Given the already sky-high expectations over the phase II efficacy of the Crohn’s disease project GED-0301 it is understandable that the actual data, revealed today in a scientific abstract, caused barely a ripple in Celgene’s stock.
This should not detract from the fact that GED-0301, now referred to as mongersen, looks at least as powerful as biologicals, with oral delivery to boot. Attention should now turn to the design of a phase III trial, the US FDA’s likely requirement for approvability, and competing industry projects waiting in the wings.
The assumption in the market was that phase II data would be outstanding, otherwise Celgene would not have forked out $710m up front to get its hands on the Nogra Pharma-originated project (Event – Celgene’s chance to prove that Crohn’s bet was worth it, October 14, 2014). Today’s abstract from the United European Gastroenterology Week meeting pretty much confirms the base-case scenario.
In the phase II trial 72.1% of patients responded to 160mg/day, the highest dose of mongersen, an orally delivered antisense DNA oligonucleotide (p<0.0001 versus placebo). Of the responders, 65.1% were in remission after two weeks – the study’s primary endpoint – also hitting statistical significance versus placebo with p<0.0001.
In phase I mongersen resulted in 100% response and 86% remission, but this was a single-centre, uncontrolled trial, so no one can realistically have expected the same in phase II. ISI Group’s Mark Schoenebaum, for instance, hoped for 40-60% remission, so the phase II result of the highest dose was at the top of his expectations.
Celgene has also been helped by an unusually low placebo remission rate of 9.5%, making the placebo-adjusted efficacy look even more stellar. A lack of serious adverse events, and an excellent dose response – remission was 12.2% with 10mg/day (no statistical significance) and 55.0% with 40mg/day – should boost confidence.
A direct comparison with approved biologicals puts mongersen ahead, though the approved agents’ phase III data, and one-month response and remission, are clearly a more exacting standard versus mongersen’s two-week results. For instance, with Remicade 57-81% of patients responded, and 48% of those were in remission at one month.
It will be vital for mongersen remission to be maintained longer term to allow a real comparison with biologicals, and for the project to have a shot at the important Crohn’s maintenance setting. Failing that, of course, it still has the convenience of being dosed orally.
So what about phase III? Historical precedent would suggest enrolment of around 1,000 patients into two studies, measuring efficacy separately across induction and maintenance settings. Unlike mongersen many recently approved Crohn’s disease drugs were already available for other indications, so it will be interesting to see whether the FDA demands anything extra of Celgene.
Another important consideration is that competition in this space will not ease up any time soon, though most novel projects are delivered by injection. Among oral competitors, Toray Industries has TRK-170 in phase II, while Avaxia Biologics reported phase I data on AVX-470 – an intriguing oral anti-TNF polyclonal antibody – earlier this year.
Celgene’s pivotal studies should kick off by the end of this year, and with Nogra in line to receive an additional $815m in regulatory/development milestones, plus over $1bn in sales-based milestones and an escalating royalty, investors will continue to keep a close eye on progress.
One thing is for sure: in a large phase III programme involving multiple US centres mongersen’s efficacy is likely to fall below that seen in phase II. But this need not necessarily be a bad thing.