Allergan’s Two-Year NASH Data Fail To Show Fibrosis Benefit

A year after acquiring cenicriviroc in its Tobira buyout, Allergan says two-year data from a Phase IIb trial supports continued development, but analysts think the drug’s prospects have dimmed.

Allergan PLC tried to put the most positive spin on it, but top-line two-year data from a Phase IIb study of its lead NASH candidate cenicriviroc has analysts wondering what’s the drug’s benefit will be if any. With Allergan revealing Sept. 22 that after two years of treatment, cenicriviroc (CVC) showed no meaningful difference compared to placebo in reducing fibrosis score in NASH patients, Credit Suisse went as far as removing potential revenue for the drug from its modeling.

The Dublin-domiciled specialty pharma claimed that the two-year data from CENTAUR testing CVC, a dual CCR2/CCR5 inhibitor, “supports continued development” of the drug in a Phase III trial initiated this past April. The AURORA study will enroll 2,000 patients and use a composite primary endpoint of reduction in fibrosis by at least one stage with no worsening of NASH after one year of treatment.

Allergan obtained CVC in a $1.7bn buyout of Tobira Therapeutics Inc. roughly a year ago – that deal brought the firm two NASH candidates and it simultaneously acquired Akarna Therapeutics Inc., giving it a preclinical farnesoid X receptor (FXR) agonist to go with CVC and a Phase III DPP-4 inhibitor from Tobira. (Also see "Allergan’s Tab For Tobira’s NASH Cocktail With Akarna Chaser Tops $1.7bn" - Scrip, 21 Sep, 2016.) Prior to the sale, Tobira had positioned CVC as offering strong efficacy in reducing fibrosis in NASH patients, although the drug had failed to meet the primary endpoint of improvement in non-alcoholic fatty liver disease (NAFLD) score in one-year data from CENTAUR. (Also see "Tobira Says Secondary Endpoint In NASH Will Carry CVC Into Pivotal Study" - Pink Sheet, 25 Jul, 2016.)

The Allergan data coincided with safety concerns about Intercept Pharmaceuticals Inc.’s Phase III NASH candidate Ocaliva (obeticholic acid), currently approved to treat primary biliary cholangitis, that may create upheaval in the race to bring the first NASH therapy to market. Intercept, Allergan and competitors Genfit SA and Gilead Sciences Inc. have NASH candidates in Phase III at present.

Allergan stressed that CVC showed better efficacy than placebo in reducing fibrosis without worsening of NASH in patients who crossed over to the treatment arm from placebo after one year. Twenty percent of these patients demonstrated one stage of fibrosis improvement without NASH worsening compared to 13% who remained on placebo for a second year. In addition, when measuring only fibrosis reduction without evaluation of NASH status, 35% of those who crossed over after year one showed a one-stage improvement or better in fibrosis, compared to 20% of those remaining on placebo, the company said.

Although there was no significant difference in fibrosis reduction between CVC and placebo for patients treated for two years, Allergan pointed out that CVC-treated patients with higher baseline fibrosis scores – in other words, more seriously ill patients – showed better outcomes over two years.

CVC May Offer More Benefit In Sicker Patients

In the top-line data release, Allergan did not provide much data detail and did not say whether the signs of improvement it cited were statistically significant.

“The data that have accumulated convinces us, and also very importantly our external advisory experts, that CVC indeed has antifibrotic activity in NASH patients, Allergan Chief R&D Officer David Nicholson told Scrip. “CENTAUR allowed us twice to show independently a reduction in fibrosis following one year of treatment.”

“The antifibrotic activity is most marked in patients with the most advanced disease and in contrast to the placebo-treated patients, it was durable in the patients receiving CVC,” he added. “In other words, for the majority of patients who received CVC for two years, we looked at the antifibrotic activity at one year and then at two years and in the majority of patients responding at one year, they continued to respond at year two. And this contrasted with the placebo-treated patients.”

Allergan Chief R&D Officer David Nicholson

Source: Allergan PLC

Nicholson said the finding that patients treated with CVC for two years did not show significant improvement in fibrosis compared to placebo may have been confounded by patients lost to follow-up. Because CENTAUR required biopsies at initiation of treatment and after years one and two, an unusual number of patients may have dropped out, he suggested. He also said there had been “high variability” within the placebo arm, including results seen in patients in early stages of NASH.

In a Sept. 22 note, Credit Suisse analyst Vamil Divan said he was removing sales estimates for CVC from his Allergan modeling. The model had only assumed up to $160m in probability-adjusted revenues for the drug previously, he added.

“The two-year CENTAUR data are apparently better in patients with higher baseline fibrosis scores so there may be more of an opportunity for the drug to succeed in that population,” Divan wrote. “It is also possible that using CVC in combination with other therapies could have a more meaningful impact.”

Nicholson said combination therapy is a big part of Allergan’s strategy in NASH, hence its deal-making to bring in three different mechanisms of action for treating the disease. The company also is partnered in a Phase IIb combination study with Novartis AG, pairing CVC with one of the Swiss pharma’s FXR agonists. (Also see "Could High Profile Combo Be Allergan/Novartis Answer To Late-Stage NASH Programs?" - Scrip, 19 Apr, 2017.)

“We’re very interested in using CVC as a baseline therapy and building on top of CVC other mechanisms of action,” the exec said. “So, we’re working together with Novartis, which have an FXR agonist which targets the metabolic disturbances in NASH, to get proof-of-concept of the combination of FXR and CVC.”

Might One-Year Fibrosis Reduction Have Been ‘A Fluke’?

David Risinger of Morgan Stanley said the failure to show a meaningful difference in benefit between CVC and placebo after two years was “the most important point” in the data disclosed by Allergan. “Additional efficacy data disclosed suggest some activity, but there was no mention of statistical significance,” he wrote Sept. 22

The two-year data suggest the one-year benefit in fibrosis reduction seen with CVC in CENTAUR “may have been a fluke.” The one-year data showed that 20% of patients in the treatment arm achieved one stage or greater of fibrosis reduction without worsening of NASH, compared to 10% of placebo-arm patients. Technically, those data were not statistically significant because the study had missed its primary endpoint, he added.

“We view that liver biopsies can be highly variable, even in the same patient at the same time,” the analyst said. “This is because the liver is a big organ, especially relative to biopsy, and fibrosis is not uniform. Lastly, some experts view one year as too short a time period to show improvement in fibrosis.”

Risinger also reminded that upon announcing the Tobira deal Sept. 20, 2016, Nicholson has said to expect a greater separation of benefit between treatment and placebo after two years.

Allergan began enrolling the 2,000 patient Phase III AURORA study in April and hopes to produce data in 2019 based on results of one year’s treatment in the first 1,000 patients. Former Tobira CEO Laurent Fischer, now head of liver therapeutic area for Allergan, said the company plans to discuss the latest data with regulators to determine whether the Phase III design should be changed, perhaps to stress treatment of sicker patients.

Datamonitor Healthcare analyst John Allen said CENTAUR’s disappointing results may have stemmed partly from enrolling too many patients in the early stages of NASH and with stage-one fibrosis. “I speculate that the overall results for the trial would have been stronger had they enrolled more severe patients,” he told Scrip. “Moving forward, I would expect for them to target more severe patients in coming clinical trials.”