To Novo Nordisk watchers, the FDA’s late decision to call an advisory committee to review long-acting insulins Tresiba and Ryzodeg was unexpected, casting doubt on how friendly the US regulator would be toward claims of reduced hypoglycaemia, as well as raising concerns over a cardiovascular safety signal.
But if you ask executive vice president Mads Krogsgaard Thomsen, it was entirely predictable given the regulatory changes – two sets of PDUFA amendments and 2008 diabetes drug development guidance – that have taken place since the last time an insulin was approved in 2006: “If you had asked me a year ago when we submitted, I would have said, ‘It’s pretty likely we’ll have an adcom',” Mr Thomsen tells EP Vantage. “The funny thing is it came so late.”
Indeed, the date of the expert panellists’ meeting, at which they supported approval by an 8-4 vote, took place after the original PDUFA action date, and the two drugs now stand in a state of limbo; a decision is thought to be coming in the next few months (Doubts linger after Novo Nordisk insulins scrape through US adcom, November 9, 2012). The debate centred on a statistically insignificant cardiovascular imbalance spotted in 10 million pages of data, a discussion Mr Thomsen says he understands even if it has complicated the approval pathway in the world’s biggest drug market.
“I would expect them to go stone-hard in terms of stress testing the safety profile of this drug,” he says. “If the agency sees something, whether they believe it or not, that they can call a signal … if I were them I would do the same. If they ever get a new Avandia, or even worse a Vioxx or a fen-phen case, they will get hammered.
“So it’s much easier for them to say – which is their prerogative – ‘Well fine, we’ll call an adcom because there’s something we’re unsure about.’ It’s a cover-your-rear-parts type of response, but in the US political system I think that is what is needed.”
With the minority voting against Tresiba and Ryzodeg – which together constitute the Danish group’s biggest growth driver with a consensus forecast of $3.19bn in 2018, according to EvaluatePharma – and some lingering safety questions, it certainly raises the odds of a complete response letter. However, as reason for confidence Mr Thomsen points to research suggesting that adcom votes of two-thirds or more tend to yield first-cycle agency approval.
Label and launch
If approved, the question will then be whether it gets the generous label – most importantly, a statement that Tresiba can reduce episodes of nocturnal hypoglycaemia when compared to Sanofi’s long-acting insulin Lantus – that the European Medicines Agency has recommended. The two agents are awaiting final approval from the European Commission.
“I think we were positively surprised by the European label,” Mr Thomsen says. “On hypoglycaemia we will not get a (US) label as strong as we have in Europe. We will still be able to promote, as we are doing for Levemir, the excellent hypoglycaemia profile and how that is distinctly better than human insulin. Just to get something in there on hypoglycaemia, stating this benefit, is really what we’re going for and have been from day one.
“From now on it’s a good discussion with the agency about what they want and what they will accept.”
Speaking of the discussion between staff and experts regarding the hypoglycaemia benefit, he says, “To my mind they wanted to test it to the extreme before they potentially granted the first insulin label with a distinct hypo benefit.”
That could be essential as it is the second time Novo has taken on Lantus. Sales of Levemir, launched in 2004, have never measured up to those of Sanofi’s long-acting insulin mainstay.
The delay has of course scuttled any hopes of getting Tresiba and Ryzodeg off the launch pad in the US in 2012, something that does not appear to bother the intractably optimistic Mr Thomsen, who says the insulin giant had made some conservative launch plans in anticipation that agency action would not be straightforward.
“Our original plan was actually to launch next spring. It’s still a first half of next year launch we are expecting and hoping for,” he says. “We have the pens. We have the drug. The sales force is on board; they have received training. So they are helping out on the insulin side of things and then will shift onto Tresiba once we have approval.”
From diabetes to obesity
The first half of next year will bring another potentially value-creating event for Novo: readout of pivotal obesity trials of GLP-1 agonist Victoza, currently forecast to be the second-biggest-selling non-insulin drug in the diabetes space in 2018. Many analysts have begun to pencil in sales for obesity; 16% of its $3.87bn forecast sales in 2018 will be in this indication, according to EvaluatePharma.
The Victoza obesity programme has run quietly in the shadow of the breakthrough approvals last year for Vivus’ Qsymia and Arena Pharmaceuticals' Belviq. Losing first-mover advantage should be an event that makes a pharmaceutical executive nervous, but Mr Thomsen says Novo has been cautious given that discussing the trials could be seen as off-label promotion until results are known.
However, should data be positive, he believes Victoza is differentiated because much of the research has focused on very heavy individuals with metabolic dysfunctions sometimes called “pre-diabetes” and may be candidates for bariatric surgery.
“If you ask patients, ‘Do you want (bariatric surgery)?’ only 10% will respond affirmatively” he says. “And then another 10% get convinced during the dialogue with the doctor.
“But three-quarters to four-fifths of such a population never get bariatric surgery because they don’t want to. The portion sizes and the quality of life … it’s not a lot of fun,” he says. “We want this as a medical product for people with a true unmet need with a health economics story we can put together.”
A successful Victoza obesity programme would only be icing on the cake – the cake being approval of the two long-acting insulins. Given that approval is baked in, the launch needs to go flawlessly, which is surely why the labelling decision is so key as Novo tries to avoid another Levemir disappointment. Despite the occasional surprise that has spiced up its near-continuous rise in value the last three years, investors have kept the faith with Novo. The next few months will show whether they will be rewarded for their fidelity.