The US FDA’s task in deciding the fate of Lilly’s Olumiant was not made any easier after an advisory panel yesterday supported only the lower of two doses over risks of thromboembolic events in rheumatoid arthritis patients.
The mixed vote in favour of a 2mg daily dose complicates agency decision-making because Lilly had sought a label allowing 4mg at initiation, followed by a reduction in patients whose disease becomes controlled. The clear message from the adcom members was that the risk of blood clots needed to be clarified before they could support that higher dose.
In the grab-bag of votes the advisory committee voted 9-6 that the 2mg safety was adequate for approval, and 10-5 that the risk-benefit balance was favourable. The 4mg dose did not fare as well, losing 10-5 on both safety and risk-benefit balance.
Shares in Incyte, which licensed Olumiant to Lilly, opened down 7% this morning.
Lilly still seems confident that it can get both the 2mg and 4mg doses approved in the US. Executives on its earnings call today pointed to Olumiant's safety record in markets outside the US in which the drug is currently approved, adding that the majority of use was with the 4mg dose.
Christi Shaw, president of Lilly Bio-Medicines, hinted that Lilly might seek different patient populations for each dose, saying the 4mg could be used in a “carve-out indication that benefits patients the most”, while 2mg could be available to milder patients.
Ms Shaw shrugged off the question of whether Lilly would choose not to launch Olumiant if both doses were not approved.
Lilly is bidding to make Olumiant the second Jak inhibitor approved in rheumatoid arthritis after Pfizer’s Xeljanz, and had refined its request for approval from its initial application, which the FDA rejected last year.
That first filing had been for a broad label with the 4mg dose, but the resubmission now is in patients who have failed on more than one disease-modifying anti-rheumatic drug, with a dose-tapering – and presumably risk-reducing – option for those who achieve disease control.
Lilly had long argued that the venous thromboembolism (VTE) signal, which scuttled its first application, lacked a mechanistic explanation, and in any case a lack of a dose response, along with no sign that it exceeded background VTE rates, pointed to a chance finding.
The group attempted to clarify the risk further by comparing trial and post-marketing surveillance data from countries where Olumiant is approved – the EU and Japan have both given it a green light – against VTE data from marketed DMARD drugs along with those relating to Xeljanz taken from payer databases.
This analysis suggested that the VTE rate for Olumiant is no higher. But the FDA cautioned that this was not an appropriate comparison because the Olumiant findings were from US and European trials, while data from the other drugs were US only.
What the FDA does now is anybody’s guess.
Its initial rejection was one of the bigger biopharma surprises of 2017, and the Jak safety issue has become mildly contagious to contenders like Abbvie and Gilead Sciences. And the fact that the adcom supported only the low dose, rather than the 4mg to 2mg reduction strategy sought by Lilly, only complicates matters.
Approval of 4mg looks fairly unlikely, but the FDA has shown itself to be increasingly industry-friendly under its current administrator, Scott Gottlieb, so it is not inconceivable that it would choose to ignore its advisers. Certainly the Japanese and EU approvals ought to give some hope to Lilly and Incyte that this is one possible outcome.
On the other hand, the less than unanimous vote in favour even of 2mg means that a second complete response letter could be within the realms of possibility. The obvious bet would be on the go-ahead for the 2mg dose, of course, although even this approval would not necessarily be positive for Olumiant’s perception or launch trajectory.
Although Lilly does not need the 4mg dose to sustain its growth this would be a nice boost to sentiment. But spare a thought for Incyte, which after its setback in oncology earlier this month clearly could have done with some better news.