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Ocaliva POISE'd to move beyond PBC with long-term fibrosis finding

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By Marie Powers
News Editor

PARIS – Biopsy data from a subgroup of patients enrolled in Intercept Pharmaceuticals Inc.'s phase III POISE study of Ocaliva (obeticholic acid, or OCA) for the treatment of primary biliary cirrhosis (PBC) confirmed stabilization or regression of fibrosis/cirrhosis in 85 percent of the cohort following three years of treatment. The findings provided the first evidence that improvements in biochemical markers of PBC observed in previous studies are accompanied by antifibrotic effects suggested in preclinical trials of Ocaliva, which gained accelerated approval in 2016 to treat individuals with PBC who had an incomplete response to ursodeoxycholic acid (UDCA).

The data were presented at the 2018 International Liver Congress (ILC), the annual meeting of the European Association for the Study of the Liver (EASL), and featured in Friday's press conference.

The POISE study enrolled more than 200 individuals with a diagnosis of PBC consistent with practice guidelines from the American Association for the Study of Liver Diseases and EASL. Findings showed that Ocaliva, a farnesoid X receptor, or FXR, agonist, used primarily in combination with UDCA, led to significant reductions in serum alkaline phosphatase (ALP) and improvements in other biochemical liver markers, paving the way for the FDA nod. (See BioWorld Today, June 1, 2016.)

The biopsy substudy involved patients who underwent liver biopsies prior to and following three years of Ocaliva treatment. Biopsies were centrally read and assessed using a six-tier staging system, from no fibrosis to cirrhosis. Although 27 participants enrolled in POISE consented to biopsies at baseline, due to drop-outs and other factors, only 13 patients – all treated with UDCA at baseline – had paired biopsies that were adequate for analysis, according to Christopher Bowlus, professor and division chief of gastroenterology and hepatology at the University of California Davis, though he emphasized that demographics of the substudy were reflective of the larger trial population.

At baseline, nine of the patients presented with pre-cirrhotic fibrosis and four with cirrhosis. At the last visit before the final biopsy, serum ALP was reduced and direct bilirubin levels were comparable to baseline (median changes from baseline: -99 U/L and 0 μmol/L, respectively). Following the three years of treatment with Ocaliva, six patients improved and five maintained their histological stage, while two patients had an increase in fibrosis by one stage.

Of the four patients with baseline cirrhosis, three improved to fibrosis without cirrhosis on Ocaliva.

Three years was considered a sufficient period to expect "some degree of fibrosis progression," Bowlus told BioWorld. However, he discounted the prospect that patients who improved might be maintained on a lower dose of the drug.

The biopsy substudy findings were consistent with antifibrotic effects seen in Intercept's placebo-controlled phase II study of Ocaliva in individuals with nonalcoholic steatohepatitis (NASH), Bowlus said, but he was reluctant to suggest a larger read-through to the development effort in NASH, which has moved into phase III.

Intercept is running the event-driven phase IV COBALT study to assess whether the biochemical improvements seen in POISE and the biopsy-based results generally translate to improved clinical outcomes in PBC.

"We view ICPT's robust safety and efficacy data and physician experience obtained to date as a high bar for competitors to overcome in the near-to-medium-term and continue to believe ICPT shares are undervalued based on the PBC and NASH opportunities, even if impact from competition in the PBC space remains worth watching longer-term," RBC Capital Markets analyst Brian Abrahams wrote in an EASL update, singling out the real-world biopsy data for the advanced PBC patients.

"Given differences in histology, it does not necessarily translate directly to fibrotic improvements in NASH," he added, "though we believe it does indirectly support its antifibrotic potential in this indication."

On Friday, Intercept's shares (NASDAQ:ICPT) gained $2.28 to close at $73.07.

