Arena Pharmaceuticals’ claims of best-in-class efficacy with its ulcerative colitis candidate etrasimod, based on phase II data released yesterday, seem to have been taken at face value by the market. The group’s stock was up as much as 34% today on results that appear to stack up well against those previously seen with Celgene’s rival project, ozanimod.
Of course the usual caveats about cross-trial comparisons apply, but there are several reasons to be cautious about etrasimod. These include lingering cardiac safety concerns about the whole S1P class and doubts about how fast Arena will be able to enrol its phase III trial, particularly if Celgene gets ozanimod to the market first.
There are also questions about whether the high-dose group in the Oasis trial of etrasimod – which was the only arm to show a statistically significant benefit over placebo – was skewed towards patients with less severe disease at baseline. This cohort included patients who were, on average, younger with a shorter duration of disease.
Fundamental differences between the etrasimod and ozanimod trials did not stop Arena making comparisons on a conference call yesterday. The primary endpoints varied, and Oasis evaluated a 12-week treatment period while the phase II Touchstone study of ozanimod looked at outcomes over eight weeks, all of which makes a direct comparison tricky.
|Phase II cross-trial comparison of etrasimod and ozanimod|
|Oasis trial of etrasimod – 12-week data||Placebo||2mg||p value||1mg||p value|
|Reduction in 3-component Mayo Clinic Score*||1.5||2.49||0.009||1.94||0.146|
|% of patients achieving endoscopic improvement||18||42||0.003||23||0.306|
|% of patients achieving clinical remission (using total Mayo Clinic score)||6||25||0.004||15||0.077|
|Touchstone trial of ozanimod – 8-week data||Placebo||1mg||p value|
|% of patients achieving endoscopic improvement||12||34||0.002|
|% of patients achieving clinical remission (using total Mayo Clinic score)*||6||16||<0.05|
|*Primary endpoint; Source: Company presentations.|
Analysts had differing takes on the results: Mizuho said that Oasis put etrasimod “roughly in line” with ozanimod, while Leerink touted the best-in-class promise of Arena’s project.
Maybe phase III data will shed more light on the relative merits of these projects. Arena should start pivotal trials of its project next year but was tight-lipped about its plans apart from hinting, unsurprisingly, that the 2mg dose will be the way forward.
Timing could be everything for Arena. Ozanimod’s phase III Truenorth trial has a primary completion date of September 2018 – which itself has been delayed owing to slow enrolment, something that could bode ill for etrasimod too.
Things could get even tougher for Arena if ozanimod is approved before etrasimod’s pivotal trial is fully recruited. Celgene’s project could get the go-ahead in ulcerative colitis as early as 2020, but this is not a given, particularly after last month’s refuse-to-file letter in ozanimod’s lead indication, multiple sclerosis (Celgene’s ozanimod snafu adds insult to injury, February 28, 2018).
It is unclear at present what the issues with ozanimod are, or whether they could affect other indications. Celgene has claimed that there are no problems with efficacy or safety.
Safety is particularly important for the S1P modulator class because of heart problems with older, less selective molecules like Novartis’s Gilenya, which have led to stringent monitoring requirements.
The theory is that more selective compounds like etrasimod and ozanimod could avoid these issues. While Arena was keen to tout its project’s safety profile in Oasis, there were two cases of asymptomatic atrioventricular block, which could make investors wary given the class's history.
Arena also plans to evaluate etrasimod in Crohn’s disease and has programmes in primary biliary cholangitis and pyoderma gangrenosum. When asked if it might look at other indications, such as multiple sclerosis, chief executive Amit Munshi said that ulcerative colitis and then Crohn’s were the top priorities, and stressed that Arena was a small company.
Still, the group hopes to commercialise etrasimod alone in the major markets, he added. With a rival like Celgene, Arena will need etrasimod’s best-in-class potential to bear out in phase III in order to compete – unless Celgene’s problems with ozanimod are deeper than first thought.
|Project||Study||Trial ID||Data due|
|Phase II trial in pyoderma gangrenosum||NCT03072953||Primary completion Dec 2017|
|Phase II trial in primary biliary cholangitis||NCT03155932||Primary completion Dec 2018|
|Ozanimod||Truenorth||NCT02435992||Primary completion Sep 2018|
This story has been changed to reflect the primary completion date of the Truenorth study of ozanimod.