Doubts linger after Novo Nordisk insulins scrape through US adcom

In the end, the worst-case scenario for Novo Nordisk – a US advisory panel rejection of Tresiba and Ryzodeg – did not come to pass, and the company’s stock surged 7% yesterday; the $7.1bn market cap increase has made up for the losses three days earlier when briefing documents had detailed the FDA’s concerns over the products’ cardiovascular risk.

Still, the panel’s backing is far from unequivocal, and major uncertainties remain about the novel insulins’ market potential against Sanofi’s Lantus. Even if the US agency follows the panel’s advice, lingering safety doubts could ensure Lantus’s continued dominance. And a requirement for a pre-approval cardiovascular (CV) outcomes trial would delay launch by five years – a situation investors will now be dreading.

A CV outcomes study will be necessary – the panel recommended it unanimously – and it will likely comprise 7,500 patients to ensure necessary powering given the estimated event occurrence. However, given the eight to four vote in favour of approval, there is hope that the trial could be carried out as a post-approval commitment, thus minimising the launch delay.

The big question now is how long the FDA will take to review the panel’s advice and what its actual decision will be. The majority verdict does indicate that the earlier safety signal cannot be ignored, and the ball is now back in the agency's court (Novo shaken by cardiovascular questions on Tresiba and Ryzodeg, October 26, 2012).

Tresiba, the long-acting insulin degludec, and Ryzodeg, a combination of degludec with the fast-acting insulin aspart, had had a regulatory action date of October 29, but the surprise decision to call an advisory panel – the first for an insulin analogue for over a decade – made this irrelevant.

2012 hopes dashed

Certainly, any hope Novo Nordisk might have had of launching the products in the US this year has been dashed. Leerink Swann analysts expect a six to 12-month delay, and a label citing the CV safety risk.

However, they also say the label might cite an improved hypoglycaemia profile – a big bonus – with just a mention of “unproven CV safety”.

Jefferies was more scathing, saying the mixed vote might not be sufficient for first-pass approval, and put the risk of the CV outcomes study being done pre-approval at a significant 40%. “The only cardiologist and statistician on the panel voted ‘no’ for approval,” they cautioned.

Briefing documents released on Tuesday confirmed that the reason for the surprise adcom was that the meta-analysis of 16 open-label studies had revealed a higher, but not statistically significant, risk of major adverse CV events versus comparators. The documents also questioned the reliability of hypoglycaemia data for Tresiba and Ryzodeg.

These considerations are important given the fierce marketing battle that will likely ensue between Novo Nordisk’s products and Lantus, Sanofi’s dominant basal insulin. Even if the FDA allows Novo to conduct the outcomes trial after approval, the lingering safety doubt could limit prescriptions and hit commercial potential.

Good news

But there was some good news for Novo Nordisk on the second question: the panel saw no benefit on overall hypoglycaemia, but agreed that Tresiba and Ryzodeg had a benefit on nocturnal hypoglycaemia – something Sanofi had earlier challenged. Sales reps’ ability to claim such a benefit over Lantus would be a boon for Novo.

The panel was also impressed by the flexibility of Novo's products, which is important given that current insulins struggle when a dose is missed and needs to be replaced. Indeed, Tresiba appears to be a true 24-hour insulin – current once-daily products often fall short of this.

As such the adcom did give the Danish diabetes specialist several reasons to be cheerful, and the panel decision was certainly not the catastrophic blow that Sanofi bulls might have been hoping for.

But the CV safety issue and the timing of an outcomes study will likely dog the shares, and Lantus’s position could be safe for some time to come.

To contact the writer of this story email Jacob Plieth in London at [email protected]

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