No 'under-the-radar' competitor

Last year, Intercept had a hiccup with Ocaliva, issuing a Dear Healthcare Provider letter that stressed the importance of proper dosing in patients with moderate or severe hepatic impairment (Child-Pugh B or C cirrhosis), whose recommended regimen called for 5 mg of Ocaliva once weekly with the possibility of increasing gradually to a maximum of 10 mg twice weekly. Postmarketing reports revealed that some physicians were, instead, giving those patients the starting dose of 5 mg once daily recommended for individuals with no or mild hepatic impairment (noncirrhotic or Child-Pugh A cirrhosis).

The FDA subsequently issued a safety communication that stressed proper dosing, given that six cases reported to the agency involved patients with moderate or severe hepatic impairment who experienced serious liver injury, including three deaths, after taking the daily dose of Ocaliva. The communication also pointed out five patients with no or mild decreases in liver function also experienced liver injury. (Se BioWorld, Oct. 4, 2017.)

The FDA ultimately added a black box to the label to make it clearer that doctors need to prescribe the dose that correlates with a patient's liver function. The company also stepped up efforts to reeducate doctors about the proper dosing.

Last week, Laidlaw & Co. analyst Francois Brisebois called that outcome a "best-case scenario" for Intercept, as the boxed warning targets only 2 percent to 3 percent of the PBC population "and no new monitoring requirements or changes in dosing were recommended," he pointed out. "Additionally, we are encouraged that ICPT remains on track on their NASH effort."

In addition to the biopsy substudy's key take-home that the biochemical response translated to histological changes in patients – advancing the thesis that Ocaliva improves clinical outcomes – the findings underscored the drug's long-term tolerability, Bowlus said.

The Ocaliva data contrasted a report presented at the ILC general session Friday indicating that budesonide, as add-on therapy in individuals with PBC with inadequate response to UDCA, improved markers of disease yet failed to improve patient histology. The placebo-controlled study, which randomized 62 patients with PBC, was terminated early because of slow recruitment and, thus, was not sufficiently powered to detect a histological difference between treatment groups.

Patients were required to have histologically confirmed PBC and inflammatory activity according to the Ishak score, failure to achieve serum ALP <1.5 x the upper limit of normal after at least six months of UDCA therapy and a high risk of disease progression. They were randomized to receive either budesonide 9 mg/day or placebo in addition to UDCA for the duration of the study, with the possibility to taper budesonide down to 6 mg/day upon normalization of aspartate aminotransferase (AST). The primary efficacy endpoint was improvement in liver histology with respect to inflammation (an improvement of at least three points in the Ishak score or no inflammatory activity) and no progression of fibrosis.

After a mean treatment duration of 25.3 months, the primary histological endpoint in an intent-to-treat analysis was not met, investigator Gideon Hirschfield, professor at the University of Birmingham, U.K., reported. Eleven of 26 patients (42.3 percent) in the budesonide group and five of 17 (29.4 percent) in the placebo group showed improvement in liver histology (p=0.225). However, normalization of serum ALP occurred in 14 of 40 patients (35 percent) in the budesonide group and in two of 22 patients (9.1 percent) in the placebo group (p=0.023).

Serious adverse events occurred in 10 and seven patients in the budesonide and placebo groups, respectively. Similar numbers of patients reported adverse events in each treatment group.

The study's recruitment pre-dated the approval of Ocaliva as second-line therapy, Hirschfield observed, adding that "there may be individuals in whom there is a high risk of progression and for whom the addition of budesonide to anticholestatic therapy will produce biochemical improvements in disease activity."

"We were curious if this plenary session would be an under-the-radar development," Abrahams wrote in his EASL update, but "we do not view this as a potential competitive threat to ICPT's Ocaliva vs. other agents studied in PBC (seladelpar [Cymabay Therapeutics Inc], bezafibrate [Roche Holding AG], EDP-305 [Enanta Pharmaceuticals Inc.])."

Budesonide is marketed by Dr Falk Pharma GmbH as Budenofalk.

The ILC was scheduled to conclude Sunday.