Early Data Suggest Novo Nordisk's Long-Acting Insulin DegludecOn Par With Sanofi's Lantus

Novo Nordisk has made a good start for its ultra-long acting insulin Degludec , with much-anticipated Phase II data released at the American Diabetes Association annual scientific sessions June 25 showing that Degludec is as good as Sanofi-Aventis's Lantus (insulin glargine). However, to unseat the market leader, the Danish firm will need to show its insulin analog is superior in either maintaining blood glucose control or reducing the incidence of hypoglycemia.

In oral presentations, Novo Nordisk revealed proof-of-concept data showing Degludec performed similarly to Lantus in lowering blood glucose in type 2 diabetics, with no significant differences in adverse events such as hypoglycemia.

In addition, a 180-person study of a formulation of Degludec plus insulin known as DegludecPlus measured the ability of a combination insulin to provide ultra-long-acting coverage as well as a meal-time boost to improve glycemic control in type 2 patients. The analysis showed a majority of patients taking DegludecPlus for 16 weeks met ADA's goal of a blood glucose level of less than 7 percent. No severe hypoglycemic events were reported.

The creation of an extremely long-acting insulin that competes directly with Lantus has been an important goal for Novo Nordisk, which brands itself as a diabetes company aiming to offer a full complement of therapeutic options for patients with diabetes (¹ 'Novo Nordisk: Riding High On Diabetes,' IN VIVO, June 2007). The company already markets the long-acting analog Levemir (insulin detemir), which accounts for approximately 12 percent of its current sales, but that basal insulin has struggled to gain market share because it is shorter-acting, requiring a less patient-friendly, twice-daily dosing schedule.

Calling the Degludec data "significant," Novo Nordisk VP and Chief Global Medical Officer Alan Moses said in an interview, "this is an important part of the continuum. By making minor structural changes, we can create insulins that fill patients' needs."

But the data were also closely watched for their ability to dethrone Lantus, the current market leader in the basal insulin market. Sanofi-Aventis, currently number two behind Novo in worldwide pharmaceutical sales in diabetes, has ambitions to double its diabetes sales between 2008 and 2013. It has taken aggressive steps to become an end-to-end player in this therapeutic area, with a string of alliances with players as diverse as AgaMatrix, CureDM, and, most recently, Metabolex (² (Also see "Sanofi-Aventis Takes Rights to Metabolex's Diabetes Compound" - Pink Sheet, 25 Jun, 2010.)).

The linchpin of Sanofi's diabetes strategy is Lantus, which in 2009 amassed sales of $4.3 billion and accounted for 11 percent of the company's total revenue, according to the market research firm EvaluatePharma. Thus, it's not hyperbole to suggest a superior insulin analog from a competitor such as Novo could significantly derail Sanofi's growth ambitions - especially since the French pharmaceutical company's drug has been dogged recently with renewed concerns about potential cancer risks.

Based on the data released June 25, there's no evidence yet that Degludec is superior to Lantus, although it certainly appears comparable. Moreover, the half life of Novo's molecule is such that it could theoretically be dosed only three times a week instead of the standard once daily, offering a potential dosing advantage over Lantus.

For now, analysts don't see a massive threat to Lantus sales. In a June 13 note to investors based on abstract data released ahead of the ADA meeting, Seamus Fernandez of Leerink Swann called the danger to Lantus "overplayed," writing that "second-generation insulins will be challenged to demonstrate meaningful differentiation."

However, as Sam Fazeli of PiperJaffray emphasized to investors in his coverage, "there is still an issue with current insulin therapies not achieving target Hb1Ac levels, and there is room for improvement in demonstrating reduced incidence of hypoglycemia."

And that means Degludec has the opportunity to eat away at Lantus' market-leading position when it finally reaches the market. If all goes well, Novo could file with regulators by early 2012 with the hope of launching the product in 2013. Any additional prescriptions Novo steals from Sanofi could result in significant revenue gains for the much smaller drug maker, according to Bernstein Research analyst Jack Scannell. By his calculations, each 1 percent shift from Lantus to Novo's long-acting versions would raise Novo's company sales level by roughly 0.5 percent and earnings-per-share by around 1 percent.

