Less than a month after the European Medicines Agency granted marketing authorizations for Novo Nordisk's long-acting insulins, Tresiba (insulin degludec) and Ryzodeg (insulin degludec and insulin aspart), the US Food and Drug Administration (FDA) on February 8 rejected their new drug applications. The FDA wants Novo, of Bagsvaerd, Denmark, to conduct a new cardiovascular safety study, after a meta-analysis suggested the drugs may increase the risk of heart attack. As a result, Tresiba's US launch—if it ever happens—could be delayed for several years.

“According to our forecasts, Tresiba [had it been approved] would've earned Novo Nordisk at least $5 billion in the US alone during the period from launch in 2013 to the first half of 2017,” says Sebastian Heinzmann, healthcare analyst at Datamonitor in London. “They're not in such a good position after this decision, as the US is by far their biggest market for insulins.”

Tresiba's market entry (timed to take place a year ahead of Ryzodeg) was expected to challenge the primacy of Sanofi's long-acting analog Lantus (insulin glargine) before its US patent expires in 2015. Now delayed by a few years, Tresiba will launch into a different market, potentially facing stiff competition from biosimilars being developed by Paris-based Sanofi, Indianapolis-based Eli Lilly, and Mylan of Canonsburg, Pennsylvania, partnered with Biocon of Bangalore, India.

Even in Europe, where it is already available in the UK, Tresiba is unlikely to dominate. Pricing could also limit its use, analysts think, as Novo plans to price Tresiba at a 60–70% premium over Lantus. “It will be tough for the drug to gain traction as the benefits don't really justify such a premium,” says Tim Race, pharmaceutical analyst at Deutsche Bank in London.

Tresiba is an insulin analog comprising soluble dihexamers of insulin molecules. It comes in two concentrations, may be flexibly dosed and causes less hypoglycemia than Lantus, especially at night. Tresiba, which has a 24-hour half-life, is the only insulin to form a multihexamer chain when injected, resulting in a soluble depot of insulin. After injection, the individual insulin molecules break away one at a time from the ends of the multihexamers, releasing insulin at a flat rate. According to Heinzmann, however, insulin levels in healthy individuals don't show this peakless profile and many physicians doubt it is really beneficial in clinical practice.

“The main claim is around Tresiba's long profile and low risk of hypoglycemia—an advantage that seems to be statistically, yet not really clinically meaningful for most patients,” says Race. “As such, most patients would not switch and thus Tresiba is fighting for new patients and those that have problems with other insulins.”