Physician Views: Is it time to reassess two of the front-running pipeline candidates for NASH?

Versus the exuberance for Intercept Pharmaceuticals' obeticholic acid when Phase II data were first unveiled in January 2014, expectations for the experimental NASH therapy have fallen, as has the company's share price, from a dizzying high of $450 a share to current levels of just below $100.

To some extent, this reflects a broader moderation of expectations for first-generation NASH therapies in general. First-in-class will not necessarily – indeed, is unlikely – to mean best-in-class, argue key opinion leaders. However, for two of the most advanced NASH therapies in development, including obeticholic acid, recent events suggest that commercial expectations may decline further.

Intercept's drug is already approved in the US and EU markets for the rarer condition of primary biliary cholangitis (PBC) – branded as Ocaliva – but has come under scrutiny from the FDA in recent weeks due to its safety profile. To the extent the company released a statement on Monday detailing actions it plans to take to enhance education about the appropriate use of the drug for PBC. The concern is what implications this could have on potential future use in NASH.

Intercept is not the only company to be suffering. Allergan acquired Tobira Therapeutics last year to help spearhead its move into the future NASH market, but released mixed data for lead asset cenicriviroc earlier this week from a Phase IIb trial. While cenicriviroc has, for a second time, demonstrated an improvement in fibrosis without a worsening of NASH versus placebo over a 12-month period, a longer follow-up analysis showed no benefit against this endpoint over 24 months – ViewPoints: Two steps forward, one step back for Allergan's NASH hopeful?

With both products already in Phase III studies, we are snap-polling US and EU5-based gastroenterologists to gauge reaction to these recent disclosures. Specifically, we are asking them…

The experimental NASH treatment cenicriviroc has twice (and independently) demonstrated superior improvement in liver fibrosis, of at least one stage, without worsening of NASH versus placebo over 12 months. In the Phase IIb CENTAUR trial, 20 percent of patients initially treated with cenicriviroc for 12 months achieved this endpoint versus 10 percent who received placebo.

In a follow-up analysis, 20 percent of patients who initially received placebo for 12 months and who subsequently received cenicriviroc for 12 months achieved at least one stage improvement in fibrosis without worsening of NASH versus 13 percent of patients who stayed on placebo for 24 months. However, in patients who remained on treatment with cenicriviroc for two years, there was no significant difference versus placebo in the composite endpoint.

In totality, how compelling are these data?

Very uncompelling

Moderately uncompelling

Slightly uncompelling

Neither compelling or uncompelling

Slightly compelling

Moderately compelling

Very compelling

Cenicriviroc is now being studied in the Phase III AURORA trial, the primary endpoint of which is comparison to placebo at improving liver fibrosis, of at least one stage, without worsening of NASH versus placebo over 12 months. Is this a compelling clinical endpoint?

Very uncompelling

Moderately uncompelling

Slightly uncompelling

Neither compelling or uncompelling

Slightly compelling

Moderately compelling

Very compelling

If cenicriviroc achieved this endpoint in the Phase III study – with a similar magnitude of benefit to that demonstrated in the Phase IIb trial – what level of utilisation would you anticipate for the drug as a monotherapy for NASH?

None

Minimal

Moderate

Significant

Very significant

Moving onto a different drug, last week the FDA indicated that since Ocaliva (obeticholic acid) was approved for the treatment of primary biliary cholangitis (PBC) in May 2016, it has identified 19 cases of death and 11 cases of serious liver injury associated with use of the drug. The agency noted that Ocaliva "is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose."

Given that larger doses of Ocaliva are being developed for the treatment of NASH, and taking into account your own assessment of the safety profile in PBC if you have prescribed the drug in this setting, do you anticipate these toxicity concerns impacting potential future utilisation for the treatment of NASH? 

No

Yes – marginally

Yes – moderately

Yes – significantly

Yes – very significantly

If Ocaliva was to meet either component of its primary endpoint in the Phase III REGENERATE trial – proportion of patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH at 18 months or proportion of patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis at 18 months – what would be your expectation for utilisation?

None

Minimal

Moderate

Significant

Very significant

Minimal – but only if hits on fibrosis improvement

Moderate – but only if hits on fibrosis improvement

Significant – but only if hits on fibrosis improvement

Very significant – but only if hits on fibrosis improvement

Minimal – but only if hits on NASH resolution

Moderate – but only if hits on NASH resolution

Significant – but only if hits on NASH resolution

Very significant – but only if hits on NASH resolution

Results and related analysis will shortly be published for FirstWord Pharma PLUS subscribers to read, with the opportunity for non-FirstWord Pharma PLUS subscribers to purchase these findings. To be notified when poll results and analysis become available, please click here.

As always, FirstWord would very much like to receive your feedback and suggestions. Note: FirstWord Polls are powered by Medefield MedePolls, a fast-turnaround service to conduct instant polls of up to five questions with guaranteed samples that include physicians from dozens of specialties and over 100 markets. To conduct this poll with a different audience, or an entirely different poll, contact us at info@firstwordpharma.com.

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