Sanofi-Aventis/Zealand Pharma have gained some ammunition as they prepare to enter the competitive GLP-1 agonist market, with data from a head-to-head study showing their lixisenatide to be non-inferior to Lilly/Amylin/Alkermes' Byetta (exenatide).

Sanofi and Zealand released top-line results from the GetGoal-X study on Feb. 2. The trial is part of a large clinical development program, and it wasn't intended as a pivotal trial. It is the third of ten Phase III lixisenatide trials ongoing in 4,000 patients across 38 countries. The drug is on track for a filing in Europe at the end of 2011 and in the U.S. in late 2012.

[Editor's note: This story originally suggested that lixisenatide had a shot at being the next GLP-1 agent approved in the global market, due to setbacks for Lilly/Amylin/Alkermes' Bydureon in the U.S. and the cancellation of the taspoglutide program; however, Bydureon has a European review deadline in the first half of 2011 and could receive FDA approval in advance of the lixisenatide filing.]

The randomized, open-label GetGoal-X study included about 640 patients not able to achieve desired blood sugar targets on metformin. After 24 weeks of treatment, lixisenatide had comparable efficacy for lowering hemoglobin A1C levels to exenatide.

But lixisenatide's side-effect profile was better. In the lixisenatide arm of the study, three-fold fewer people reported symptomatic hypoglycemia (2.5% vs. 7.9%). And the number of hypoglycemia events was dramatically lower in the lixisenatide arm compared to exenatide (8 vs. 48). Weight loss results, which are important for diabetes drugs, were not reported.

A number of analysts noted that commercially speaking, non-inferiority may not be good enough considering that Victoza showed superiority in a head-to-head study against Byetta. In the randomized, open-label LEAD-6 study, liraglutide produced a statistically significant greater drop in hemoglobin A1C levels compared to twice-daily Byetta (1.12% vs. 0.79%) (Also see "Victoza Outperforms Byetta In Head-To-Head Trial" - Pink Sheet, 8 June, 2009.).

"The company stresses that there was a lower incidence of hypoglycemia in the lixisenatide arm than in the Byetta arm, which will likely be the marketing angle that SNY takes," ISI Group analyst Mark Schoenebaum wrote in a Feb. 2 note. But, "It's unclear how compelling this will be in the absence of superiority on A1C control."

Putting The Results In Perspective

In an interview, Zealand CEO David Solomon responded that the GetGoal-X study of lixisenatide and LEAD-6 of liraglutide are not comparable. GetGoal was designed as a non-inferiority study whereas LEAD-6 was set up to show superiority, he pointed out.

"GetGoal met every expectation of study design," he said.

Among other factors, background therapy and inclusion/exclusion criteria also differed.

Furthermore, the exec said, the study is just one of ten trials, and in the end, lixisenatide's profile will be based on a whole package with more data and labeling. Victoza's approval came with many strings attached, including a "black box" warning about thyroid C-cell tumors observed in pre-clinical rodent studies, a Risk Evaluation and Mitigation Strategy, and significant post-marketing studies (Also see "FDA Clears Victoza, But Warnings And More Studies Pose Hurdles" - Pink Sheet, 1 February, 2010.).

"This is not the be-all and end-all of lixisenatide performance," Solomon said. "To take one study in isolation is like saying a child's test score on one day in Grade 6 tells you everything about that child."

Competition in the space will be even trickier given lixisenatide's once-daily dosing. While it is an advantage over Byetta's twice-daily regimen, the market is anticipating longer-acting GLP-1 analogues.

The GLP-1 class is of high interest in the competitive diabetes space, and convenient dosing is an important differentiating factor. Victoza, the second GLP-1 on the market after Byetta and a once-daily option, has been very well-received (Also see "Novo Nordisk's GLP-1 Victoza Off To A Good Start" - Pink Sheet, 27 April, 2010.).

Greener Pastures In Lantus Combo

Jefferies International analyst Peter Welford observed that the partnership with Sanofi should ensure blockbuster commercial success for lixisenatide, largely driven by a combination in development with Sanofi's market-leading basal insulin Lantus (Also see "Sanofi's Lixisenatide/Lantus Combo Could Be A Critical Growth Driver" - Pink Sheet, 30 September, 2010.).

Schoenebaum also noted great promise for the combo, but concluded that in the end, however, once-weekly GLP-1s will win dominant market share, with Bydureon (long-acting exenatide) in the lead, followed by GlaxoSmithKline's Syncria (albiglutide).

After a number of regulatory setbacks, Amylin announced in its Jan. 26 earnings call that FDA has signed off on the design of a new thorough QT study of Bydureon (Also see "Can Bydureon Bounce Back? Amylin's Proposed Cardio Safety Trial Is A Faster Option" - Pink Sheet, 10 January, 2011.). Amylin has said it plans to resubmit the application by the end of this year and the type of design accepted by FDA encouraged analysts that this could happen sooner than expected in the second half of 2011.

During the earnings call, executives also said they were looking forward to getting results in the first half of this year from the head-to-head DURATION-6 superiority study of Bydureon vs. liraglutide.

"We know that when you can demonstrate efficacy compared to maximum doses of competitive therapies ... we get real traction with managed care plans," said Vincent Mihalik, chief commercial officer. "And to us, competitive access is a key strategic advantage in launching any new drug."

There is one fewer once-weekly GLP-1 candidate coming down the track. On Feb. 2, Ipsen announced that Roche had formally given back rights to once-weekly taspoglutide. The Phase III program for the anti-diabetic had been suspended due to nausea and hypersensitivity reactions (Also see "Roche/Ipsen's Suspended Taspoglutide Could Become Another Diabetes Casualty" - Pink Sheet, 10 September, 2010.).

Ipsen said that due to high costs, it does not plan to develop the drug on its own and is considering its partnership opportunities.

Roche, however, has gained an early-stage once-weekly candidate that combines a GLP-1 agonist with a gastric inhibitory peptide agonist through its acquisition of Marcadia Biotech in late 2010 ([A#1410229001]). Roche disclosed details of the deal on Feb. 2 in its year-end financial report: CHF 273 million (about $289 million) in cash. Marcadia also stands to gain another CHF 234 million ($250 million) in milestone payments.

Jefferies is forecasting worldwide sales of $2.5 billion for once-daily GLP-1s by 2018, with "convenient once-weekly forms potentially catapulting the market to over $4.5 billion."

Zealand's Solomon said that Victoza's success and the struggles for the once-weeklies suggest that the once-dailies will become the sine qua non in GLP-1s. It was the higher levels of exposure in the long-acting formulation that caused trouble for Bydureon, due to concerns that the greater exposure could pose safety problems in renal-impaired patients.

There is no plan to develop a once-weekly formulation of lixisenatide.

-Emily Hayes (e.hayes@elsevier.com)

Sanofi/Zealand Release Head-To-Head Data For Lixisenatide Vs. Exenatide

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