EASL 2019 – Intercept builds a case for Ocaliva

A look at the abstract on Intercept’s Regenerate trial seems to confirm the earlier topline result, ahead of a full data presentation later today.

Intercept is building up to present full data from the Regenerate trial of Ocaliva in Nash this afternoon, and the abstract unveiled yesterday did not seem to contain any nasty surprises. One new aspect is the company’s resorting to a subgroup analysis that flatters the efficacy data, a fact that highlights the results’ shortcomings.

Safety data look in line with topline results released earlier this year, while a couple of secondary endpoints detailed suggest other signals of efficacy, though only for the high 25mg Ocaliva dose. A key focus at today’s full presentation of the data will be the precise breakdown of liver toxicities.

Investors were not taken in by the spin, with Intercept's shares opening down 10% this morning.

Regenerate was already known to have hit on only one of its co-primary endpoints – improvement in fibrosis – and only at 25mg. The co-primary Nash resolution endpoint was decisively missed. Newly released secondary endpoints include a finding that 35% of intent-to-treat patients receiving the 25mg dose showed improvements in hepatocellular ballooning, and 44% had improvements in lobular inflammation.

Both are disease markers that physicians will be encouraged to see heading in reverse, though some might be concerned that there is still no benefit seen for the distinctly safer lower dose.

On safety the abstract outlines numbers already released in February, though the full presentation of the data in Vienna will be scrutinised closely. All that is known at present about liver toxicity is that this occurred with less than 1% frequency in each group, but that numerically it was highest at 25mg (Intercept’s Nash hopes rest on Ocaliva’s borderline hit, February 19, 2019).

Liver toxicity, along with a rise in LDL cholesterol, and are the big concerns, while a 51% rate of pruritus at the 25mg dose is a talking point as to whether a therapeutic window exists for Ocaliva. Such issues have become especially relevant because Intercept stock has regained the losses it sustained when Regenerate was toplined in February.

Intercept's EASL presentation of Regenerate
  Placebo Ocaliva 10mg Ocaliva 25mg
Stage 2 & 3 fibrosis patients (ITT) n = 311 n = 312 n = 308
Fibrosis improvement + no worsening of Nash 11.9% 17.6% (p=0.0446) 23.1% (p=0.0002)
Nash resolution + no worsening of fibrosis  8.0% 11.2% (p=0.1814) 11.7% (p=0.1268)
Improvement in hepatocellular ballooning* 23.2% 27.2% (p=0.2423) 35.1% (p=0.0011)
Improvement in lobular inflammation* 35.7% 39.1% (p=0.3380) 44.2% (p=0.0322)
 
Pruritus** 19% 28% 51%
Cardiovascular SAEs** 2% 1% 2%
Gallstones** 1% 1% 3%
Hepatic disorder SAEs** <1% <1% <1%
Overall study discontinuations (ITT) 16% 17% 15%

*New data; **safety analysis comprises 1,968 subjects, including added group with stage 1 fibrosis; hepatic disorder SAEs were most common in 25mg group. Source: EASL abstract.

As for the new subgroup analysis, this concerned efficacy in 668 of the 931 intent-to-treat Regenerate subjects. These 668, Intercept said, had completed at least 15 months’ treatment, had a month-18 or end of treatment biopsy, were on Ocaliva for at least 30 days before the biopsy, and did not deviate from protocol.

As is to be expected, this flattered the result – not least because it will have excluded most of the subjects who had dropped out of Regenerate owing to toxicity. However, all the efficacy metrics cited by Intercept for this subgroup related not to the 10mg but to the 25mg dose.

For instance, a two-stage or greater improvement in fibrosis, an important EU regulatory endpoint, was seen in 13.3% of the 25mg cohort in the subgroup, versus 4.5% for placebo. Though the company provided supporting statistics, it stressed that these were nominal – logical since an analysis of this sort is supportive only and by definition incapable of yielding any statistically significant data.

Commercial potential?

EvaluatePharma’s sellside consensus has sales of Ocaliva reaching $2bn by 2024, though the real commercial potential is still very much an open question. As well as toxicity concerns that will prompt regulators to look very hard at the more effective higher dose, there is much debate around the ultimate target population.

Restricting the drug to those with advanced fibrosis or implementing a requirement of biopsy-diagnosed Nash, for example, are big swing factors. Still, the need for pharmacological options in a disease that is growing in prevalence is likely to be frequently cited in Vienna over the next few days.

“These data are very exciting as they demonstrate for the first time in a phase III trial that medical therapy, in this case obeticholic acid, is able to improve liver fibrosis compared to placebo – a key treatment goal in Nash,” Professor Philip Newsome, vice-secretary of EASL, was quoted as saying in a conference press release.

Full data are being presented at 3:15pm today, and all eyes are on the details.

This is an updated version of a story first published yesterday.

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