem in Ocaliva’s approved indication, primary biliary cholangitis – remains a big question mark.

Given that expectations for Ocaliva in Nash account for most of Intercept’s $3.5bn market cap, any hint of a problem in the Regenerate dataset could see the group’s stock heavily punished.

Nonalcoholic steatohepatitis (Nash) is an advanced form of nonalcoholic fatty liver disease. In both disorders fat accumulates in the liver, but in Nash there is also inflammation and liver cell damage. 

Developers of Nash candidates are therefore looking to show improvements in measures including liver fibrosis – the formation of scar tissue in the liver – as well as hallmarks of Nash such as steatosis, the buildup of fat in the liver, inflammation and liver cell ballooning. Ultimately, Nash drugs should also demonstrate longer-term benefits. 

The upcoming readout concerns an interim analysis of the Regenerate study in around 750 patients at 72 weeks. The trial is set to enroll a total of 2,300 non-cirrhotic Nash patients with advanced liver fibrosis.

If the interim data are positive they will serve as the basis for a filing in Nash. Intercept needs Ocaliva to show an improvement over placebo on either of two surrogate co-primary endpoints: liver fibrosis improvement without worsening of Nash, or Nash resolution without worsening of fibrosis.

Intercept obviously hopes for a positive result on both outcomes, although a win on one should be enough for approval. The final analysis of Regenerate will evaluate mortality and rates of liver-related events such liver transplant or progression to cirrhosis.

Mixed Flint

Of the two surrogate endpoints, fibrosis looks more likely to be hit, at least if history is anything to go by. The phase II Flint trial did not show a significant benefit on Nash resolution. 

However, Flint did show promise on fibrosis, with 35% of Ocaliva patients having at least a one-point improvement in fibrosis score versus 19% in the placebo group. Fibrosis, which is traditionally measured using biopsy, has five stages, with a score of 0 representing no scarring and 4 representing cirrhosis. Regenerate is also designed to show at least a one-point improvement here.

Still, Evercore ISI analysts have described fibrosis as a “messy” endpoint, making predicting the outcome of Regenerate tricky.

And even if the trial hits on one or both endpoints there is still the question of safety. Flint found an increase in pruritus, with 23% of the Ocaliva-treated patients experiencing this versus 6% in the placebo group. Ocaliva was also associated with increases in LDL cholesterol.

This might be why Intercept has included a lower 10mg Ocaliva dosing arm in Regenerate, as well as the 25mg dose tested in Flint. 10mg is the highest dose of Ocaliva approved for primary biliary cholangitis, where it has a black box warning for liver injury.

If similar side effects are seen in phase III this could hinder Ocaliva’s uptake in Nash, particularly in mild or moderate patients. Regenerate has enrolled a broad range of subjects, including those with F1 fibrosis and comorbid risk factors like diabetes and obesity. However, the primary endpoint analyses will only include the more severe F2 and F3 patients, and Intercept has said it will focus commercialisation efforts on the advanced end of the Nash spectrum.

To this end, the company has already begun a phase III trial, Reverse, in patients with cirrhosis.

FXRs are thought to work by regulating bile acid production; however, the fact that Ocaliva also led to modest weight loss in the Flint trial could indicate that it has a broader effect on metabolism, the Evercore analysts noted.

Ocaliva is far from the only FXR agonist in development. Gilead, which has several bets on Nash, also made a big push into this space with the acquisition of Phenex in 2015 for up to $470m. However, it has already discontinued one Phenex-originated asset, Px-102.

And Gilead's Nash efforts with its other FXR, GS-9674, appear to be focused on a combination with its Ask1 inhibitor selonsertib and its ACC inhibitor GS-0976. This might not bode well for Intercept's chances with monotherapy – but even a failure in Regenerate would probably not stop other players vying for a piece of the Nash pie.