Building A Case For Degludec

Pressure to show superiority over an existing medicine doesn't faze Novo executives. They've faced the situation before with their GLP-1 receptor agonist Victoza (liraglutide), which won U.S. approval in January 2010 and has mounted a fast launch despite onerous labeling and competition from Amylin and Lilly's twice-daily Byetta (exenatide)(³ (Also see "Novo Nordisk's GLP-1 Victoza Off To A Good Start" - Pink Sheet, 27 Apr, 2010.)). According to IMS, total prescriptions of Victoza were up 14.8 percent week-over-week for the period ending June 11, giving the brand a 21. 2 percent share of the GLP-1 analog market.

And just as the Danish firm has amassed head-to-head data showing Victoza's superiority to other diabetes drugs, including both Byetta and Merck's popular DPP-IV inhibitor Januvia (sitagliptin), the company will use a similar strategy to position Degludec.

According to Mads Krogsgaard-Thomsen, Novo's executive vice president and chief science officer, the company is already testing both Degludec and DegludecPlus in 10,000 patients in 20 different Phase III trials in the BEGIN and BOOST programs. "This will give us a similar platform to demonstrate superiority, which will be driven by the ability to show Hb1Ac levels as good as Lantus but with lower levels of hypoglycemia," he said an interview.

As analysts eagerly await publication of the pivotal data - an event expected in the first quarter of 2011 - they are dissecting the results provided at ADA, which Novo's Moses called "very encouraging" despite the small number of patients involved.

Most of the focus has centered on the Phase II 0040 study, a 16-week open-label study comparing Degludec administered once daily or three-times weekly to Lantus dosed once daily in type 2 diabetics whose glucose levels are no longer controlled by oral antidiabetics. At ADA, Novo announced Degludec improved glucose control, regardless of the dosing schedule, with HbA1c reductions of 1.3 percent and 1.5 percent for the once-daily and thrice-weekly regimens. These results were comparable to the 1.5 percent reduction achieved with Lantus. Final mean Hb1Ac levels of Degludec dosed once daily or thrice weekly were slightly higher than the 7.2 percent achieved by Lantus at 7.4 percent and 7.3 percent respectively.

Importantly, rates of confirmed hypoglycemia were low and only one severe event was reported. Indeed, when Degludec was dosed once daily, the rate of confirmed hypoglycemia, as measured by events per patient year, was just 0.6. That was lower than the rate observed for either the three-times-per-week Degludec regimen (2.3) or Lantus (1.1). The differences were not statistically significant, however, due to the low numbers of patients in the individual treatment arms.

However, as PiperJaffray's Fazeli noted to investors, it's impossible to determine if Degludec is superior to Lantus without knowing the percentage of patients achieving the 7 percent HbA1c target. "Given the final mean HbA1c for glargine was lower than for Degludec once-daily, the detailed data may show that more patients achieved the seven percent target on glargine. On the other hand, the starting mean A1c level for each group may have been different."

Will Potential Dosing Advantage Drive Adoption?

Novo has been playing up Degludec's ultra-long acting duration and thus the need for fewer injections as a means of increasing patient compliance, a notoriously difficult issue for many type 2 diabetics. "Our market research suggests patients are very enthusiastic about a three-times weekly dosing schedule," said Moses. "Our goal is to provide different insulins that allow more patients to reach their target goals."

It's not immediately apparent if physicians, or payers, will view the potential for less frequent dosing as a truly differentiating attribute that will drive them to substitute Degludec for Lantus, however. In a survey of key opinion leaders, PiperJaffray discovered that a majority of respondents placed greater priority on improved glycemic control with lower incidence of hypoglycemia than on the need for fewer injections.

Thus, without data showing a vastly superior product, it seems unlikely that Degludec's arrival will result in wholesale switching away from Lantus, at least in the near term. According to Bernstein's Scannell, there is a great deal of inertia in the insulin market, given physicians' familiarity with Lantus and the relative ease of initiating therapy with that medicine. "If, in well-powered clinical trials, Degludec simply looks 'as good as' Lantus, this kind of inertia will be hard to overcome without, for example, using price to buy better formulary status," he concluded in a June 21 note to investors.

- Ellen Foster Licking ( ⁴ [email protected] )