Sanofi Aventis SA's announcement that its Lyxumia (lixisenatide)-Lantus (insulin glargine) combination program has been delayed by up to a year has provided a nice boost to Novo Nordisk AS' ambition to push Lantus off its top-spot.

The Danish firm may be a leader in diabetes as a whole (three-quarters of its $12 billion revenues come from diabetes), but the French pharma's $5 billion-a-year Lantus is by quite a way the top-selling insulin. And with Lantus' patent due to expire in 2015, and several biosimilars on the way, Sanofi is aggressively defending - and building upon - the Lantus brand (Also see "Biosimilar Insulin Worth The Effort? For Some, Maybe" - Pink Sheet, 25 July, 2011.).

Combining Lantus with lixisenatide, a GLP-1 agonist licensed from Zealand Pharma AS, is an important component of that defense strategy. The combination used to be ahead of Novo's own in-house program combining its next-generation insulin, the ultra-long-acting Degludec (not yet approved), with its marketed GLP-1 agonist Victoza (liraglutide). However, apparently due to device-related difficulties, Sanofi announced July 28 that it doesn't expect to begin Phase III trials of its insulin/GLP-1 combination until 2013, meaning a launch is unlikely before 2015. It's the second delay for the project.

That puts it well behind Novo, which announced during its second-half results release Aug. 4 that IDegLira, a fixed-ratio Degludec-liraglutide combination, has begun a Phase IIIa trial and could in theory be filed in 2013.

Currently seven out of 10 new insulin patients in the U.S. go onto Lantus, with only three taking Novo's Levemir (insulin detemir) -not a situation that Novo's happy with. "My anticipation is that we'll reverse that picture and thus completely change the dynamics of the U.S. market," CEO Lars Rebien Sørensen declared boldly on the Aug. 4 conference call. He didn't provide a timeframe.

Lantus Beware: Here Comes Degludec

Granted it's Degludec itself, which the company expects to file in the U.S. and the EU "within months" (along with DegludecPlus, a combination with the rapid-acting insulin aspart NovoRapid), rather than IDegLira that's most critical to achieving that aim. But given that Novo itself acknowledges it won't be able to turn the tables that quickly (not least given Sanofi's commercial firepower and its dependence on its diabetes franchise), each new addition to the armamentarium will help.

Novo has already shown that Degludec has twice Lantus' half-life and very flexible dosing that may allow it to be taken, to equally beneficial effect, "at any time of day, on any day," asserted CSO Mads Krogsgaard Thomsen (Also see "Novo Highlights Degludec's Advantage Versus Lantus In Fewer Night-Time Hypoglycemic Events" - Pink Sheet, 30 December, 2010.). Degludec will also likely be launched with Novo's new ultra-easy-to-use device, the FlexTouch pen, which gained European approval in July.

Together, these small advantages should give Novo the firepower it needs to at least give Lantus a run for its money, reckoned Morgan Stanley analyst Peter Verdult. The fact that Degludec has been proven to lead to fewer nocturnal hypoglycemic events than Lantus "won't be a catch straight away," he said, adding that it will take "years" to generate data to show conclusively that Degludec is better than Lantus. But along with the device and the dosing flexibility, Novo "will have a few hooks to grab new patients." Indeed, if the dosing flexibility gets onto the label, that would be a "key differentiator," Verdult said, in a market where convenience counts for a lot.

Verdult is expecting approval for Degludec in the third quarter of 2012 and that Novo will "massively expand" its U.S. sales force, in preparation for strong resistance from Sanofi (whose reps have done well at keeping Levemir off their backs by suggesting it's really a twice-a-day drug).

Sanofi isn't sitting still, of course. Enhanced promotional efforts behind Lantus have helped generate a 14% sales increase in the first half of 2011, to €1.9 billion ($2.7 billion), and the French group also hopes that its sideways move into devices, via its 2010 deal with AgaMatrix Inc., will help it cling to insulin leadership: the partners' first blood glucose monitoring devices were launched in France and Germany in the second quarter.

Similar Combo; Different Purposes

Sanofi's main problem, though, as Thomsen pointed out, is that "it doesn't have a next-in-line insulin" analogous to Degludec. As such, for the French group, the Lantus-lixisenatide combination is arguably even more critical than IDegLira is for Novo - all the more so given that lixisenatide itself, which is still in Phase III, "is at best a me-too," according to Verdult. He thinks the differentiating data, centered on improved post-prandial plasma glucose levels, is uncompelling.

With no next-in-line insulin in the pipeline - and believing, perhaps with some justification, that Lantus is good enough - Sanofi is likely looking to its Lantus-lixisenatide combination to become the upgraded version of Lantus.

And that may be why the French group is widely believed to be going for full flexibility within the combination, allowing dose titration of both the insulin and GLP-1. IDegLira comes in a fixed-dose ratio.

For Thomsen, far from being a disadvantage, this offers added convenience. "Individually titrating [both doses] would be tedious for patients, adding a number of steps to the [administration] process," he suggested. Novo's aim is to offer extreme flexibility and extreme convenience: if patients on Victoza want to optimize doses of that drug and of Degludec, "they can just add Degludec separately," he said. Those looking for convenience can take IDegLira.

As such, "we don't see IDegLira as a successor to Degludec," explained Thomsen, but as offering a convenient treatment for those already on either Victoza or on basal insulin.

Novo apparently had thought about a dual flexible dosing combination; Thomsen noted it's just difficult to do in a user-friendly way. That may be why Sanofi - which has filed patent applications for both fixed combinations of Lantus and lixisenatide and for devices that will allow them to flex the dosages - has gotten delayed (consistent with the thought that the delay is device-related). Besides the inherent challenge, Sanofi doesn't have the best track record with devices anyway, pointed out one analyst.

Novo's main focus now is to get Degludec approved, and to get its pricing and reimbursement secured before Lantus generics arrive and significantly lower the base point for price negotiations. That should be do-able, even though not all analysts share Thomsen's confidence that Lantus generics won't eat into sales of other basal insulins.

Meantime, strong first half sales growth for Victoza and for its modern insulins will have given Novo confidence in its ability to challenge Lantus. Victoza sales were up 263% in local currencies to DKK 2.3 billion ($437 million) accounting for over half of sales growth in diabetes care, with modern insulins (Levemir, NovoRapid and NovoMix (rapid and intermediate-acting insulin)) up 10% in local currencies to DKK 13.7 billion.

Victoza is now taking more than 49% of total GLP-1 scrips and capturing more than 60% of new patients in the U.S., according to Sørensen. Since launch in February 2010, Victoza has grown the class by nearly 55%, he claimed. Likewise, in Europe the GLP-1 market has more than doubled since Victoza's launch and the drug is leading the class in Germany, the U.K. and France. Verdult claimed Victoza was on track to reach $2 billion in peak sales by 2018 in diabetes alone; it has also begun Phase III trials in obesity.

The company said it's confident that 10% average annual growth for its insulin franchise is still viable "assuming no major further health care reforms." The bullishness comes despite lower insulin growth in the first half of 2011 due to the impact of U.S. health care reform, competitive pressure in Europe, Japan and the U.S., and aggressive price-driven competition from Eli Lilly & Co. in the human insulin market. "In 2012 and especially as we get into 2013, when we start to see the impact of Degludec and Degludec plus, [10% annual growth] is do-able," Sørensen told analysts.

-Melanie Senior (m.senior@elsevier.com)

[Editor's note: This story has been corrected. The original version stated that Novo's IDegLira combination allowed the insulin portion to be titrated independently of the GLP-1 component. In fact, the product is offered in a fixed dose ratio.]

Sanofi Delay Boosts Novo's Bid For Insulin Dominance

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